Herpes Simplex Virus Ebooks Catalog

Herpes Eliminator

Herpes Eliminator is an all-natural, organic method to eliminate herpes that is based on thousands of years of Eastern medicine. It is a powerful self treatment process which borrows it's formulation from scientific facts and ancient remedies. Herpes Eliminator works quickly to reduce and eliminate unsightly genital sores caused by the Herpes Type 2 virus . along with other types of herpes . and even eliminates the virus from your body forever and it works for both men & women! Here is a Small Sample of What You'll Learn When You Download Your Copy of Herpes Eliminator Today: Discover Evertyhing you need to know about Herpes, Exactly what causes outbreaks and blisters, if you understand this, you will understand how it's possible to stop outbreaks. The proven step-by-step multi-dimensional Herpes Eliminator system that has helped thousands of men and women to put an end to their outbreaks and eliminate both types of herpes completely within 30-60 days. Why lacking in only one important element leaves you at the mercy of herpes outbreaks. The types of foods you should never eat. The shocking truth about conventional herpes treatments and medication trap, and why this specific herpes remedy has been covered up. Exactly how this science-based, proven method allows your body to kill the herpes virus. How to quickly eliminate herpes rash and blisters using another amazing and cheap substance

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Discovery and Classification of Human Herpesvirus6 HHV6

AHHV-6 Foundation, 285 San Ysidro Road, Santa Barbara, CA 93108, USA bDepartment of Microbiology & Immunology, Georgetown University School of Medicine, Washington, DC, USA The discovery of herpesvirus-6 (HHV-6) dates back to early 1985 when Zaki Sal-ahuddin, in Dr. Robert Gallo's Laboratory of Tumor Cell Biology, was establishing long-term cultures from peripheral blood and splenic tissue of AIDS patients. He frequently found large syncytia that were distinct from HIV-1-induced syncytia. What he really saw in the peripheral blood mononuclear cells (PBMCs) of at least 6-8 patients with B-cell lymphoma were large, refractile cells (Fig. 1), always either single or, occasionally, two or more together. These cells began to disappear after a few days in culture, even in the presence of IL-2. The individuals with these cells were all AIDS patients with or without lymphoma. When these cells were stained with Giemsa, they were often multinucleated, or two large nuclei basically covered...

HHV6 Genome Similar and Different

Roseoloviruses, human herpesviruses 6 and 7 (HHV-6, HHV-7) are widespread T lymphotropic and neurotropic viruses causing mostly benign infections. However, particularly for HHV-6, during some primary as well as secondary reactivated infections, which can follow immune aberrations or deficiencies, there can be severe complications which can lead to fatalities. Thus, this is of relevance for immuno-suppressed HIV AIDS or transplantation patients, as well as increasingly, for those with neurological disease, including encephalitis and a link with multiple sclerosis (primarily HHV-6A). Understanding when and how this virus does or does not cause disease is key to developing effective treatments plus evaluating the impact of HHV-6 infections on worldwide populations. Studies on the virus genome provide a foundation for this exploration and can guide the way towards development of new anti-virals as well as possible novel treatments for immune-related pathologies using this well-adapted...

Characterization of HHV6specific antibodies

The determination of antibody isotype is an important issue in the general strategies of viral diagnosis. In most acute viral infections, IgM is the predominant antibody produced at the early phase of primary immune response, and its detection in a single serum specimen is sufficient to suggest that the infection is recent. However, in the case of herpesviruses, IgM may also be detected during viral reactivation from latency. The heterotypic reactivation of IgM, for instance during human cytomegalovirus (HCMV) and EBV infections is also possible and may obscure the interpretation of results. The presence of rheumatoid factor may induce false-positive results. The use of conjugated anti-human IgM antibody in IFA as well as ELISA does permit to detect HHV-6-specific IgM (Sutherland et al., 1991 Salonen et al., 2002) but the limitations mentioned above should be kept in mind. A first reaction step designed for the capture of IgM is known to improve assay specificity, and has been...

Epstein Barr Herpes Simplex and Herpes Zoster Infections

& Complications and Prognosis 128 & Summary 129 & Herpes Simplex Virus Type 1 129 & Introduction 129 & Definition 130 & Epidemiology 130 & Pathogenesis 130 & Clinical Manifestations 131 & Diagnosis 137 & Treatment 137 & Complications and Prognosis 139 & Herpes Zoster Virus 139 & Introduction 139 & Epidemiology 140 & Pathogenesis 140 & Clinical Manifestations 140

General cellular pathology of HHV6 infection

In vitro studies show the immediate effects of HHV-6 binding to cells, infection of susceptible cells and intracellular replication (see also Chapter 2 Ultrastructure of HHV-6). Susceptible cells (e.g. HSB2, cord blood cells) show upon exposure to HHV-6 blastic transformation with or without giant cell formation, intranuclear inclusions, eventual mitoses and production of viral particles with cellular degeneration and apoptosis (Fig. 1 Biberfeld et al., 1987 Kramarsky and Sander, 1992 Kirn et al., 1997). Blastic transformation with giant cells can occur in cells upon virus contacts even without subsequent internalization and replication of viral particles (Boehmer, 1987). Typical Reed-Sternberg-type giant cells were induced by HHV-6 in established Hodgkin cell cultures without spontaneous giant cells (L428, L540, L591, HDLM2, KMH2) and without subsequent viral replication in these cells (Fig. 1 Krueger et al., 1991, 1992, 1995). Internalization of virus particles and their replication...

HHV6 a helper virus for other herpesviruses in DRESS

HHV-6 reactivation may be associated in DRESS with other viral infections. Other herpesviruses such as Epstein-Barr virus, HHV-7, or CMV have been reported in association with HHV-6 reactivation (Suzuki et al., 1998 Aihara et al., 2001 Descamps et al., 2003c Mahe et al., 2004 Sekiguchi et al., 2005). We reported a case of severe allopurinol-induced DRESS with pancreatitis associated with EBV infection (Descamps et al., 2003c). An active EBV infection was demonstrated by the detection of EBV DNA in PBMC and a seroconversion in two consecutive sera. In two recent reports this HHV-6 and EBV coinfection was fatal (Mahe et al., 2004 Sekiguchi et al., 2005). Sequential reactivation of HHV could explain the observed flare-ups of this disease (Kano and Shiohara, 2004). Independently of the DRESS, this association of viral coinfection has been observed in transplant recipients (Desjardin et al., 2001). Moreover, sequential reactivation of herpesviruses has been demonstrated after bone marrow...

Herpes Simplex Virus Thymidine Kinase Gene Ganciclovir

One approach to the development of more effective therapies for prostate cancer is to initiate a cascade of molecular cellular events locally within the primary tumor that generate a localized and systemic antitumor immune response through the transfer of specific immunomodulatory genes. It has been considered that it might be possible to use specific genes to generate localized antitumor cytotoxicity as well as to initiate a systemic antitumor immune response. This strategy has evolved from purely cytotoxic-based gene therapies to more immunomodulatory gene therapies and various combinations to ultimately achieve the objective. Our initial gene therapy trials used the selected herpes simplex virus thymidine kinase (HSV-t ) gene delivered with a replication deficient adenoviral vector. HSV-t + ganciclovir (GCV) gene therapy has been shown to elicit widespread cytotoxic activities through direct and well-defined bystander activities and to elicit nonspecific and specific antitumor...

Herpes Simplex Virus Thymidine Kinase

One specific molecular chemotherapy approach involves tumor cell transduction with the herpes simplex virus-thymidine kinase (HSV-tk) gene via a viral vector, followed by the systemic administration of the chemotherapy agent ganciclovir (GCV) (1). GCV is a prodrug that must be phosphorylated initially by the HSV-tk gene product to a monophosphate form and, subsequently, by the mammalian kinases to the cytotoxic triphosphate form. Once activated by this process, GCV functions as a purine analog that inhibits DNA polymerase thereby preventing DNA synthesis and inducing cell death (2,3). In addition, HSV-tk gene therapy mediates a bystander effect, whereby nontransduced neighboring cells are also killed. This bystander effect appears to result from the transfer of active GCV metabolites through intercellular gap junctions between the transduced cells and the neighboring cells (4,5). Gene therapy with HSV- tk coadministered with GCV has been shown to be effective in various tumor models...

Pityriasis rosea and HHV6

Pityriasis rosea is a common, acute, self-limiting papulosquamous skin disorder. The initial skin lesion is called the herald patch,'' and typically appears on the trunk as a 2-3 cm oval scaly plaque with a central salmon-colored area and a darker erythematous peripheral zone. The disease normally resolves spontaneously within 4-8 weeks. The clinical and epidemiological features of this disease suggest a pathogenic role for an infectious agent. Drago et al. (1997) first suggested that reactivation of human herpesvirus 7 (HHV-7), which is the virus most similar to HHV-6, was linked to pityriasis rosea. An association between HHV-7 and the disease has been debated since then, and some investigators have suggested that HHV-6 is also linked to pityriasis rosea (Kosuge et al., 2000 Watanabe et al., 2002 Broccolo et al., 2005). HHV-6 latently infects peripheral blood mononuclear cells, and highly sensitive detection techniques such as nested PCR could falsely identify active HHV-6 infection...

Cytomegalovirus Infection

Cytomegalovirus (CMV) infection caused by platelet transfusions has been a substantial cause of morbidity and mortality in immunocompromised patients with cancer. Patients who receive allogeneic bone marrow progenitor cell transplantation are at risk for contracting the virus present in blood products because of cytotoxic preparative regimens, immunosupressive (cyclosporin and corticosteroid) therapy or graft-vs-host disease (GvHD) (14). Up to 60 of this patient population will become infected with CMV, and 50 will have CMV disease if no pre-emptive therapy is given. The risk of CMV infection ranges between 28 and 57 for patients receiving a bone marrow transplant and who are seronegative and receive standard blood products (15). Even with CMV-negative blood products, CMV seroconversion has been reported in 1-4 of CMV-negative donor-recipient transplant patients (16). A recent analysis of our own program identified CMV viremia in only 2.5 (1 of 39) of CMV-negative donor-recipient...

