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Stop Herpes Now

You'll discover: What foods are bad for you, encouraging outbreaks. What foods are good for discouraging outbreaks. The connection between genital herpes and stress. What herbs actually suppress the herpes virus. How to heal your body naturally and safely. How to manage stress in your life.

Stop Herpes Now Summary


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Author: Dr. David Hogg
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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

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...

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...

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...

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...

HHV6 Genome Similar and Different

Hhv6 Treatment

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...

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 the...

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...

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...

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...

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 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...

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...

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.

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...

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...

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

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

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...


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.


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.


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 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.

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...

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).

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...

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.

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

Penis Schingles

Penis Schingles

Before an aetiologic role is assumed 18 . Using quantitative PCR (fig. 2) it is possibly to find low numbers of genome copies in latently infected ganglionic cells without showing infectious virus forms or subsequent disease 14, 19, 20 . For special cases a molecular characterisation of VZV isolates can be ruled out by DNA sequencing, which allows to ascertain relatedness of different clinical isolates and detection of some acyclovir resistant mutations 21, 22 . Virus isolation in cell culture remains, in cases of positive testing, the most reliable method for the proof of infectious virus. It is less sensitive than direct immunofluorescent antibody staining, since viable virus persists shorter in vesicles and is more labile than viral antigen 23 . Usually results of viral cultures cannot be obtained fast enough to influence clinical decisions, but they can confirm diagnosis of VZV infection made by other methods, e.g. the antigen assay 24 . In addition, drug resistance of virus can...

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...

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...


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.''

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...

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...


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...

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...

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...

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...

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,...

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...

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.


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...

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...


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...

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.

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...

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...

Other Clinical and Preclinical In Situ Cytokine Gene Therapy Approaches

Delivery of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene in either a herpesvirus vector (83) or a canarypox vector (84) has been explored in preclinical models. The GM-CSF gene was combined with IFN-a gene for liposomal delivery in a bladder cancer model (85).

Antenatal and Postnatal Infection and CLD

Viral infections, particularly with adenovirus or cytomegalovirus (CMV) have been associated with the development of CLD. Sawyer et al. (1978) identified 32 infants born with a birth weight less than 2000 g as being infected with CMV over a five year period. Of these 24 (75 ) went on to develop CLD compared to 12 of

Clinical Evidence for Deficiencies of TCell Mediated Immunity in the Neonate

Cytomegalovirus (CMV) is a ubiquitous herpes virus that ultimately infects 50-90 of the population. For the vast majority of children and adults, infection, which usually occurs after mucosal contact with bodily secretions, is either asymptomatic or results in a self-limited non-specific viral syndrome characterized by fever, hepatosplenomegaly, leukopenia, and myalgias (Gandhi and Khanna, 2004). During active infection, virus is shed from mucous membranes and is detectable in both urine and saliva. Cell-mediated immunity is essential for control of the disease, and onset of T-cell immunity in results in resolution of viremia, although latent virus can be detected in tissues for life (Harari, 2004). In adults, severe systemic disease is seen only in settings of substantial immunodeficiency, such as concurrent HIV infection or following hematopoietic stem cell transplantation, where infection can result in pneumonitis, hepatitis, retinitis, and other organ dysfunction (Gandhi and...

Peptide Binding Versus Adjuvanticity

The Van Eden laboratory has proposed that some HSP can play an important role in regulating immune responses by inducing a regulatory phenotype in T-lymphocytes which helps to control potentially damaging autoimmune responses (Wendling et al., 2000). The potentiation of immune responses to chaperoned peptides may reflect a balance between the generation of IL-10 secreting regulatory T-cells specific for HSP epitopes versus effector cells specific for the chaperoned peptide (van Eden et al., 2003). In a previous study, a role for Mycobacterial Hsp70 in the DC mediated cross-presentation of viral peptides derived from Influenza A (Inf A) and human Cytomegalovirus (huCMV) was shown to be dependent on the induction of an intracellular calcium signaling cascade within the DC, and not on the direct stimulation of the cells to produce cytokines and chemokines. However, the provision of a second signal mediated by effector T-cell DC interactions, greatly augmented the HSP effect on the DC...

