Hepatitis Ebook

Alternative Hepatitis C Treatments

The therapeutic goals of Natural treatment for Hepatitis C are as follows: Decrease iral load Normalize liver enzyme levels. Enhance/regulate immune system function. Strengthen and promote healthy liver function. Protect the liver, prevent further damage. Virological response; i.e. viral clearance, viral reduction or elimination of the virus. Starve the virus by limiting levels of iron. Optimizing cellular levels of glutathione in the body, making detoxification of the liver possible and enhancing the immune system. Stimulate regeneration of the damaged liver cells. Use of antioxidants to combat the effects of free-radicals generated by the virus. Reduce inflammation. Slow viral replication. Replace all of the inflammation-damaged liver cells. Regulate immune function/prevent auto-immune problems. Cancer preventative measures. Reverse fibrosis to prevent and improve cirrhosis

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Mechanisms of Interferon Action and Resistance in Chronic Hepatitis C Virus Infection Lessons Learned from Cell Culture

Abstract Alpha interferon, usually in combination with ribavirin, is currently the standard care for patients infected with hepatitis C virus. Unfortunately, a significant number of patients fail to eradicate their infection with this regimen. The molecular details concerning the failure of many patients to achieve sustained clearance of the virus infection after interferon therapy are currently unknown. The primary focus of this chapter is to provide an overview of interferon action and resistance against hepatitis C virus (HCV) based on our understanding developed from in vitro experiments. Interferon first binds to receptors on the cell surface this initiates a cascade of signal transduction pathways leading to the activation of antiviral genes. Using a cell culture model, we determined that the activation of an interferon promoter (interferon inducible genes) is important for a successful antiviral response against HCV. The level of activation of the IFN promoter by exogenous...

CD4 T Cells During Acute and Chronic HCV Infection CD4 T Cells in Acute Infection

Most studies investigating CD4+ T cell responses in HCV have been performed using human peripheral blood mononuclear cells (PBMC). Early studies have suggested that most patients in whom the virus persists develop a defective blood CD4+ T cell response to the recombinant HCV proteins' core, nonstructural protein 3 (NS3), NS4, and NS5 during the acute phase of the disease (Diepolder et al., 1995) (Figure 2). In contrast, individuals who resolve infection exhibit robust HCV-specific CD4+ T cell proliferation (Figure 3). Although there are some exceptions (Thomson et al., 2003), these results have been confirmed in subsequent studies Fig. 2 Schematic representation of the evolution of HCV infection and of the cellular immune response in individuals developing persistent infection. Dashed lines and question marks represent hypothetical pathways of activation or regulation Fig. 2 Schematic representation of the evolution of HCV infection and of the cellular immune response in individuals...

Early Events Influencing the Outcome of HCV Infection

Several studies have characterized anti-HCV immune responses during the acute phase of infection when both CD4+ and CD8+ T cells are detectable, in an attempt to determine whether there are differences that distinguish self-limiting versus persisting infections. Although these studies have provided important information on the breadth and repertoire of these responses, it is tempting to speculate that differences

Hepatitis C Virus and Hepatocellular Carcinoma

As early as the days of Hippocrates, hepatitis has been described as a disease that occurs in the young and shows the cardinal symptom of jaundice, which sometimes develops into a critical condition. Ironically, research on hepatitis progressed rapidly during World War II because injuries and the terrible sanitary conditions of the battlefields caused serious hepatitis epidemics. People recognized that hepatitis could be classified into two types infectious and serumal. The former became known as hepatitis A and the latter as hepatitis B. After the war, the hunt for hepatitis viruses had begun. First, the hepatitis B virus (HBV) was identified in 1967 by Blumberg, who was awarded a Nobel Prize in recognition of his discovery. Next, the hepatitis A virus (HAV) was discovered in 1973. These discoveries were thought to have clarified the causes of hepatitis, but by the following year, it was acknowledged that many cases of hepatitis were not caused by either HAV or HBV (Prince et al.,...