HHV6 infection can induce atypical lymphoproliferations

Atypical lymphoproliferations (APLs) constitute a heterogenous group of lesions that clinically mimic malignant lymphomas, but are lacking the criteria of mon-oclonality and malignant transformation. The incidence of APL seems to be increased in patients with immune disorders, and persistently active infection by lymphotropic viruses is frequently found in APLs. They can be defined as prema-lignant lymphoproliferations and may finally transform to malignant lymphomas. Type B reticulum cell sarcoma'' or the Moloney and Gross virus-induced lymphoblastic lymphomas in mice represent similar polyclonal cell proliferations preceding virus-induced lymphomas. In humans, the majority of reported cases are associated with herpesvirus infections, namely EBV and or HHV-6. HHV-6 prevalence in lymph nodes from HD patients HHV-6 prevalence in lymph nodes from HD patients

HHV6 is found essentially in scleronodular HD in young adults

EBV, another herpesvirus frequently associated with HD, is not distributed equally among the different subtypes of EBV-positive HD 70 of mixed cellularity, > 95 of lymphocyte depleted, 10-40 of nodular sclerosis, and almost absent from lymphocyte-predominant HD subtypes. In addition, HD cases associated with EBV occurred most frequently in children or in elderly people. Previous epidemiological studies suggested multiple etiologies for HD and led to the hypothesis of an infectious viral non-EBV etiology for cases occurring in young adults. It was therefore interesting to look for the presence of HHV-6 sequences according to HD subtype. Torelli et al. (1992) described three HHV-6-positive HD, belonging to the nodular-sclerosis-lymphocyte-depletion subgroup, which occurred in young women (27-, 28- and 31-years old). Similarly, different authors obtained the highest prevalence and highest mean copy for the scleronodular subtype of HD (Table 1). In a large study conducted on 86 adult HD...

Local Delivery Of Herpes Simplex Virus Into Gliomas

Herpes simplex virus type I (HSV-1) is an enveloped, double-stranded, linear DNA virus with a genome of 152 kb which encodes more than 80 genes. About one half of the genes are essential for viral replication whereas the other (nonessential) genes encode proteins which support the viral life cycle within the host cell. The major advantages and disadvantages of HSV-1 for tumor oncolysis are illustrated in Table 1.

Ultrastructure and Assembly of Human Herpesvirus6 HHV6

Ultrastructure Herpesvirus

Human herpesvirus-6 (HHV-6) is a ubiquitous member of the betaherpesvirus subfamily of the Herpesviridae family. The HHV-6 genome is arranged colinearly and codes for approximately 67 of proteins in common with human cytomegalovirus (HCMV), and 21 with all other herpesviruses. Sequence comparison shows that it is closely related to HHV-7 and HCMV. HHV-6 is a lymphotropic herpesvirus infecting up to 90 of the population and establishing latent or persistent infections for a lifetime (Salahuddin et al., 1986 Josephs et al., 1988 Levine et al., 1992 Krueger et al., 1998a). Clinical features of HHV-6 infection are described in Part II of this book. There are two variants of HHV-6, HHV-6A and HHV-6B with obvious gen-omic polymorphism within a variant (Ablashi et al., 1991, 1993 Schirmer et al., 1991). Both also vary in their tissue distribution in human and in their tissue culture cells for propagation (Lusso et al., 1988 Black et al., 1989 Ablashi et al., 1991 Di Luca et al., 1994). Some...

HHV6 association with CFS

One of the first reports of isolated post-infectious fatigue associated with encephalitis, lymph proliferation, and the presence of HHV-6 infection, was made by Buchwald et al. (1990). Daugherty et al. (1991) also reported a group of patients with profound fatigue lymphadenopathy and cognitive dysfunction associated with evidence of HHV-6 reactivation, although variant analysis was not available at that time. Early studies of CFS patients demonstrated an increase in serum IgG and IgM for HHV-6 in a large number of patients compared with control subjects. However, increases in antibodies to other viruses, particularly other herpesviruses, were also detected. Serological measurements of IgG and IgM titers have limited ability to suggest active infection, because most adults have been infected with HHV-6. These immunoglobulins might only indicate exposure, but not active or persistent infection. Studies using molecular analysis (in subsequent years) generally showed higher prevalence of...

HHV6 therapy in CFS patients

CFS patients with active infection by HHV-6 (variants A or B) can be treated with antivirals or immune modulatory agents in order to relieve the symptoms of fatigue and minimize CNS complaints. Acyclovir has remained the gold standard of treatment for herpes viral infections in general. However, pilot studies using acyclovir and ganciclovir showed persistence of HHV-6 variant A in spinal fluid even after treatment (Peterson, unpublished studies). HHV-6 does not encode thymidine kinase, and thus is not highly sensitive to acyclovir and its analogs (Gomples et al., 1995). Non-guanosine derivatives, however, have been shown in vitro to be of greater efficacy against HHV-6 specifically. De Clercq et al. (2001) demonstrated increased efficacy of the non-guanosine compounds S2242, cidofovir, and foscarnet, both in T lymphoblast cells, and in fresh blood lymphocytes, though it should be noted that only foscarnet and cidofovir are commercially available. Cidofovir, the first nucleotide analog...

Human Herpesvirus6 Infection in Solid Organ and Stem Cell Transplant Recipients

Seroepidemiologic studies have shown that infection due to human herpesvirus-6 (HHV-6) is usually acquired during the first year of life the virus subsequently persists in the host. Seroprevalence in healthy adults exceeds 90 . Serology is unable to differentiate between the two subtypes and therefore it is possible that seropositive patients might get a new infection with the second subtype presumably most commonly subtype A. Most transplant patients will therefore be seropositive prior to transplantation. Previous HHV-6 infection has been documented in 87-91 of solid organ transplant (SOT) recipients by serologic assays (Dockrell et al., 1997 Ihira et al., 2001) and by the detection of HHV-6 DNA sequences in the peripheral blood mononuclear cells in 32 of the patients (Chapenko et al., 2001). Similar percentages have been noted in stem cell transplant (SCT) recipients. Yoshikawa documented pretransplant seropositivity in 100 of SCT recipients (Yoshikawa et al., 2002) while...

Herpes Simplex Virus Type 1 Thymidine Kinase HSVtk Ganciclovir

The herpes simplex virus type 1 thymidine kinase enzyme (HSVtk) approach is the most widely studied suicide gene strategy. The HSVtk system was developed in 1986 6 , and was the first approach used in patients with malignant brain tumors in 1992 7 . This approach has been conducted in combination with guanosine-based prodrugs, such as ganciclovir (GCV) and acyclovir, which were originally developed as antiviral agents 8 . These prodrugs are nontoxic nucleoside analogs, which are converted by HSVtk into phosphorylated compounds. Consequently these compounds directly inhibit DNA polymerase and render the formed DNA molecule unstable, leading to DNA synthesis arrest and cell death. The most commonly used prodrug, GCV is an acyclic analog of the natural nucleoside 2'-deoxyguanosine 9 . GCV is a specific substrate of the HSVtk, which is many orders of magnitudes more efficient than human nucleoside kinase at monophosphorylating GCV (see Fig. 23.1) 10 . 15 . This cytotoxic effect of...

Herpes Simplex Virus Type

One study using a combination of acyclovir and cloves administered orally found this to be superior to acyclovir alone in the treatment of herpes simplex virus type 1 infection (Kurokawa et al 1995). The combination significantly reduced the development of skin lesion and or prolonged survival times of infected mice and reduced viral loads.

Epidemiology of Herpes Zoster What has Changed

Segmente Zoster

Herpes zoster (shingles) is an inflammatory neurodermatologic disease, usually localized on a skin segment of the body which is innervated by a sensory nerve. More than 100 years ago, an association between Varicella and herpes zoster has been suggested (see preface of the book). Shingles is a secondary disease to passed Varicella virus (VZV) infection, which latently persists lifelong in the spinal ganglia of the host. The presumably proviral latency is switched to productive infection by several trigger factors resulting in shingles ('girdle rose'). The most important trigger factor is a waning cell-mediated immunity to VZV along a big time interval after primary infection during childhood. Thus, the majority of patients are elderly or those who suffer from immunocompromising diseases. Nevertheless, many case reports remind that herpes zoster occurs also in immunocompetent adolescents and even in children. Numerous clinical observations have elucidated the epidemiology of herpes...

DRESS and HHV6 the first reports

Interestingly, all of the clinical and biological manifestations described in the DRESS are observed in some viral infection and especially HHV-6 infection. In 1993, Akashi et al. reported a severe infectious mononucleosis-like syndrome and primary HHV-6 infection in an adult (Akashi et al., 1993). A 43-year-old man was admitted with high fever, generalized exanthe-matic eruption followed by an exfoliative dermatitis, lymphadenopathy, atypical lymphocytes, hepatitis, and renal dysfunction. Lymphocyte population was mainly T-cell lymphocytes (52.6 CD8). CD19 and CD20 lymphocytes' levels were very low, 0.8 and 0.6 , respectively. The skin biopsy analysis demonstrated a diffuse infiltration with atypical lymphocytes in the dermis. HHV-6 infection was demonstrated by serial changes in titers of antibody against HHV-6 associated with an HHV-6 viremia. HHV-6 DNA was demonstrated in serum samples collected on days 10 and 13. We had the opportunity to report the...

Nonprimary HHV6 infection and the respiratory tract

As more than 95 of HHV-6 infections occur during the first two years of life, most HHV-6 infections observed at later ages (especially in teens and adults) are probably reactivations of latent infections or de novo infections with a second virus (Krueger et al., 1998b Ablashi and Krueger, 2003). Non-primary HHV-6 infections of the respiratory tract occur preferentially in immunodeficient patients, yet may occasionally also be seen in not obviously compromised persons. Any conclusion about HHV-6 being the etiological agent for a pulmonary inflammation is complicated by the fact that there is a high incidence of HHV-6 DNA in lung tissues from not obviously sick persons (Cone et al., 1996) suggesting this organ as one site of viral persistence after primary infection. The diagnosis of HHV-6 caused pneumonitis must consequently be based upon the triad, (a) evidence of an ongoing active infection (serology and or virus isolation), (b) demonstration of replicating virus at the site of the...

Herpes Infection

Based on the herb's antiviral activity against HSV-1 in vitro, it is also used in the treatment of herpes infections. Genital herpes A prospective, double-blind, placebo-controlled crossover trial conducted over 1 year investigated the effects of an extract of the plant and root of E. purpurea (Echinaforce 800 mg twice daily) on the incidence and severity of genital herpes outbreaks in 50 patients (Vonau et al 2001 ). The study found no statistically significant benefit compared with placebo after 6 months of therapy.