Stable Gene Transfer Vectors

In lentiviral vectors, have been generated by deleting promoter and enhancer sequences from the U3 region of the 3' LTR (23-25). Following reverse transcription, this modification is duplicated to form the 5' U3 region. Thus, promoter and enhancer functions are effectively removed from both proviral LTRs. SIN vectors are a major improvement in safety, as they reduce the capacity for recombination or rescue from exogenous virus, and deletion of the 3' U3 sequences may reduce the frequency of insertional activation. Transgene expression in SIN vectors is achieved by the insertion of an internal promoter, a range of which have been evaluated for HSC gene therapy, including the ubiquitous cytomegalovirus (CMV), elongation factor 1a (EF-1a), and phosphoglycer-ate kinase (PGK) promoters (17,26). Vector comparisons utilizing the green fluoores-cent protein (GFP) reporter indicate that the EF-1a promoter provides the most robust multilineage hematopoietic expression levels (26). Additional...

FIGURE 19 Aphthous ulcers Source Courtesy of the International AIDS SocietyUSA From Refs 3 4

KS has been strongly associated with human herpes virus Type 8 (HHV8), also known as KS-associated herpes virus, believed to be transmitted orally. Recurrent Aphthous Ulcers. Aphthous ulcers of unknown etiology are relatively common in HIV disease, becoming more severe with worsening immunosuppression. Contrary to those found in the general population, aphthous ulcers (canker sores) are often large and not of the minor (herpetiform) type in HIV-infected persons. They can persist for weeks or even months, causing severe pain and disability with resultant malnutrition, which further complicates the problem. Empiric therapy with high-dose acyclovir usually fails. Most often, biopsy and cultures are performed to exclude specific treatable causes such as fungal or viral infection (especially CMV). In most cases, no etiologic agent is found (3). Topical treatment with steroid paste (Lidex) can sometimes be useful, but large lesions require more aggressive management, and oral thalidomide...

Gastrointestinal Conditions Associated With Spasm And Nervousness

HERPES SIMPLEX TYPE I EXTERNAL USE The topical use of lemon balm preparations for HSV Infection Is very popular In Europe. Results from a randomised double-blind study In 66 subjects with a history of recurrent herpes lablalls ( 3 episodes year) found that standardised lemon balm ointment (700 mg crude herb per gram) applied four times dally for 5 days significantly shortened healing time, prevented Infection spread and produced rapid symptom relief (Koytchev et al 1999). Decreased symptoms and Increased rate of healing were also observed In another double-blind study of lemon balm cream In 116 subjects (Woelbllng & Leonhardt 1994).

Targeting Genetic Vaccines

One of the most commonly used mammalian promoters in genetic vaccines is the cytomegalovirus promoter (pCMV). This is an extremely strong viral promoter that is capable of mediating high levels of antigen expression in many cell types. However, some of the expression products in a genetic vaccine, such as the immunomodulating

Continuing maintenance consultations

Wasting and neurological signs. o Examine for signs of cytomegalovirus retinitis. o Look for early signs of AIDS-related dementia. Tests o chest X-ray and induced sputum (if cough, SOB), faeces microculture if diarrhoea persists, Candida mouth swabs and herpes swabs appropriately Treat intercurrent illness (Table 24.6).

Special entities of lymphoma

There is a characteristic close association with the herpes virus HHV-8, which can be detected in the malignant cells. Recently, a solitary variant has been reported, which is neither morphologically nor immunophenotypically distinguishable from the classical PEL types (Chadburn 2004). The response to CHOP is usually poor and poorer than that of centroblastic NHL (Simonelli 2003). Case studies with complete remission on HAART alone have been described (Boulanger 2001, Hocqueloux 2001). We have, however, seen two PEL patients who have also died of progression despite CHOP and HAART after only a few months.