Hepatitis Delta Virus

The cover illustration is a simplified structure of hepatitis delta virus showing the internal ribo-nucleoprotein complex, which contains the circular RNA genome and the two forms of the hepatitis delta antigen the envelope proteins ofhepatitis B virus form the exterior of the virus. The inset is an electron micrograph of purified hepatitis delta virus particles, and was kindly provided by Dr. John Gerin. The background immunofluorescence image is oftransfected cells expressing hepatitis delta antigen, and was kindly provided by Dawn Defenbaugh.

Functional Analysis by HCVpp Assay

Because they incorporate envelope glycoproteins from heterologous viruses and integrate and express reporter genes from defective genomes, retrovirus vectors have been very useful in investigating the mechanisms by which various viruses attach and enter their target cells (21-23). The retrovirus-based HCVpp assay described in this chapter, developed by Bartosch et al. (10), Fig. 6. Immunoprecipitation of the E1E2 hetrodimer. Radiolabeled proteins from the cell extracts (CE, panels A and C) and medium (HCVpp, B and D) of HEK 293-T cells co-transfected with the MLVgag-pol + MLV-GFP (lane 2) + a plasmid expressing E1E2 derived from HCV genotype 1a (lane 1) were immunoprecipitated using an anti-E2 MAb AP33 and the immune complexes analyzed under reducing and non-reducing conditions as shown. Aggr, aggregate. Fig. 6. Immunoprecipitation of the E1E2 hetrodimer. Radiolabeled proteins from the cell extracts (CE, panels A and C) and medium (HCVpp, B and D) of HEK 293-T cells co-transfected...

Hepatitis Delta Book Rizetto

Hepatitis delta virus (HDV) has been recognized to be an important cause of acute or chronic hepatitis in humans. HDV infection may occur as coin-fection with hepatitis B virus (HBV) or as superinfection of a chronically HBV-infected patient (Rizetto et al. 1984). The course of simultaneous infection is similar to HBV infection alone and clearance of HBV is accompanied by elimination of HDV. HDV superinfection of chronically HBV-infected patients results in chronic HDV infection in more than 80 of cases. This often progresses rapidly to liver cirrhosis and hepatocellular carcinoma (Fattovich etal. 1987). Vaccination studies might also give insight into the role of the immune response in HDV infection. Woodchucks chronically infected with woodchuck hepatitis virus (WHV) can be superinfected with HDV and therefore can be a good model to test vaccine candidates. Different strategies have been investigated to establish a protective vaccine against HDV superinfection. Synthetic peptides,...

Role of the Innate Immune System During HCV Infection

Of events leading to innate intracellular immunity. In the case of HCV, the double-stranded RNA initiates two major pathways of host defense by binding to Toll-like receptor 3 and retinoic-acid inducible gene I (RIG-1) reviewed in (Gale & Foy, 2005) . Several reports in both chimpanzee and humans indicate that the virus activates the innate immune response before and during acute infection by inducing secretion of endogenous type I interferon (IFN-a and - ) and by activating NK cells. Analysis of gene microarray experiments from experimentally infected chimpanzee liver biopsies has revealed the induction of a broad range of IFN-a inducible genes (ISGs) (Bigger et al., 2001, 2004 Su et al., 2002), including some involved in the regulation of NK cells, confirming the induction of IFNs during the course of acute infection. Expression of IFN has three major roles (1) to induce ISGs that have an antiviral action (2) to induce the maturation of immune effector cells and (3) to create a...