Hhv6

HHV-6, a recently discovered DNA virus, causes exanthem subitum (roseola) in children. Two variants of HHV-6, A and B have been described. HHV-6B causes most human infections whereas no specific human disorder has been linked to HHV-6A. HHV-6 typically causes rash and fever in children but, in addition, this virus commonly enters the CNS during acute primary infections, occasionally resulting in meningitis or other neurological complications (4,113-115). HHV-6 has also been reported to cause encephalitis in immunosuppressed adults and has been linked in a few instances to encephalopathic and myelopathic disorders as well as to human demyelinating disease (116-122). Almost all children are infected early in life by this ubiquitous virus, with HHV-6 seropositivity being seen in 90 of all children by two years of age (113-115). Like other herpes family viruses, HHV-6 persists lifelong in brain and other tissues in most normal individuals, and as with other herpes viruses HHV-6 may be...

Herpes simplex

Infections with herpes simplex viruses are a frequent and inconvenient problem for HIV-infected patients (Chang 1995). Two viruses should be distinguished. HSV-1 is transmitted by direct contact with mucosal membranes, as well as by kissing, and causes the typical, itchy perioral herpes blisters on the lips, tongue, gums or buccal mucosa. HSV-2 is sexually transmitted and leads to herpetiform lesions on the penis, vagina, vulva and anus. Herpes lesions have a tendency to spread with decreasing immune status. Chronic disease is frequent, particularly with severe immunodeficiency (below 100 CD4 T cells l). In severe cases, other organs may be affected. These include mainly the esophagus (ulcers), CNS (encephalitis), eyes (keratitis, keratoconjunctivitis, uveitis) and respiratory tract (pneumonitis, bronchitis). In such cases and with persistence of lesions for a period of more than four weeks, herpes simplex infection is an AIDS-defining illness.

Herpes zoster

Herpes zoster is the reactivation of an earlier infection with varicella virus, which subsequently resides lifelong in the spinal ganglia. Herpes zoster episodes occur even in HIV patients with relatively good immune status, and are also seen during immune reconstitution (Martinez 1998). With more advanced immunodeficiency, herpes zoster tends to become generalized. In addition to involvement of one or more dermatomes, dangerous involvement of the eye (affecting the ophthalmic branch of the trigeminal nerve, herpes zoster ophthalmicus, with corneal involvement) and ear (herpes zoster oticus) may occur. Most feared is involvement of the retina with necrotizing retinitis. The neurological complications include meningoencephalitis, myelitis and also involvement of other cranial nerves (Brown 2001).

HHV6 and PML

After several reports had suggested an association of HHV-6 with MS, Mock et al. (1999) examined the possible association of HHV-6 with the demyelinative lesions of PML. In this study, a highly sensitive, two-step in situ PCR (ISPCR) procedure was used to amplify HHV-6 DNA from formalin-fixed paraffin-embedded archival brain tissues from normal, AIDS, and other neurological disease controls. A significantly higher frequency of infected cells was found in PML white matter compared to control tissues. Of interest, the HHV-6 genome was detected primarily within oligodendrocytes (Mock et al., 1999). Immunocytochemistry for HHV-6 antigens revealed active HHV-6 infection of the abnormal oligodendro-cytes within demyelinative PML lesions, but not in adjacent, unaffected tissue or control tissues, including brains from individuals with HIV-1 encephalopathy. The detection of active HHV-6 infection coupled with the collocation of JCV large T antigen and HHV-6 in swollen intralesional...

Cytomegalovirus

Cytomegalovirus (CMV) is a large DNA virus of the Herpes virus group. It is estimated that 50 to 80 of adults have prior evidence of CMV infection (58). The infection is usually subclinical when contracted by immunocompetent infants and adults and infrequently may lead to a mononucleosis-type syndrome. However, significant sequelae exist from in-utero infections as well as infections in immunocompromised patients.

Herpes Simplex Virus

The HSV 1716 (an HSV-1 mutant attenuated in its ability to replicate in neurons of the CNS) is another herpes-virus strain that has made its way from animal studies to early clinical trials. In addition to avirulence in SCID mice, efficacy studies showed antineoplastic effects against intracranially injected melanoma and human embryonal carcinoma (NT2) tumors (31-33). The virus was also found to be unable to replicate within neuronally differentiated counterparts of NT2 cells underscoring the selectivity of this virus for tumor cells (33). These results have lead to early trials to assess the safety and toxicity profiles of HSV1716 as an innovative anti-glioma agent in humans (34). As with G207, HSV1716 was well tolerated and an MTD could not be established as no patient exhibited signs of encephalitis postinjection even with the highest dose administered. Additionally, further studies have suggested that HSV 1716 replicates in at least some of the HGG treated with intratumoral...

Herpesviruses

Cytomegaloviruses are also known as salivary gland viruses. Several species-specific strains exist, among these, strains infecting mice, rats, and guinea pigs. Megalic cells and nuclear inclusions in the glandular epithelium of the salivary glands characterize infection. Infection is rare in laboratory colonies. Mouse thymic virus infects only mice, in which it may be found in the thymus and the salivary glands. Infection with mouse thymic virus is occasionally reported in laboratory mouse colonies, in which it may reach high prevalences. Acute herpesvirus-related disease may be induced experimentally in suckling mice,122 but in general, infection in rodents is asymptomatic. But, in guinea pigs, clinical disease may be observed in breeding females, and transmission in utero cannot be excluded.48,123 For all herpesviruses, diagnosis can easily be achieved by serology.

U48 and U82 gH and gL

Formation of the glycoprotein gH gL heterooligomer has important implications for understanding the pathology of HHV-6-associated disease because this complex is essential for infectivity and fusogenic cell-to-cell spread (Josephs et al., 1991 Liu et al., 1993a,b Qian et al., 1993 Anderson et al., 1996 Takeda et al., 1997 Anderson and Gompels, 1999). Definition of the HHV-6 gH domain involved in protein-protein interactions is addressed by targeting regions defined by conserved cysteines identified by alignment of gH amino acid sequences representative of all herpesvirus subfamilies. The N-terminus of HHV-6 gH includes a 230-amino-acid domain required for interaction with HHV-6 gL encompassing residues conserved specifically among betaherpesviruses. HCMV homologues, UL75 (gH) or UL115 (gL), can substitute for HHV-6 glycoproteins and participate in heterologous complex formation (Anderson et al., 1996). Furthermore, the region that governs this heterologous gL binding also maps to the...

Serologic assays Techniques

Indirect immunofluorescence antibody assays (IFA) were the first ones to be used for the detection of HHV-6 antibodies (Salahuddin et al., 1986 Linde et al., 1988 Lopez et al., 1988) and remain still widely employed. In these tests, HHV-6-infected cells are fixed on a glass slide, a serum dilution is added and a fluorochrome-conjugated anti-immunoglobulin antibody is then applied to detect the binding of serum antibodies to specific antigens. When illuminated with ultraviolet light, the number of fluorescent foci as well as the characteristic pattern of cell staining observed with the microscope constitute the main parameters to be taken into account for the result. The staining of uninfected cells with a counterstain partly quenching non-specific fluorescence is also important, in particular, to check that the ratio of infected to uninfected cells is in agreement with the known characteristics of cell preparation. Infected cells consist of primary cells such as cord blood mononuclear...

Primary infection characteristics and diagnostic considerations

Major issues in designing diagnostic tests for primary HHV-6 infection include (1) to provide a rapid assay for useful information in a short time, and (2) to distinguish between primary virus infection versus viral reactivation or latent infection (Table 1). Of particular concern is the fact that viral DNA is likely to be present in circulating peripheral blood mononuclear cells (PBMC) from all HHV-6-infected individuals, regardless of whether that infection was recent or not. Thus, one must rely on the unique features of primary infection to distinguish it from latency persistence or subclinical reactivation reinfection. The most important feature of primary infection is the high levels of viremia (Asano et al., 1991) so that infectious virus can readily be cultured from patients' PBMC and viral DNA is detected in cell-free plasma samples. In addition, quantitative PCR assays can reveal high cell-associated viral DNA loads in the PBMCs, in contrast to latent or persistent infection....

The epidemiology of roseola from historical observations

The epidemiologic picture of human herpesvirus 6 (HHV6) has continually evolved over its known life span of 2 decades. Still, it remains more of a collage than a completed portrait, for HHV6 has multiple characters. It is a covert companion of life, and yet a mimicker of many maladies. Although HHV6 was named relatively recently, this virus probably has long been recognized as an exanthematous disease of childhood. In papers and texts from the 1800s, an acute infection of young children with rash was given such sobriquets as roseola infantilis, exanthem criticum, exanthem subitum, the rash of roses, and prophetically, the sixth exanthematous disease of childhood. These old descriptions suggest that even in ages past infections likely from HHV6 were common, geographically widespread, and occurred in young children, primarily infants. Kempe and co-workers (1950) subsequently also attempted unsuccessfully to isolate the virus. They did, however, show that the infectious agent was present...

Lymphatic and hematopoietic system see also chapters 14 and

In chronic persistent HHV-6 infection, viral DNA load and cellular changes show certain cyclic changes, suggesting some fluctuation in viral replication (Krueger et al., 2001). In about 6 , heterophile-negative infectious mononucleosis is caused by HHV-6A or B infection (Steeper et al., 1990 Horwitz et al., 1992 Akashi et al., 1993). More frequent is the reactivation of latent HHV-6 in patients with classical EBV-induced infectious mononucleosis resulting in a more protracted course of the disease with elevated liver enzymes (Bertram et al., 1991). Occasionally caused by HHV-6, preferentially variant B, are angioimmunoblastic lymphadenopathy (Luppi et al., 1993 Daibata et al., 1997), hemophagocytic syndromes (Sugita et al., 1995 Tanaka et al., 2000) and Langerhans cell histiocytosis (Leahy et al., 1993). HHV-6 (preferentially subtype A) and or increased viral DNA loads were found in certain malignant lymphomas, including subtypes of Hodgkin's disease (Krueger et al., 1989 Torelli et...

General Aspects of Therapy

Patients suffering from herpes zoster should be encouraged to see a physician as early as possible for immediate medical care based on administration of systemic antiviral therapy. In addition symptomatic local therapy and analgetic therapy in order to achieve painlessness are equally important. Since years it has become clear, that systemic antiviral therapy is indicated for most patients suffering from herpes zoster. In general the aims of therapy for herpes zoster comprise the following decrease viral replication as early as possible, thus lowering the viral load, accelerate healing, limit or relieve severity and duration of acute and chronic pain (postherpetic neuralgia, PHN). Further options are to prevent or alleviate other acute and chronic herpes zoster complications and reduce the risk of cutaneous extension and visceral dissemination of VZV, which is particularly a problem in immunocompromised patients. Alternative therapies such as hypnosis and others are definitely of...