Biology of AAV Life Cycle

Virus, generally an adenovirus or a herpes-virus (1). AAV has both a broad host range and wide cell and tissue specificity, and replicates in many cell lines of human, simian, or rodent origin provided an appropriate helper virus is present. There may be some limitations to AAV tissue specificity in vivo or at least some significant differences in efficiency of transduc-tion of different tissues and organs. These limitations may reflect the receptor and coreceptors apparently used by different AAV serotypes for entry into cells as well as cellular trafficking of AAV. This aspect of AAV biology is becoming of increasing importance for development of AAV vectors. A second set of parameters that may impact AAV tissue and organ specificity and its replication reflect the nature of the helper function provided by helper viruses.

Potential Side Effects

Risk of wild-type virus recombination (reversion) is another concern. Whereas herpesvirus can be eliminated by acyclovir, effective antibiotics are not readily available for other virus species, and the sequelae of circulating wild-type virus in patients are largely unknown, especially with HIV-based lentivirus. Although recombination has not been shown in preclinical and clinical studies, patients undergoing viral vector-mediated gene therapy should be closely monitored for replication-competent and wild-type virus recombination.

Combining Viral Oncolysis With Delivery ofAnticancer Genes

Several groups have constructed genetically engineered oncolytic viruses encoding a prodrug-converting enzyme. These enzymes convert nontoxic prodrugs into cytotoxic metabolites and are often soluble to allow for spreading within the tumor. Using this approach, a tumor-selective herpes virus was engineered encoding the rat cytochrome P450 (CYP2B1) transgene (62). This liver enzyme activates the prodrug cyclophosphamide into an active anti-cancer and immunosuppressive metabolite (63). Addition of cyclophosphamide potentiated oncolytic effects of this HSV mutant against cultured tumor cells and subcutaneous tumor xenografts established in athymic mice (62).

AIDSHuman Immunodeficiency Virus

Central nervous system disease is present in 69 of cases, with the peripheral nervous system affected in 8 of HIV cases. Of the peripheral nervous system dysfunctions, the facial nerve is most common, found in approximately 5 of patients (61). A similar study of 170 AIDS patients found a 4.1 incidence of facial paralysis (62). Facial paralysis is abrupt in onset and usually unilateral (63). The mechanism of facial nerve injury may be a direct effect of the neurotropic virus, secondary involvement due to parotid or other neoplastic processes, or immunosuppression leading to reactivation of herpes zoster or other viruses. Multidrug therapy is the current standard therapy for HIV infection. Reverse transcriptase and protease inhibitors are effective and block HIV replication fusion inhibitors are also used and block HIV entry into the cell. The prognosis for facial paralysis is good, with the majority of patients having complete or near-complete recovery of facial function (64).

Delivery Vehicles For Local And Systemic Gene Therapy

Currently, targeted gene delivery can be achieved in one of two ways by delivering the gene of interest selectively to target cells (vector targeting), or by creating vector constructs with tissue-specific promoters such that the delivered genes can only be expressed in certain cell types (cell- or tissue-specific gene expression). Moreover, viral vectors employed for gene therapy of human gliomas can be further divided into replication defective vectors and conditionally replicative vectors. A great deal of effort has been generated toward the use of viral agents as nonreplicating vectors for gene insertion in treating cancers. Renewed interest in the use of viruses as oncolytic therapy was sparked with the development of a herpes simplex virus (HSV) containing an inactivating mutation in the thymidine kinase gene (11). With the demonstration of a replicating virus, capable of infecting neoplastic cells, producing progeny, and lysing the host cell, came excitement over the...

Medical Importance of the PPP Family

Used immunosuppressive drugs cyclosporin and FK506 (see Chapter 101). In addition, DNA tumor viruses (SV40 and polyoma virus) and HIV-1 have been shown to compromise the function of PP2A by producing proteins that compete with specific regulatory subunits 17 . Somewhat similarly, the dsRNA virus herpes simplex produces PP1-binding proteins that recruit Ppp1c from host cell complexes in order to enhance its own replication and evade host cell defense mechanisms 25 .