RNA Editing in Hepatitis Delta Virus

Abstract Hepatitis delta virus (HDV) relies heavily on host functions and on structural features of the viral RNA. A good example of this reliance is found in the process known as HDV RNA editing, which requires particular structural features in the HDV antigenome, and a host RNA editing enzyme, ADAR1. During replication, the adenosine at the amber W site in the HDV antigenome is edited to inosine. As a result, the amber stop codon in the hepatitis delta antigen (HDAg) open reading frame is changed to a tryptophan codon and the reading frame is extended by 19 or 20 codons. Because these extra amino acids alter the functional properties of HDAg, this change serves a critical purpose in the HDV replication cycle. Analysis of the RNA secondary

Memory T Cells in HCV Infections

Humans and chimpanzees resolving HCV infection develop acute hepatitis characterized by expansion of both CD4+ and CD8+ T cells and control of viremia. In these individuals, T cell numbers increase and then decrease as in other cellular immune responses. These individuals sometimes develop a resurgence of HCV replication that might reflect transient viral escape before the establishment of a stable memory CD4+ and CD8+ T cell pool (Bowen & Walker, 2005a) (Figure 3). Once established, T cell memory lasts for many years (Lechner et al., 2000 Takaki et al., 2000 Chang et al., 2001 Day et al., 2002, 2003b Rosen et al., 2002 Wertheimer et al., 2003) even when antibodies to HCV can no longer be detected in serum. As it is the case for several viral infections, it is not clear whether memory T cells persist in the total absence of HCV or whether there is a reservoir of HCV that maintains the memory response. Memory T cells identified in the blood using MHC tetramers are present at extremely...

Hepatitis Delta Virus Background

HDV was discovered following the detection of a novel antigen-antibody system in hepatitis B virus (HBV) carriers (Rizetto et al. 1977). Currently, HDV is classified as a subviral satellite of HBV due to an obligate relationship with HBV infections in nature. However, unlike other satellite viruses, the dependence of HDV on HBV is limited solely to the provision of an envelope of hepatitis B surface antigen for virus assembly. Nevertheless, this dependence requires that natural HDV infections occur as either a co-infection with HBV or as a super-infection of HBV carriers, with the resultant disease usually being more severe than that with HBV alone. Following HDV infection, the

Pathogenesis of HHV6associated hepatitis

As described above, HHV-6 can directly cause hepatitis, but its mechanism of liver injury is unknown. HHV-6 may directly damage hepatocytes, or the immune and inflammatory response to the virus may cause liver damage. HHV-6 DNA, RNA, and antigens were detected in the hepatocytes of affected livers by in situ hybridization analysis (Mason et al., 1996 Ozaki et al., 2001 Ishikawa et al., 2002). These observations strongly suggest HHV-6 has the potential to directly damage he-patocytes during active infection. HepG2 cells, a well-differentiated liver cell line, are permissive for HHV-6 infection (Cermelli et al., 1996 Inagi et al., 1996). Infected HepG2 cells produce HHV-6 antigens and infectious viral progeny. Moreover, HHV-6 infection leads to the release of transaminase, a marker of liver cell damage (Cermelli et al., 1996). Inflammatory cytokines likely play an important role in the observed liver dysfunction, and the development of viral hepatitis is closely associated with the...

Role of MHC Haplotype in HCV Persistence

It is unlikely that the outcome of the immune response is entirely genetically determined. For CD4+ T cells, it is possible that the MHC class II haplotype and thus the range and type of epitopes that are targeted during the immune response play some role in HCV persistence. Some MHC class II allotypes, such as HLA-DR 1*0701, have been associated with HCV persistence (Fanning et al., 2001), while other allotypes (DR 1*0101, HLA-DR 1*1101, and DQ 1*0301) are linked to sustained T helper response and or a self-limited disease (Alric et al., 1997 Minton et al., 1998 Thursz et al., 1999 Harcourt et al., 2001). Likewise, the CD8+ T cell response during acute hepatitis does not seem to be preferentially biased toward any particular HCV protein or epitope. Some MHC class I allotypes, such as HLA-Cw*04, have been associated with HCV persistence (Thio et al., 2002) and HLA-B27 with protection (Neumann-Haefelin et al., 2006). However, some studies (Cooper et al., 1999 Lauer et al., 2002...