Discussion and conclusions

Twenty years after its discovery, HHV-6 is an emerging pathogen with an increasing body of data to support disease associations spanning the self-limiting rash of childhood to the ravages of multiple sclerosis. Applying scientific rigor to assessing these associations will be necessary to verify the etiology of these diseases particularly those like fibromyalgia, which remains very difficult to diagnose. The development of additional immunological research tools (both cellular and humoral) as well as molecular, which can also distinguish variants A and B will be synergistic to scientific discovery while providing future tools for monitoring the efficacy of therapy, whatever is the eventual target of treatment. By virtue of its dual tropisms for lymphocytes and nervous tissue, HHV-6 is one of a growing list of viruses, which present both the research challenge and excitement of bridging two important disciplines immunology and neurobiology. This critical connection has enormous...

Diseases of blood vessels

Replicative and latent infection of vascular endothelium by HHV-6 was repeatedly shown in vivo and in vitro using immunohistochemical and molecular techniques (Wu and Shanley, 1998 Rotola et al., 2000 Caruso et al., 2003). In vitro infection of human umbilical vein endothelium (HUVEC) with HHV-6 was followed by the expression of early and late viral antigens in 37.6 and 6.5 of HUVEC, respectively, with persistence of the antigens for up to 27 days. Although virus was not obviously released from these cells, it could be recovered by cocultivation (Wu and Shanley, 1998). Endothelial cells obtained from the aorta, vasa vasorum, or from cardiac microvessels of immunocompetent patients with aortic insufficiency or aneurysm revealed HHV-6 by nested polymerase chain reaction (PCR) even in cases where viral DNA was not recovered from peripheral blood mononuclear cells (Rotola et al., 2000). Viral transcripts from immediate-early (U91, U42) and late (U22) genes were detected in aortic...

Chronic fatigue syndrome

Since the initial reports and the definition of CFS was established by the CDC in 1994, many viruses have been implicated and studied, including enteroviruses, re-troviruses, and the human herpesviruses (HHVs). A substantial body of literature documents the association of HHV-6 with CFS. Some studies examining the relationship between CFS and HHV-6 have produced ambiguous findings. This might be due in part to overly broad selection criteria for the patient sample, small sample sizes, failure to match control subjects with patients, and the use of inappropriate techniques for detecting active HHV-6 infection. Furthermore, because latent HHV-6 infection is nearly universal in adults, only tests that can differentiate between active and latent infection are likely to produce meaningful results. Additionally, early published studies in particular not only failed to differentiate active and latent infection, but they also did not differentiate between HHV-6 variant A or variant B.

Solid organ transplant recipients

Overall, 38-55 of renal, 22-54 of liver, 36 of heart and up to 57 of heart-lung lung transplant recipients have been shown to develop HHV-6 infection (Morris et al., 1989 Okuno et al., 1990 Herbein et al., 1996 Dockrell et al., 1997 Lautenschlager et al., 2000 Rogers et al., 2000 de Ona et al., 2002). Following living related liver transplantation, HHV-6 infection has been documented in 48 of the patients these included 4 4 patients who were seronegative and 42 (15 36) of those who were seropositive for HHV-6 prior to living related transplantation (Ihira et al., 2001). Most HHV-6 infections occur between 2 and 4 weeks after SOT this characteristic timing distinguishes HHV-6 from other betaherpesvirus infections that usually occur later post-transplantation (Singh and Carrigan, 1996). In a study, in liver transplant recipients, where HHV-6 and HHV-7 DNA detection was sought in the plasma, HHV-6 infections occurred in 38 (15 40) patients 67 of the infections occurred at 2 weeks...

Prevention and therapy

In vitro studies show that ganciclovir, cidofovir and foscarnet should be effective against HHV-6. Tokimasa et al. (2002) reported a lower rate of HHV-6 reactivations in patients receiving ganciclovir as CMV prophylaxis. Wang et al. (1996) showed in an epidemiological study that patients who received high-dose acyclovir had lower HHV-6 DNA levels and were less likely to suffer from a delayed marrow engraftment. However, in other studies, no effect on the viral load by acyclovir has been seen (Ljungman et al., 2000 Zerr et al., 2005). Antiviral therapy with ganciclovir or foscarnet has been shown to lead to reduction in HHV-6 viral load in CSF (Zerr et al., 2002) and blood (Mendez et al., 2001 Zerr et al., 2002). Ganciclovir is also able to reduce HHV-6 viral load in saliva (Ljungman et al., 2001). Both ganciclovir and foscarnet have been reported being effective against HHV-6 meningo-encephalitis after transplantation and the superiority of either ganciclovir or foscarnet over the...

Lieve Naesens Leen De Bolle Erik De Clercq

In contrast to other human herpesviruses such as herpes simplex virus (HSV) or cytomegalovirus (CMV), HHV-6 has not been the subject of extensive antiviral screening, the main reason being the uncertainty about the large need for specific anti-HHV-6 therapies. Transplant recipients commonly show laboratory signs of HHV-6 reactivation, but the frequency by which this is associated with serious disease is still ill defined (Yoshikawa, 2004). Even more controversial is the role of HHV-6 in chronic neurological disorders, such as multiple sclerosis (MS) or chronic fatigue syndrome (CFS). In the absence of HHV-6-specific therapies, treatment of HHV-6 infections currently relies on the relatively broad-spectrum antiherpetic agents (val)ganciclovir and foscarnet. Although these drugs offer an indisputable benefit in the therapy or prophylaxis of CMV, their clinical efficacy against HHV-6 can only be estimated from a number of heterogeneous case reports. Long-term administration of these...

Live Attenuated Varicella Vaccine

39 Thomas S, Wheeler J, et al Contacts with varicella or with children and protection against herpes zoster in adults a case-control study. Lancet 2002 360 678-682. 40 Brisson M, Gay N, et al Exposure to varicella boosts immunity to herpes-zoster implications for mass vaccination against chickenpox. Vaccine 2002 20 2500-2507. Gross G, Doerr HW (eds) Herpes Zoster.

Proposed pathogenic model of CFS

Human Fatigue Model

Alternatively, viruses and bacteria that have been maintained in a latent state and controlled by an intact immune system might be allowed to replicate and exacerbate symptoms of illness under circumstances of stress or co-morbid infections. It is currently not known whether the presence of HHV-6 (variant A or B) indicates a primary causative role in CFS, or simply the opportunistic exploitation of a suppressed immune system. As early as 1994, Ablashi postulated that CFS might essentially represent an immunological disturbance, which allows reactivation of latent herpesviruses, such as HHV-6 (Ablashi, 1994). Ablashi concluded that the evidence at that time showed a much stronger association of CFS with HHV-6 than with other herpesviruses, including EBV, cytomegalovirus (CMV, or HHV-5), or herpes simplex viruses (HSV-1 and HSV-2). Once reactivated, these viruses could directly contribute to existing morbidity and produce abnormal immune responses. Recently, Smith et al. (2005) reported...

Reactivation transplantation Solid organ transplant

In 1992, Yoshikawa first published that 14 of kidney transplant recipients developed HHV-6 viremia in the first 2-4 weeks posttransplant and 55 showed an increase in anti-HHV-6 antibody titer in the first 3 months (Yoshikawa et al., 1992). Since then, Singh and Carrigan (1996), Singh and Patterson (2000), Ljung-man (2002), and Lautenschlager et al. (2000) have reported HHV-6 as an emerging pathogen in solid organ transplantation. HHV-6 is expressed in the early weeks posttransplant, often exacerbating the severity of other diseases in the transplant recipient (Des Jardin et al., 1998, 2001 Dockrell et al., 1997, 1999), including cytomegalovirus (CMV) (Humar et al., 2000 Boeckh and Garret, 2003). of morbidity and mortality (Tolkoff-Rubin and Rubin, 1998). Serologically CMV-negative patients receiving an organ from a CMV-positive donor are at greatest risk, although use of potent immunosuppressives like anti-lymphocyte globulin, steroids, and mycophenolate mofetil as well as a history...

Antiviral Therapy of Shingles in Dermatology

The major goals of therapy in patients with herpes zoster are (5) prevention of other complications, e.g. ophthalmic involvement. Recent research has shown that antiviral therapy with acyclovir, valacy- clovir, famciclovir, and brivudin, started as early as possible, can significantly shorten viral replication, prevent lesion dissemination and reduce intensity and duration of ZAP particularly in elderly patients, provided that treatment is started early in the course of disease. This suggests that antiviral therapy (table 1) should be offered to all patients as soon as herpes zoster is diagnosed, preferably within 72 h after onset of rash. In patients of any age with ophthalmic herpes zoster and in all immunocompromised patients antiviral therapy should be started even later as long as viral replication can be considered in skin and nerves, e.g. as long as new blisters appear in the skin. Dermatologists are trained to diagnose early skin lesions as herpes zoster and should be...

Postherpetic Neuralgia and Other Neurologic Complications

Postherpetic Neuralgia

The acute herpes zoster radiculoneuritis affects mainly elderly patients with an incidence of 125 100,000 per year. The clinical onset of acute herpes zoster infection is heralded by pain in the affected segment (preherpetic neuralgia). The characteristic vesicopapular rash usually appears a few days after the onset of pain and takes 3-4 weeks to heal. In most patients, the rash and pain disappear completely within a period of 1-2 months. These patients develop neither local neuropathy nor other cutaneous sensory changes. In other patients, the acute neurocutaneous symptoms may be followed by irreversible skin damage and sensory abnormalities and, in a significant number of patients, there is persistent pain or the initial pain subsides and a second pain, often of different character, begins. This condition is called postherpetic neuralgia (PHN). In the overall population on average 12-20 suffer from pain at the time of skin healing and 2-5 at 1 year after zoster. The incidence of PHN...

IE proteins

HHV-6 gene transcription follows a similar pattern that characterizes herpesvirus, with immediate-early (IE), early and late proteins expressed (Dockrell, 2003). IE proteins are the first proteins expressed following viral entry, independent of de novo protein synthesis and play a crucial role in the initiation of infection, and the establishing productive infections, regulating reactivation from latency and evading immune recognition. HHV-6 immediate-early A locus (IE-A) locates in the position analogous to the human cytomegalovirus (HCMV) major IE (MIE) locus that is well-known to play critical roles in viral infection. Similarly to HCMV MIE, HHV-6 IE-A consists of two genetic units, IE1 and IE2, corresponding to ORFs U90-U89 and U90-U86 87, respectively (Papanikolaou et al., 2002). However, the HHV-6 IE-A locus exhibits limited sequence homology with the HCMV MIE locus. IE2 proteins derived from the U86 87 region with apparent molecular mass of 100, 85 and 55 kDa are detected in...