Differential Diagnosis

In NUG, the interdental papillae undergo necrosis beginning at the tips and extending toward the crest of the dental alveolar bone. As a result of the soft-tissue necrosis, the interdental gingival papillae exhibit a punched out blunted, crateriform area covered by a fibrinonecrotic membrane (Fig. 39). The gingiva are exquisitely sensitive and often exhibit spontaneous bleeding. A fetid odor accompanies the soft-tissue necrosis. There may be associated systemic symptoms of fever, malaise, and lymphadenopathy. Primary herpetic gingivostomatitis also presents with exquisitely sensitive gingiva, but there is neither necrosis nor the characteristic fetid oral odor (36). Primary herpes simplex also involves the nonkeratinized oral mucosa, while NUG is confined to the gingiva.

Transgenic Paradigms for Achieving Cell Specific Ablation

Cell lineage has also been investigated through use of a vector encoding thymidine kinase of herpes simplex virus 1 (HSYTK). In contrast to the mammalian enzyme, HSVTK has the capacity to phosphorylate nucleoside analogues such as acyclovir, gancyclovir, or FIAU Incorporation of any one of these analogues into replicating DNA causes chain termination and ultimately blocks cell replication (Borrelli et al., 1988, 1989 Heyman et al., 1989). The advantage of this approach is that the viral enzyme is usually not harmful until the animals are treated pharmacologically with a nucleoside analogue. This permits temporal control over cell-specific ablation. One disadvantage, however, is that nonreplicating cells may not be responsive, implying the need to start treatment early in fetal life, although there have been instances where ablation was obtained in adult animals thyrotropes (Wallace et al., 1991) and gonadotropes (Markkula et al., 1995) . There may also be situations where transgenic...

Complementation Systems

Herpes simplex virus also can be used in production of AAV vectors by generating 2 types of HSV AAV hybrid viruses. One approach (117,118) uses an HSV AAV hybrid virus in which the AAV rep-cap genes, under control of their native promoters, were inserted into the HSV genome. This HSV AAV rep-cap virus could generate AAV vector when

Dopamine Synthesis Gene Therapy

Later studies accomplished the delivery of such genes directly to striatal cells with viral agents. A study by During et al. demonstrated that direct striatal transmission of tyrosine hydroxylase to rats by defective herpes simplex virus (HSV) produced substantial increases in levodopa and dopamine (as measured by striatal microdialysis), and produced a 60 reduction in amphetamine-induced spinning behavior which was maintained for a full year after treatment (86). Another study demonstrated the adeno-associated virus (AAV) delivery of aromatic amino acid decarboxylase (AADC) in a rat model of PD. Transfer of the AADC gene restored dopamine production from 5 to 50 of normal in 6-OHDA-lesioned rats. In these rats, behavioral effects were also noted, but this required the administration of systemic levodopa, although in smaller doses (87).

Genetic Delivery of Neurotrophins

Numerous studies have demonstrated success of viral GDNF therapy in rats. Several viral vectors have been used to deliver GDNF to the striatum and SNc, including adenovirus, AAV, herpes virus, and lentiviruses. Of these, herpes viruses were noted to be problematic, providing only limited benefit and demonstrating significant toxicity related to purification methods (97). The other models have demonstrated the ability to generate stable and sufficient quantities of GDNF, to maintain or restore tyrosine hydroxylase activity, and, in several cases, to improve parkinsonian behavioral correlates (98,99).

Chromosome Engineering In The Mouse

In addition to Cre-loxP-mediated chromosome engineering, other approaches have been developed to generate chromosome rearrangements. One of these approaches is to irradiate F1 hybrid mouse ES cells (36). The irradiated ES cells have a negative selection marker, Herpes simplex virus thymidine kinase (HSV-TK), targeted by homologous recombination to a defined locus. If deletions caused by irradiation encompass the TK-tagged locus, the cells will survive in medium. The advantage ofthis approach is that from a single experiment, multiple deletions of various sizes centered on the tagged locus can potentially be recovered. These deletions are useful for estimating haploinsufficiency tolerance of various chromosome regions in ES cells and may be used directly for in vitro genetic screens (37). Importantly, ES cells carrying these irradiation-induced deletions still retain their ability to contribute to germline development in chimaeras. Thus, large genomic deletions from these experiments...