U53 proteinase

HHV-6 U53 encodes its own proteinase, which is essential for capsid maturation, DNA packaging and the ultimate formation of new virus particles (Tigue et al., 1996). The mature proteinase consists of 230 residues, but is synthesized in the form of a precursor, which has an additional 298 residues attached to the C terminus of the mature enzyme. Autolytic removal of these residues, which themselves constitute a form of the viral assembly protein) releases the N-terminal proteinase in its mature form processing takes place at two locations positioned, respectively, at the C terminus of the proteinase. Autoprocessing of the precursor form of HHV-6 proteinase at two sites (termed M and R) is required to generate the mature enzyme, which could represent targets for novel antivirals against HHV-6 (Tigue and Kay, 1998a,b). Despite sharing 40 identity with other betaherpesvirus protein-ases such as human cytomegalovirus proteinase, the one-chain HHV-6 enzyme is distinguished from these...

Cellular homologues

Herpesviruses provide examples of viral piracy of host genes, which may play roles in immune evasion. HHV-6 encodes several chemokine and chemokine receptor homologues (Isegawa et al., 1998 Menotti et al., 1999 Zou et al., 1999 Milne et al., 2000 Bradel-Tretheway et al., 2003 Luttichau et al., 2003). U83 encodes a functional chemokine (Zou et al., 1999). Although the gene has relatively little sequence similarity to human chemokine genes, the protein expressed has the typical cysteine residues of a chemokine, transduces signals that involve calcium fluxes and induces chemotactic activation. The recombinant U83 protein is capable of inducing transient calcium mobilization in THP-1 cells and of chemotactically activating THP-1 cells (Zou et al., 1999). Furthermore, the U83 has been found to cause calcium mobilization as efficiently through the CCR2 receptor (Luttichau et al., 2003), suggesting that the U83 protein might play an important role in HHV-6 propagation in vivo by activating...

U100 gQ

U100 gene, the glycoprotein Q (gQ) that is unique to the genus Roseolavirus of human herpesviruses (Gompels et al., 1995 Dominguez et al., 1999 Isegawa et al., 1999). The U100 gene is subject to differential splicing, and a number of envelope-expressed polypeptides result. In contrast to the other glycoprotein-encoding genes, U100 of HHV-6A and HHV-6B demonstrate only 72.1 sequence identity (Isegawa et al., 1999). This glycoprotein may therefore have a role in the differential effects of HHV-6A and HHV-6B infections. Along with gB and gH, the gQ contains epitopes recognized by neutralizing antibodies and therefore represents a target for variant-specific neutralizing antibodies (Pfeiffer et al., 1993, 1995). Recently, it was found that HHV-6 gH gL complex associates with the 80-kDa form of gQ (gQ-80 K) that is found on the viral envelope. Besides gQ-80 K, the gQ gene encodes an additional product whose mature molecular mass is 37 kDa (gQ-37K) and that is derived from a different...

Species specificity

HHV-6 has a restricted range of susceptible species, essentially limited to humans and selected nonhuman primates. Antibodies to HHV-6 or to a closely related simian herpesvirus have been demonstrated in monkeys (Higashi et al., 1989), and a simian HHV-6 homolog has been recently identified in mandrill and drill monkeys (Lacoste et al., 2000) as well as chimpanzees (Lacoste et al., 2005). Although an established rodent model of HHV-6 infection is not presently available, preliminary experiments in human CD46-transgenic mice have shown some degree of susceptibility to HHV-6A (P. Lusso et al., unpublished). An efficient small-animal model of HHV-6 infection was developed using severe combined immunodeficiency (SCID)-hu Thy Liv mice, in which human fetal liver and thymic tissues are implanted under the renal capsule (Gobbi et al., 1999). These mice can be successfully infected with HHV-6A and -6B, but the infection remains confined to the human graft. In vitro, HHV-6 was shown to...

Latent infection

Like other herpesviruses, HHV-6 establishes latent infection in vivo and thereby can persist in the host indefinitely after primary infection. The best-characterized in vitro model of latent infection is represented by long-term (30 days) cultured macrophages, which after exposure to HHV-6 survive a transient period of low-level productive infection (Kondo et al., 1991). Latency-associated HHV-6 transcripts from the IE1 IE2 locus have been identified in latently infected macrophages both in vitro and in vivo (Kondo et al., 2002b). A second in vitro model of HHV-6 latency was described in papillomavirus-immortalized cervical epithelial cells, in which high numbers of viral genome copies were shown to persist in an episomal form for prolonged periods of time in the absence of any sign of productive infection (Chen et al., 1994). Latent HHV-6 infection was also reported in an EBV-negative Burkitt's lymphoma cell line (Bandobashi et al., 1997). Although circulating monocytes and...

Immune modulation

The broad immunotropism of HHV-6, particularly of variant A (Table 1), may dramatically affect, directly or indirectly, the function of the cellular and humoral arms of the immune system. As discussed above, both variants have a primary tropism for CD4+ T cells, which are pivotal in the orchestration of the immune responses. Variant A also efficiently infects different types of cytotoxic effector cells such as CD8+ T lymphocytes, NK cells, and gd T lymphocytes. Moreover, both mononuclear phagocytic cells and DC can be infected, albeit usually in a nonproductive fashion, and the infection results in dramatic phenotypic and functional alterations. In accordance with the above observations, multiple lines of clinical and experimental evidence suggest that HHV-6 may be an immunosuppressive agent in its own right. One such hint comes from the SCID-hu Thy Liv mouse model in which infection with either HHV-6 subgroup A or B results in a rapid destruction of the thymic grafts with dramatic...

Molecular biology

The genomic architecture shared by HHV-6A and B and HHV-7 is unique (Braun et al., 1997 Campadelli-Fiume et al., 1999 Clark, 2000) among human herpesviruses, and resembles that of channel catfish virus. The unit length of the HHV-6A and B molecule ranges approximately between 162 and 170 kb and is composed of 143 kb unique, long segment bracketed by direct repeats of DRL (left) and DRr (right) that can vary in length from 8 to 13 kb, upon passage in vitro. The complete sequence of HHV-6A (U1102) has been determined (Gompels et al., 1995). The u segment is 143-147 bp in length, and is flanked at each terminus by an 8.087 by DR, for an overall length of 159.321. HHV-6A mostly contains 119 open reading frames (ORFs), 9 of which are absent in HHV-6B strain. Splicing (U1102) is predicted, resulting in 97 unique genes, 88 of which have counterparts in HHV-6B. In comparing HHV-6B (Z-29) to HHV-6A (U1102), 9 ORFs in variant A do not have a counterpart in variant B as a result of either the...

Concluding remarks

The data reviewed in this chapter describe various aspects of HHV-6 variants. Based on the findings, the following conclusions can be drawn 1. The HHV-6A and B variants are two distinct viruses and should be reclassified according to the nomenclature of herpesviruses 2. The existing epidemiology of HHV-6 is confusing because there are no sero-logical tests to assess the prevalence rates of variants A and B in various parts of the world. 5. The consequences of HHV-6 infection and its concurrent complications are still being underestimated.

Future assay methods

New approaches to the detection and quantitation of HHV-6 DNA in clinical specimens include non-PCR-based gene amplification or detection methods such as branched DNA (bDNA) hybridization (Urdea et al., 1987) and isothermal amplification (Guatelli et al., 1990 Walker et al., 1992 Ihira et al., 2004). Fig. 1 Alignment of HHV-6A and HHV-6B. A Inter-variant alignment (HHV-6A U1102 and HHV-6B Z29). B Intra-variant alignment (HHV-6B HST and HHV-6B Z29). Shown is a visual overview of the overall genetic conservation between (panel A) and within (panel B) variants of HHV-6, based on available genomic sequences (HHV-6A U1102, HHV-6B Z29 and HHV-6B HST respectively, GenBank Accession Numbers X83413, AF157706 and AB021506). The alignments are color-coded dark regions represent areas of greatest sequence divergence and numbers represent the genomic location (in base pairs). Gapped regions are indicated by darkly shaded semicolons ( ) these correspond to regions where there are sequence...

Congenital infection

Congenital infection with HHV6 could result from maternal infection acquired through transplantation or by inheritance via parental transmission of chromosomally integrated HHV6. Intrauterine transmission of HHV6 has recently been documented to occur in about 1 of children in a large and several smaller studies of normal newborns (Adams et al., 1998 Dahl et al., 1999 Daibata and Miyoshi, 1999 Hall et al., 2004). Intrauterine transmission had been suggested in a few cases by HHV6 DNA detection in fetuses and placentas, as well as cord blood (Ando et al., 1992 Aubin et al., 1992 Leach et al., 1994 Maeda et al., 1997a Adams et al., 1998 Daibata et al., 1999 Ashshi et al., 2000 Baillargeon et al., 2000 Ohashi et al., 2002). The detection rate of HHV6 DNA in cord blood has ranged from 0 to 1.6 in studies examining 58-305 cord blood (Adams et al., 1998 Dahl et al., 1999 Daibata et al., 1999). In a study examining 5638 cord blood, the rate was 1 of live births, similar to that for...

Resume

Various inflammatory reactions occur in the respiratory tract, both in primary and in non-primary infections with HHV-6. They are usually mild and rarely afford hospital admission except for the immunosuppressed patient. Similar to human cytomegalovirus and Epstein-Barr virus, HHV-6 constitutes a major risk factor in transplant recipients and in patients with acquired or inherited immune deficiency syndromes. In such patients, HHV-6 may also be a copathogen to other infectious organisms. In addition, the observation of frequent HHV-6 reactivations in patients with certain autoimmune disorders, including in the lungs, poses the question whether this virus may be one possible copathogenic factor in the development of idiopathic pulmonary fibrosis.''

Abstract

The emergence of human immunodeficiency virus (HIV) in the 1980s heightened our awareness that immunodeficiency could be acquired through viral infection. Historically, measles and hepatitis B and C viruses were implicated as immuno-suppressive viruses however, there is growing evidence that a number of the her-pesviruses have properties similar to HIV with serious clinical sequelae. This chapter is devoted to a discussion of the impact of human herpesvirus-6 (HHV-6) infection on the immune system, focusing on the cell-mediated immune response. It is unclear whether preexisting immunodeficiency is a prerequisite for infection with HHV-6 or whether these viruses use stealth strategies for initial entry, establish latency and then exert their immunosuppressive effects. Given the complexity of the immune system, the mechanism(s) by which this virus family exerts its effect is not well understood. This chapter will review the range of evidence of immune system involvement from in vitro...

Summary

CFS patients often show evidence of immune dysfunction and or dysregulation, such as low suppressor cell numbers, low numbers and efficacy of NK cells, and abnormal RNase L. These dysfunctions are manifest when the immune system is challenged by a virus or other infection, suggesting that there might be a viral trigger that initiates and or perpetuates CFS. Active infection by HHV-6 is found in association with patients suffering from CFS in significantly greater proportion than in the healthy immunocompetent population. In this subgroup of CFS patients, HHV-6 might be the viral trigger for CFS. The fact that HHV6 is not found universally in CFS patients might be because (a) other viruses agents or events can also precipitate CFS by triggering faulty immune response or (b) the nature of HHV-6, as with all herpesviruses, is cyclical and thus a snapshot of a group of CFS patients would also include those patients in the latent phase of chronic, recurring HHV-6 infection. Anecdotal...

Kshv

Gamma Herpesviruses Plate 4 Sub-families of Human Herpesviruses. (see page 8). Plate 5 CryoEM imaging and 3D reconstruction HSV-6 capsid. (a) A gallery of cryoEM particle images of HHV-6 capsids. (b) Shaded surface representation of HHV-6 capsid reconstruction at 30 A resolution. The structure is color coded according to capsid radius so that the capsid shell is in yellow, the triplexes are in green, and the upper domains of the pentons and hexons are in purple. (see page 17). Plate 7 Indirect immunofluorescence assay of HHV-6-infected cells. The HSB-2 cells infected with HHV-6A (stem GS) were stained with monoclonal antibody for IE1 (a) U27 (b) or gB (c) at 86 h p.i. (a) IE1 locates in nucleus with punctuated pattern. (b) U27 locates in nucleus hke forming replication compartment. (c) gB locates n the cytoplasm. (see page 49). Plate 8 Cellular reactions in HHV-6-infected cells. Top Row HHV-6A-infected HSB2 cells in culture blastic transformation of infected cells (left) and nuclear...

A5021 297

Serologic testing 91-100 acute lymphoblastic leukaemia 195 acute primary infection 65, 143 acyclovir 258, 286-7, 293, 296 adenovirus 238, 248 AIDS 271, 272-4 HHV-6, opportunistic agent 269, 270 related LD 194-5 alpha interferon 338 alphaherpesvirus 12, 13 amplicons 28 ampligen 259 (AILD) 193-4 animal models 305-16 anti-herpesvirus therapy, new targets 297-9 anti-inflammatory (Th2) cytokine 203-4 antibodies 54, 61, 91, 307 biological aspects, of HHV-6 variants 82-3, 134 by HHV6 and HIV-1 264f, 265-6 CD8 70, 324 CD34+ 65, 186 HHV-6 and HHV-7 25, 37 central nervous system (CNS) 84-5, 142, 255, 256-8, 295 CNS demyelination 312-6 febrile seizures 214-5 HHV-6 infection 213-4, 215, 257f mesial temporal-lobe epilepsy (MTLE) 215 multiple sclerosis (MS) 215-8 progressive multifocal leukoencephalopathy (PML) 219-20 cerebral lymphomas 194 characteristic tissue reaction 140f chronic allograft nephropathy 205, 286 chronic fatigue syndrome (CFS) 86-7, 207-9, 251-2, 309 clinical algorithm 257f CNS,...

Joseph H Brewer

Crossmatching Incompatible Microscope

The potential therapeutic approaches for human herpesvirus-6 (HHV-6) infections include antiviral therapy and immune therapies. Several experimental therapy approaches have possible benefits for such infection based on theoretical grounds as well as clinical studies. These therapies may alter viral infection via immune-mediated mechanisms, which relate to either humoral immunity or cell-mediated immune function. There may also be direct or indirect antiviral effects. Herein, these therapy alternatives are reviewed in terms of experimental and clinical data. Most of the clinical studies regarding these therapies that have implications for patients with HHV-6 infection have generally been done in groups of patients with disease states or syndromes that are possibly associated with HHV-6 infection. The main examples of such clinical syndromes that are addressed in this section are chronic fatigue syndrome (CFS) and multiple sclerosis (MS). Several commercially available intravenous...

Eukaryotic Expression Systems

Cytomegalovirus Promoter for Expression in Mammalian Cells The Cytomegalovirus Enhancer-Containing Promoter 214 Positive Regulation 216 Experimental Procedures 219 Effects Upstream of the Cytomegalovirus Enhancer 221 Effects Downstream of the Cytomegalovirus Promoter 222 Negative Regulation 223

Past Role Of Laboratory Animals

In 1877, the German scientist Robert Koch built upon observations that were already over a decade old, namely that anthrax could be transmitted from animal to animal. Koch's animal experiments proved that the Bacillus anthracis bacterium caused a particular disease, and that the isolated and purified bacterium from an initial host could cause the same disease in a new, second host. Hence, Koch's postulates were born.2 Koch's observations gained general acceptance and helped lay the foundation for the more-intensive use of laboratory animals, especially for investigations of infectious diseases. Even today, over a century later, Koch's postulates form a cornerstone for infectious-disease biology and research. These simple principles are applied in their original form or in an updated, more molecular version to emerging diseases, such as the Four-Corner-disease in 1993, which is caused by the hantavirus sin nombre, and Kaposi sarcoma, which was etiologically linked to human herpes virus...

Benign cellular changes

Infection-herpes simplex virus Pap smear has a poor sensitivity, but good specificity, for HSV. Positive smears usually are caused by asymptomatic infection. The patient should be informed of pregnancy risks and the possibility of transmi ssion. Treatment is not necessary, and the Pap should be repeated as for a benign result.

And W Martin Kast PhD

Viruses implicated in the development of human cancer include hepatitis B (HBV) and hepatitis C (HCV) viruses, human papilloma virus (HPV), Epstein-Barr virus (EBV), human T-cell lymphoma virus, and human herpes virus 8. Together they contribute significantly to the total incidence of cancer worldwide. Current work in each of these virus systems seeks to understand the mechanisms of viral action and identify strategies of immune intervention to combat viral infection and subsequent transformation. It is thought that oncogenic proliferation may be instigated by the presence and expression of viral oncogenes, which may be integrated into the host genome. Critical viral genes may also interfere with host genes, resulting in the activation of cellular proto-oncogenes and or the inactivation of anti-oncogenes and their products. Targeting such viral proteins through various vaccination strategies offers both therapeutic and prophylactic strategies against viral induced malignancies. In...

Nonneoplastic Conditions

Infective oesophagitis may be seen in otherwise healthy individuals but is more commonly encountered where there is alteration of either local or systemic immunity (e.g., AIDS). Underlying ulceration, broad-spectrum antibiotics, diabetes, corticosteroid therapy and immunosuppressive drugs can all alter the local gut flora resulting in superimposed infection. Causative agents are candidal fungus, herpes simplex virus (HSV 1 and 2), cytomegalovirus (CMV), and atypical mycobacteria.

Other Biological Functions Of Hdac1

In recent years, evidence has emerged that HDAC1 is involved in cellular defense against viral infection. For example, viral transcription mediated by open reading frame 50 (ORF50), an activator of early and late genes in the lytic cycle of the Kaposi's sarcoma-associated herpesvirus, is repressed upon association with HDAC1 (83,84). Furthermore, inhibition of HDAC activity appears to be important for viral infection. For example, Gaml, an early gene product essential for the replication of the avian adenovirus CELO, can interact with HDAC1 and inhibit its enzymatic activity (85). The bovine herpesvirus 1 immediate-early protein (bICPO) has also been shown to associate with HDAC1 and activate transcription by interfering with MAD MAX-dependent transcriptional repression, thereby promoting viral infection in differentiated cells (86). Viral transforming proteins such as the human papillomavirus oncoprotein E7 are also known to interfere with the binding of HDAC1 to pRB, thereby...

Applications Of Retroviral Gene Transfer For Cancer Therapy

Another interesting concept to improve the efficacy of anticancer treatments with gene therapy is to manipulate the immune response after hematologic transplants. Following allogeneic BMT or HSC transplantation in leukemia lymphoma treatment, donor lymphocytes are known to mediate a graft-vs-leukemia effect (GVL). However, a major problem with this approach is the potential development of graft-vs-host diseases (GVHD). One promising solution to prevent GVHD is to genetically modify donor T-cells with a suicide mechanism that can be activated by administration of a prodrug if this life-threatening complication should occur. This strategy has been confirmed preclinically by several groups using retroviral vector-mediated gene transfer of the herpes simplex virus thymidine kinase (HSV-t r) suicide gene, which encodes an enzyme that phosphorylates and thereby activates the antiviral prodrug ganciclovir (GCV) (53-55). The clinical utility of this system was recently confirmed in a phase 1...

Promotes Wound Healing

An ointment containing 5 calendula flower extract, as well as an ointment containing two different fractions of calendula extract combined with allantoin, has been shown to stimulate physiological regeneration and epithelisation in experimentally induced surgical wounds. The effect is thought to be due to more intensive metabolism of glycoproteins, nucleoproteins and collagen proteins during regeneration of the tissues (Klouchek-Popova et al 1982). A combination of calendula, Actium lappa and Geranium robertianum has been shown to improve healing of ulceration in 52 patients suffering herpetic keratitis compared with treatment with acyclovir alone (Corina et al 1999).

Local Delivery In Rat Brain Tumor Models

Gene therapy remains very attractive as a treatment strategy for brain tumors since local delivery is feasible and likely to have a major impact on the disease 19, 20 . Several gene therapy approaches are based upon prodrug-activating enzymes, inhibition of tumor neovascularization, and stimulation of antitumor immune responses. The most widely explored paradigm is based on the activation of ganciclovir to a cytotoxic compound by a viral enzyme, thymidine kinase, which is expressed by tumor cells, after infection by a retroviral vector containing the gene. Thus, the transfer of the gene coding for the thymidine kinase of the herpes simplex virus (HSV-tk), followed by ganciclovir administration, has been described as a treatment for a variety of cancers but especially for brain tumors. When Cool et al., 21 stereotactically injected cells producing up to 3 x 105 HSV-tk retroviral particles per ml into 9L brain tumors and administered ganciclovir to the animals, there was no increase in...

Finding The Achilles Heel The y1345 Gene Controls Hsv1 Neurovirulence

The breakthrough in creating attenuated HSV-1 strains resulted from characterizing viruses containing engineered mutations in the y 4.5 genes. Embedded within a repetitive genome component (see Fig. 2A), the y 4.5 gene is expressed with Y1 late kinetics and is not required for growth in cultured monkey kidney cells. Strikingly, its impact on viral neurovirulence is greater than any single HSV-1 gene identified to date (11-13). Although the LD50 of many wt HSV-1 strains is less than 300 pfu following intracranial delivery, it is not possible to accurately measure the LD50 for y34.5 mutant viruses. Indeed, upwards of 106-107 pfu of y34.5 mutant viruses have been safely injected intracranially into mouse, non-human primate, and human brains (11-18). In studies designed to examine the efficacy with which y34.5 mutants were able to destroy human or murine gliomas implanted into mice, not only had the attenuation problem been solved, but the treated mice survived longer than their untreated...