Flow Cytometric Analysis of Antigen Specific T Cells Using PeptideMHC Tetramers

Recently, it has become possible to directly visualize antigen-specific T cells by using soluble multimeric MHC-peptide complexes. In 1997, Altman and Davis (31) demonstrated that flourescently labeled, tetrameric peptide-MHC complexes could indeed bind stably, specifically, avidly to antigen-specific T cells. Another methodology for multimer generation involves using an antibody to link two peptide-MHC complexes, forming peptide-MHC dimers, often termed MHC-Ig complexes (32,33). In theory, only T cells with receptors specific for the peptide used in the complex will be recognized by these approaches. Using standard flow cytometric analysis, one can gate on the T cells and look for expression of the antigen-specific TCR. Analysis of peripheral blood T cells specific for potent immunogens such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV) demonstrated that between 0.2 and 6 of circulating CD8+ cells were specific for peptides representing these antigens. The quantitation of...

Preclinical p202 Gene Therapy Studies

(polyethylenimine) complex into MCF-7 cells greatly inhibited tumor growth as compared with PEI alone in estrogen-supplemented nude mice (74). Based on this encouraging result, we then developed a systemic delivery system that would allow delivery of p202 gene through intravenous (iv) injection to the primary and metastasized tumor sites. To this end, we undertook two approaches and compared the efficacy of systemic p202 gene therapy treatment using either a p202-expressing recombinant adenovirus (Ad-p202) or CMV-p202 SN2 liposome complex in an orthotopic MDA-MB-468 breast cancer xenograft model. CMV-p202 is a p202 expression vector driven by a cytomegalovirus (CMV) promoter. SN2 liposome formulation has been tested and shown to be an efficient gene delivery system in systemic gene therapy models (47). The tumor growth was significantly reduced in both Ad-p202 and CMV-p202 SN2 treatment groups (79), (Wen and Hung, unpublished data). These results strongly suggest the feasibility of a...

Host Responses And Toxicity

Immune responses to the transgene expressed by an AAV vector vary and may depend on the route of delivery. Both MHC class II-restricted antibody responses and MHC class I cytotoxic T lymphocytes have been reported, but this may vary with the route of administration (199). In some studies, such as intramuscular delivery in mice, there was no immune response to an expressed foreign reporter gene such as bacterial p-galactosidase, and it was suggested that AAV may be a poor adjuvant or may not readily infect professional antigen-presenting cells in muscle (202,203). However, an AAV vector expressing the herpes simplex virus type 2 gB protein was delivered intramuscularly into mice and elicited both MHC class I-restricted CTL responses against the gB protein and anti-gB antibodies (204). Following intramuscular delivery of an AAV human factor IX vector (205,206), there was an antibody response but not a CTL response against the FIX protein. The rules governing immune responses to foreign...

Treatment of gastrointestinal viruses

The most common enteric viruses responsible for diarrhoea are rotavirus, enteric adenoviruses, caliciviruses including the Norwalk agent and astrovirus. These infections are usually mild to moderate in severity, self-limiting and of short duration and thus, specific antiviral therapy is not recommended. The standard management of these infections is restoration of fluid and electrolyte balance and then maintenance of hydration until the infection resolves. WHO oral rehydration therapy (ORT) was introduced about 30 years ago and has saved the lives of many infants and young children. During the last 10 years it has become evident that the efficacy of ORT can be increased by reducing the osmolality of the WHO oral rehydration solution (ORS) to produce a relatively hypotonic solution. Hypotonic ORS appears to be safe and effective in all forms of acute diarrhoea in childhood. Complex substrate ORS, which is also usually hypotonic, has been shown to have increased efficacy in...