Tropism for Dividing Cells in Cancer Gene Therapy

The selectivity of MuLV for dividing cells has been exploited in a phase III clinical trial that tested the efficacy of a suicide gene therapy approach to treating glioblastoma multiforma, a malignant brain tumor (77). The rationale of such gene therapies is to insert a gene capable of killing cells into the tumor while protecting the normal brain cells. The vector contains the herpes simplex thymidine kinase (TK) gene, which is able to phosphorylate the drug ganciclovir, resulting in a toxic derivative that is incorporated into DNA. The vector is produced in situ in the residual tumor and peritumor areas, following surgical resection of the tumor, by the injection of a mouse producer cell line that generates the retroviral particles. Although both tumor cells and healthy cells in the area of a growing brain tumor could potentially be transduced, only the tumor cells themselves and the vasculature supplying blood to the tumor are considered likely targets as they will be actively...

Infections in Human Populations

To be considered as this also affects how rapidly an infection may spread in the population. One more factor which may or may not be significant is the length of the prepatient period, the time between infection and symptoms becoming apparent, as the onset of symptoms may result in relative isolation from the rest of the population. Some infections, such as herpes simplex or hepatitis B (HBV), may be symptomatic in some individuals but to a greater or lesser degree asymptomatic in others with corresponding differences shown in infectivity, and the tendency to symptomatic vs. asymptomatic infection may vary according to age, as is shown very strongly in the case of hepatitis B (Medley et al., 2001). HBV is also a good example of an infection that may manifest itself as an initial asymptomatic infection or an acute primary infection (in this case lasting a few weeks) leading to recovery or to a persistent chronic infection which for HBV may last several decades or be effectively...

Asymptomatic Patients above 350 CD4 cellspl

It is now more widely recognized that only two studies have been able to show the advantage of beginning with HAART at these CD4 cell counts all others have not found any such advantage for the patient. Proponents of early initiation of therapy often cite a matched-pair analysis from Switzerland, which indicated a small, though statistically significant clinical benefit if HAART was started with CD4 cells above this level (Opravil 2002). 283 patients, who were started on HAART with a count above 350 CD4 cells l, were matched by age, sex, CD4 count, viral load and risk group for HIV infection with control patients who had been untreated for at least 12 months. At follow up around three years later, the AIDS risk was more than twice as high in the untreated group. However, besides considerable methodological problems due to the design of this study, one challenging question remains when looking more closely at the 52 CDC Category B illnesses (including 10 AIDS cases) which occurred...

Alphavirus For The Transfection Of Tumor Cell Lines

Protein (GFP) and herpes simplex virus thymidine kinase (HSV-rfr) gene, which allowed parallel monitoring of the infection efficency by fluorescence (GFP) and tumor killing (HSV-rfr) after ganciclovir (GCV) administration (30). To simulate in vivo conditions, only low multiplicity of infection (MOI) was applied, which resulted in fairly modest GFP expression. However, the tumor killing was much better than anticipated because of the by-stander effect previously observed for HSV-rt treatment (31). These studies, however, made it clear that the delivery of the therapeutic gene is essential and approaches such as intratumoral injections or improved targeting for systemic delivery are essential.

Biological Roles Of Hdac3

In the human virology arena, HDAC3 has been shown to regulate cytomegalovirus infection by repression of the viral major immediate early promoter in nonpermissive cells (111). In yeast, loss of HOS2 affects acetylation at ribosomal protein gene promoter regions, implying that HDAC3 might be important in the control of ribosome biogenesis (112). Unfortunately, no HDAC3 animal knockout models are currently available, and our knowledge of the biological function of HDAC3 in vertebrates is extremely limited. Overexpression of HDAC3 in THP-1 or HeLa cells led to increased cell size, aberrant nuclear morphology, and G2 M cell cycle arrest, suggesting the involvement of HDAC3 in cell cycle control (8,20). In HeLa cells, siRNA-mediated HDAC3 knockdown also caused significant morphological changes and inhibited cell proliferation (113). From these studies, it is clear that a critical concentration of HDAC3 is required for normal cell survival.

Assessment of Virus Directly From Patients for GAG Dependence

Although some viruses, such as herpes simplex virus, appear to use HS in vivo, many others are selected for HS usage during passage in cell culture. Viruses with clear evidence for adaptation include Sindbis, dengue fever, foot and mouth disease, Ross River, tick borne encephalitis, and human immunodeficiency viruses (16,22,28,29,48-51). Sindbis virus is pathogenic for mice but grows poorly in cultured cells. Within a few passages in cultured cells, the virus grows to much higher titers but is no longer pathogenic in mice. This cell culture adapted virus binds heparin much better than the original mouse virus. When injected into mice intravenously, the heparin-binding virus is filtered out in the liver, in nonproductive associations (16,28). It seems likely that there is a strong selection against HS binding in such a blood-borne virus in the animal, and a strong selection for HS binding in cultured cells.

Genetically Engineered VSV as a Gene Therapy Tool Against Cancer

Oncolytic studies indicated that wild type VSV exhibited considerable potential as an anticancer agent. However, the ability to modify VSV through genetic engineering obviously affords the prospect of creating new generations of custom-made VSV vectors that contain immunomodulatory and or suicide cassettes designed to increase their antitumor activity. In order to begin evaluating whether genetically engineered VSV carrying tumor-killing cassettes could be created and whether such viruses were more efficacious in tumor therapy than the wild-type VSV, we developed VSV vectors carrying, as models, the herpesvirus TK suicide cassette or the cytokine gene interleukin-4 (IL-4). The foreign genes were cloned as additional transcription units between the VSV G and L genes and all viruses were grown to exceptionally high titers (71,103). TK protein was synthesized to extremely high levels and was functional, being able to phosphorylate ganciclovirs (GCV). Recombinant viruses also retained...

Virus Encoded Proteins Are Developed through Targeted Evolution In Vivo

Large DNA viruses, in particular herpes- and poxviruses, have evolved a number of proteins that function as mimics of or as decoys for endogenous proteins of the host organism. Often the virus uses such proteins to evade key components of the immune system. The virus-encoded proteins are elegant examples of targeted evolution, where the virus has captured a gene from its host and through combinatorial chemistry varied its structure and thereby its function randomly through mutagenesis. Unlike biotech entrepreneurs, the virus has the advantage of being able to select the mutant protein with the optimal pharmacological property through in vivo screening in the intact organism. The virus with the most useful protein for example, the most potent or broad-spectrum antagonist will prevail. One example is the vMIP-II chemokine of human herpesvirus 8, which acts as an efficient blocker of a surprisingly large number of structurally different chemokine receptors. The chemokine system in...

The Redundant Chemokine System Is an Optimal Target for Viral Exploitation

Figure 1 Structural relationship between herpesvirus-encoded chemokine receptors (A) and highly constitutive but regulated signaling of the prototype virus-encoded receptor ORF74 (B). In the dendrogram of herpesvirus-encoded chemokine receptors structural groupings are marked with shaded areas and receptors with known constitutive activity are highlighted. Panel (B) shows how the high constitutive signaling of the most well-characterized virally encoded receptor, ORF-74 from HHV8 (Kaposi's sarcoma-associated herpesvirus), is tuned by angiogenic chemokines acting as agonists and by angiostatic angiomodulatory chemokines acting as inverse agonists. Figure 1 Structural relationship between herpesvirus-encoded chemokine receptors (A) and highly constitutive but regulated signaling of the prototype virus-encoded receptor ORF74 (B). In the dendrogram of herpesvirus-encoded chemokine receptors structural groupings are marked with shaded areas and receptors with known constitutive activity...

Multiple Virus Encoded 7TM Receptors

More than 20 G-protein-coupled receptors have been identified in various herpes- and poxviruses (Table 1 and Fig. lA). Most of these receptors display key structural elements, that identify them as belonging to the family of chemokine receptors. In general, however, it is impossible to identify a specific endogeneous chemokine receptor as the original scaffold hijacked by the virus. The extensive subsequent mutational effort performed by the virus which has generated the desired pharmacological profile has at the same time significantly altered the primary structure of the receptor. Conceivably a multitude of more or less silent mutations have accompanied the functionally important substitutions that produced the useful property of the viral receptor. A few chemokine-like virus-encoded receptors nonetheless have been convincingly de-orphanized. That is, their endogenous chemokine ligand has been identified. The best examples are US28, a broad-spectrum CC and CX3C chemokine receptor...

Antioncogenic Properties Of

The antitumor effects of AAV had been initially reported within a few years of identification of the virus itself when it was identified that infection of herpes simplex virus (HSV)-transformed hamster tumor cells with AAV delayed the appearance of palpable tumors and increased the survival time of the animals (70). Since then, several reports have confirmed the inhibition of viral oncogenesis by a variety of DNA viruses, including bovine papillomavirus-1 (71), human papillomavirus (HPV)-16 (72-74), and Epstein-Barr virus (75). Evidence from several reports also suggested that AAV infection might protect against human cervical cancer, in part, by interfering with HPV-induced tumori-genesis (76) although studies of Stickler et al. reported a lack of correlation of between AAV infection and cervical tumorigenesis in a Jamaican population (77).

Molecular Chemotherapy With rAAV

Delivery of a gene-encoded toxin into cancer cells to achieve tumor eradication is usually performed by indirect killing through activation by a prodrug. This approach has focused mainly on delivery of the herpes simplex virus thymidine kinase (HSV-tk) gene. Expression of HSV- tk results in replicating tumor cells having enhanced sensitivity to nucleoside analogs, such as ganciclovir (GCV) or acyclovir. GCV is phosphory-lated initially by TK and subsequently by cellular factors to a triphosphate form that becomes incorporated into cellular DNA (81). This inhibits both DNA synthesis and RNA polymerase activity resulting in cell death (81).

Adenovirus Mediated Protein Expression for Cell Biology Studies

The ability of more than one adenovirus to infect the same cell has also been used to coexpress multiple protein subunits. Herpes simplex virus 1 encodes a heterodimeric immunoglobulin receptor that is expressed on the surface of an infected cell. After cloning the genes for the two subunits into separate Ad vectors, Hanke et al. (1990) expressed either or both subunits simply by infecting target cells with either or both recombinant Ads. This allowed determination of the IgG-binding properties of the individual sub-units as well as of the heterodimeric complex on the surface of the infected cells.

Miscellaneous Applications

Another application for Ad-mediated gene delivery is modulation of the receptor repertoire expressed on the surface of infected cells. Lieber et al. (1995) used an Ad vector to deliver the am-photrophic retrovirus receptor (RAM) cDNA to cells that are normally resistant to infection with the amphotropic retroviral vectors commonly used in gene therapy work. Following Ad infection, target cells were markedly more infectible with a recombinant retrovirus. An Ad recombinant was used to express human CD4 on the surface of a number of CD4-negative cell lines (Yasukawa et al., 1997). In several of these lines, CD4 expression allowed infection by the herpesvirus HHV-7, confirming the role of CD4 in HHV-7 entry.

Use of Heterologous Promoters

Many different promoters have been inserted into Ad vectors and in most cases have retained their activity. Widely used viral promoters include the long terminal repeat of RSV, the SV40 early promoter, and the cytomegalovirus (CMV) major immediate-early promoter. The CMV promoter provides very strong expression of a transgene in many cell types, at least in the short term (Jiang et al., 1996 Guo et al., 1996), and has become perhaps the most widely used promoter in adenoviral vectors. Bartlett et al. (1996) have reported that the constitutively active U1 small nuclear RNA promoter, which is transcribed in essentially all cell types, has activity similar to CMV and is active when placed into an El-deleted Ad vector. A number of groups have sought to target adenovirus-based gene expression to tumor cells. Hepatoma cells often express elevated levels of a-fetoprotein (AFP) relative to normal liver. A recombinant Ad carrying AFP promoter and enhancer sequences driving the herpes simplex...

Vectors with Modified Tropism

Many vectors use the CMV immediate early promoter enhancer, which was chosen on the basis that it directs a high level of transgene expression and is expressed in most tissues studied. However, often expression in a specific tissue or cell type is more desirable and expression in other tissues might be toxic. Therefore, the promoters of genes specific to a cell type have sometimes been used for specific applications (118-120). For example, carcinoembryonic antigen and alpha-fetoprotein (AFP) are tumor-specific antigens that are not expressed by normal cells. When a therapeutic gene is expressed from an Ad vector with an AFP promoter, expression should be confined to specific tumor cells expressing AFP and not normal cells. Kaneko et al. (118) showed this theory to be correct and further demonstrated that the expected selectivity is maintained in vivo. In this context, the vector Av1AFPTK1 expressing thymidine kinase from herpes simplex virus (HSV-TK) from the AFP promoter can prevent...

Regional Connectivity

Moving from connections between individual neurons to connections between brain regions, the most widespread and valuable method delivering detailed information about directed long distance connections is neuroanatomical tract tracing (for reviews see Sawchenko and Swanson 1981 Kobbert et al., 2000 Wouterlood et al. 2002). The general approach comprises now a vast range of substances with the common feature that they are taken up by neurons and spread along their projections, where the label then can be visualized. Some substances are directly inserted intracellularly and therefore suitable for tracing of individual neurons. Most of the tracer substances, however, are applied extracellularly to the living tissue by pressure injection, iontophoresis or mechanical insertion. Most of them are actively incorporated through the neuronal membrane and transported in the cytoplasm to reveal the distant location of cell bodies (fast retrograde transport) or axonal terminals (fast and slow...

What conditions are often missed

This question refers to the common 'pitfalls' so often encountered in general practice. This area is definitely related to the experience factor and includes rather simple non-life-threatening problems that can be so easily overlooked unless doctors are prepared to include them in their diagnostic framework. Classic examples include smoking or dental caries as a cause of abdominal pain allergies to a whole variety of unsuspected everyday contacts foreign bodies occupational or environmental hazards as a cause of headache, respiratory discomfort or malaise and faecal impaction as a cause of diarrhoea. We have all experienced the 'red face syndrome' from a urinary tract infection whether it is the cause of fever in a child, lumbar pain in a pregnant woman or malaise in an older person. The dermatomal pain pattern caused by herpes zoster prior to the eruption of the rash (or if only a few sparse vesicles erupt) is a real trap. Herpes zoster

Glucocorticoids and Behavioral States Reciprocal Determinism

Social psychological influences and the corollary of interdependence. Relations across levels are particularly difficult to conceptualize when the reciprocally interacting nodes extend across broad spans of organization or analysis, as the complexity of mappings tends to increase across more distal levels. A recent line of research in psychoneuroimmunology illustrates this. It has long been recognized that psychological stressors are potent activators of the HPAC system (Mason, 1968, 1975 McEwen, 2000). In contrast to the general adaptation model of Selye (1956), it further appears that there may be fundamental differences in kind among physical and social-psychological stressors. Social reorganization stress in mice (rotation of alpha males among housing colonies) can lead to reactivation of herpes simplex Type 1 virus (HSV1), similar to the stress-related HSV1 reactivation that causes cold sores in humans (Padgett et al., 1998). In contrast, physical stressors (e.g.,...

Implications of the vIL6gp130 Tetramer Structure for the Active Gcsfgcsfr Extracellular Signaling Complex

Cesarman, E., Chang, Y., Moore, P. S., Said, J. W., and Knowles, D. M. (1995). Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas see comments . N. Engl. J. Med. 332(18), 1186-11891. 17. Hoischen, S. H., Vollmer, P., Marz, P., Ozbek, S., Gotze, K. S., Peschel, C., Jostock, T., Geib, T., Mullberg, J., Mechtersheimer, S., Fischer, M., Grotzinger, J., Galle, P. R., and Rose-John, S. (2000). Human herpes virus 8 interleukin-6 homologue triggers gp130 on neuronal and hematopoietic cells. Eur. J. Biochem. 267(12), 3604-3612.

Virally Encoded GPCRs

GPCRs encoded by viruses of the herpes virus family have drawn considerable attention recently because some may provide causative links with respect to the onset or progression of cancer. Various herpes viruses and pox viruses contain DNA sequences encoding proteins with homologies to cellular chemokine receptors.156 Since GPCRs and chemokine receptors play key roles in cellular communications and appear to play roles in cancer, the virally encoded GPCRs are believed to be of great importance in subverting cellular signaling. The Kaposi's sarcoma (KS)-associated herpes virus (KSHV or human herpes virus 8) implicated in the pathogenesis of KS, a highly vascularized tumor, encodes a GPCR designated ORF74 one of the most studied viral chemokine receptors thought to be implicated in the pathology of KS. Since other virally encoded GPCRs, for example, human cytomegalovirus (HCMV) -encoded receptors US28 and UL33,170-172 display constitutive activity and show promiscuous G protein coupling,...

RNAi In Clinical Cancer Therapy

In concept, diseases such as cancer, which are characterized by overexpression or aberrant activation of specific oncogenes, are suitable candidates for nucleic acid-based gene-silencing therapies. Several nucleic acid drugs that are based on ODNs were under clinical trials and Vitravene (sodium fomivirsen) has been used for the treatment of cytomegalovirus (CMV) infection of the eye in clinics (2,3,5). Several ribozyme-based phase I II clinical trials are in early-phase of clinical evaluation for patients with breast cancer, colon cancer, and hepatitis (3). The problems of toxicity and poor clinical efficacy with antisense and ribosome molecules remain to be solved even after more than a decade of drug development attempts. Although the term RNAi was coined just 6 yr ago (23) and the application of siRNAs in mammalian cells was started only three years ago (27,28), RNAi is rapidly taking center stage of the development of nucleic acid-based therapeutics. siRNA-based biotechnology...

Multiple Myeloma 21 Epidemiology

The role for an underlying viral etiology is controversial. In 1997, DNA sequences belonging to human herpesvirus-8 (HHV8 ) were identified in bone marrow dendritic cells and bone marrow biopsy sections of MM patients, analyzed by polymerase chain reaction (PCR) assay and in situ hybridization.14,15 Subsequent studies have yielded conflicting data however, the preponderance of evidence from molecular and seroepidemiological studies suggests there is no definitive association between HHV8 infection and MM.16,17

Richard H Pin md Maura Reinblatt md Yuman Fong md and William R Jarnagin md

The use of viruses to treat human malignancy is not a new concept but has only recently evolved into a clinically viable therapy. Spurred by advances in molecular biology that have allowed relatively easy manipulation of the viral genome, a number of different viruses have been evaluated and shown to have promise as anticancer agents. Of these, herpes simplex virus (HSV) has been perhaps the most intensively investigated. Several strains of replication competent oncolytic HSV have been developed, some of which have been used in clinical trials. Continuing research efforts are aimed at manipulating the viral genome to more specifically target tumor cells, to further enhance efficacy while maintaining safety, and to assess the role of oncolytic HSV in combination with chemotherapy and radiation therapy. Key Words Herpes simplex virus (HSV) oncolytic viral therapy.

Viral Oncolytic Therapy

Herpesviruses are effective against a broad spectrum of human tumors. G207 is a mutant HSV with deletions in both copies of y 4.5, and a mutation in UL39 (Table 1). This attenuated virus was first described in the treatment of malignant gliomas, and further research has demonstrated its efficacy in treating a wide range of tumors types, including breast, bladder, colon, gallbladder, stomach, liver, pancreas, and the oro-digestive tract (10,12-17). In these studies, G207 has been able to effectively kill cancer cells in vitro and reduce experimental animal tumor burdens in vivo. Furthermore, G207 has demonstrated preclinical safety in BALB c mice and Aotus monkeys. In BALB c mice, doses of 1 x 107 plaque-forming units (pfu) of G207 injected intrace-rebrally did not produce any adverse effects (18). Likewise, a dose of 1 x 109 pfu in Aotus monkeys did not result in any pathology (19). Clinical safety has been further confirmed in a phase I clinical trial of patients with malignant...

Transcriptionbased Screening With Reporter Genes

Inducible promoters and response elements are critical tools for the use of reporter gene technology, as they provide the ultimate on-switch that activates transcription of the reporter gene. Promoter activity is controlled or modulated by regulatory regions of the DNA that are usually, but not always, found in the 5' end of the gene. These regulatory regions encode the response elements that act as sensors of activation of a cell signal pathway. Ideally, for screening purposes, the promoter should be strong but controlled by the desired response element in a way that maintains baseline transcription at low levels in the absence of the cell activation. The cytomegalovirus promoter is a strong promoter, but constitutive expression of the reporter gene often leads to high background. The herpes virus thymidine kinase, SV40, and growth hormone promoters have been used in many constructs.

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