Vector construction and protein expression

To test whether vaccination with a DNA plasmid encoding a M. tuberculosis antigen could result in induction ofimmune responses, we constructed a vector containing the gene for antigen 85A (Ag85A). The vector backbone, termed V1Jns, contains the immediate early promoter and enhancer from cytomegalovirus (with intron A) and the transcription terminator from bovine growth hormone (Montgomery et al 1993, Shiver et al 1995), and had previously been shown to give high levels of expression for several different antigens and reporter proteins (not shown). The native mycobacterial signal sequence from Ag85A was replaced with the eukaryotic signal sequence from tissue-specific plasminogen activator protein, in order to facilitate expression and intracellular trafficking in eukaryotic cells. This

Specific interventions for gastrointestinal virus infections

Viral oesophagitis due to infection with herpes simplex virus (HSV) or cytomegalovirus (CMV) and CMV colitis are found most commonly in individuals with HIV infection. These infections in the immunocompromised host require treatment with antiviral agents. In severely symptomatic patients with HSV oesophagitis, aciclovir 5mg kg should be given intravenously every 8 hours for 7 10 days (Genereau et al 1996). In these patients oral maintenance therapy with 400 mg aciclovir orally twice daily should probably also be given. Milder infections may respond to oral aciclovir. When HSV is resistant to aciclovir an alternative therapy is foscarnet 40 60 mg kg intravenously every 8 hours for 2 3 weeks.

Transfer of Suicide Genes

Another gene therapy strategy involves the transduction of tumor cells with a gene capable of converting a nontoxic compound into a toxic metabolite. The two most commonly used genes for this are the herpes simplex thymidine kinase gene (HSV-tk) and the cytosine deaminase gene. HSV- tk that convert non-toxic ganciclovir to a cytotoxic triphosphate metabolite, and cytosine deaminase converts 5-fluorocytosine to the cyto-toxic antimetabolite 5-fluorouracil. This strategy could potentially lead not only to the killing of the transduced cells, but also to the killing of adjacent cells in a bystander effect so that only a fraction of the targeted cells are needed to be transduced for eradication of the tumor (3). Potential limitations with the transfer of suicide genes include toxicity to normal cells that are transduced at the same time. These problems may be addressed by gene transfer strategies, that selectively target tumor tissue. One strategy to selectively target lung cancer cells...

Adenovirus use in cancer vaccine strategies

With so much known about Ad biology, it was a natural step to use recombinant Ad for vaccination purposes. As a first example, E1- Ad vectors have been engineered that express genes encoding epitopes (or whole proteins) derived from a number of pathogens, including (but not limited to) malaria, bovine herpesvirus (type 1), foot-and-mouth

Reactive Lymphocytosis In Common Disease States

Reactive Lymphocytes Pics

It is normal for young children between the ages of 1 and 4 to have a relative lymphocytosis. The white cell differential in this age group will show a reversal in the number of lymphocytes to segmented neutrophils from the adult reference range. The lymphocytes, however, will have normal morphology (Fig. 10.11). By far the most common disease entity displaying variation in lymphocytes is infectious mononucleosis. This is viral illness caused by the Epstein-Barr virus (EBV), a member of the human herpes virus family, type 4. Although young children may become infected with EBV, the virus has a peak incidence at around 20 years of age. Most adults have been exposed to EBV by midlife, and this is recognized by demonstratable antibody production whether or not they have had an active case of infectious mononucleosis. The virus is found in body fluids, especially saliva, and is frequently passed through exchanges such as kissing, sharing food utensils, or drinking cups. The virus, which...

What Is Bystander Effect In 5-fu

FIGURE 23.1 Herpes simplex virus thymidine kinase (HSVtk) ganciclovir (GCV), monophosphate (MP) triphosphate (TP). in culture and in vivo 20 . Possible explanations for radiation enhancement is that DNA which has incorporated acyclovir may be susceptible to radiation-induced strand breakage, and or acyclovir might sensitize cells by inhibiting polymerase activity required for the repair of radiation-induced DNA damage. Several strategies have been developed in attempting to improve tumor cell killing. One method involves generating novel and enzymatically enhanced HSVtk mutants to induce an increased sensitivity to GCV in transfected cells 21 . The delivery of GCV was also improved by using biocompatible silicones that were directly implanted into the gliomas of experimental rodent models. The results revealed a hundredfold drug concentration over GCV that had been administered intraperitoneally 22 . One approach using a replication-defective herpes simplex virus type 1 vector...

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