Some Fundamental Aspects of HCV Infections

One of the most striking characteristics of the adaptive immune response to HCV is the inability of this response to mediate viral clearance in the majority of infected individuals, thus enabling viral persistence and ensuing chronic necroinflammatory liver disease. The outstanding question that arises from our current knowledge of the adaptive immune response to HCV could be summarized as follows Why does infection persist in the majority of individuals despite a detectable immune response in many, while some individuals control viremia and resolve infection Obviously, this is a very complex issue, with multiple mechanisms potentially involved in inhibition of the induction and maintenance of an effective anti-HCV immune response. However, any model of defective anti-HCV immunity needs to take into account the following observations 1. There is no general immunosuppression associated with HCV infections. Critically, the inability to mount an effective immune response against HCV is...

NK Receptor Expression in Chronic Hepatitis C Patients

There is no established view of NK activity in patients with HCV some researchers have reported decreased NK activity in HCV patients, while others have reported levels equivalent to those of healthy individuals (Ahmad & Alvarez, 2004 Golden-Mason & Rosen, 2006). In order to evaluate the function of NK cells in patients with HCV, we separated CD56-positive cells from the peripheral blood of patients with HCV and healthy donors and examined their cytotoxic activity. To K562 cells, a classic NK-sensitive target, CD56-positive cells in patients with HCV showed the same level of cytotoxic activity as those in healthy donors, but to hepatoma cell lines, the cytotoxic activity of CD56-positive cells decreased in patients with HCV. This suggests that the NK-cell receptor expression profile might differ between patients with HCV and healthy individuals. We next comprehensively analyzed NK receptor expression in CD56-positive cells using FACS. The results showed that for KIR, among the...

HIV and HCV Coinfection Epidemiology and Transmission

Coinfection with HIV and HCV occurs frequently, due to the fact that both are transmitted via the same pathways (parenteral, sexual, vertical). 240,000 people (30 of HIV-infected individuals) are estimated to be infected with both viruses in the USA. Several European countries have even higher rates of coinfection. In Spain, at least 50 of the 130,000 HIV-infected patients are also HCV-positive as a result of the high incidence of i.v. drug users. More than 90 of coinfected individuals are positive for HCV RNA, i.e. have chronic hepatitis C. As HCV is ten times more infectious than HIV on blood-to-blood contact, intravenous drug users and recipients of blood products are particularly susceptible to coinfection. For example, on routine testing of blood products from HIV-infected hemophiliacs treated before the discovery of HCV in the early nineties, HCV antibodies and HCV RNA were detected in the serum of over 90 of patients. The probability of transmission from needlestick injuries...

The Role of the Adaptive Immune Response During HCV Infection

Seroconversion in HCV occurs approximately 7 to 31 weeks after primary infection (Pawlotsky, 1999, 2004), and some HCV-specific antibodies are effective in blocking in vitro infection of target cells by HCV (Farci et al., 1994). However, in both chimpanzees and humans, naturally acquired anti-HCV antibodies generated during this infection do not seem to be protective upon secondary infection with HCV, indicating that these molecules play a limited role in preventing the spread of the virus (Farci et al., 1992 Lai et al., 1994). Moreover, studies in chimpanzees indicate that resolution of infection can occur without the development of detectable antibody responses (Cooper et al., 1999). In addition, recent studies using HCV pseudotyped particles indicate that neutralizing anti-HCV antibodies occur far more commonly in persistently infected individuals than in those who clear the virus (Bartosch et al., 2003 Logvinoff et al., 2004 Meunier et al., 2005). A recent report has suggested...

Post Transfusion Hepatitis

Labeling of blood from paid donors, a practice started in 1972, and the implementation of third-generation screening tests for hepatitis B surface antigen markedly reduced transfusion-transmitted hepatitis B but were found to eliminate only about 10 of all post-transfusion hepatitis cases by 1995 (6). Risk for non-A, non-B posttransfusion hepatitis was reduced when potential HIV-positive donors were excluded and was decreased again when donors were tested for the surrogate markers alanine aminotransferase (a marker for acute liver inflammation) and antibody to hepatitis B core antigen (evidence of previous hepatitis B infection) (9). Even greater reductions in the risk of transmission of non-A, non-B hepatitis were described after implementation of a test for antibody to the hepatitis C virus (Table 2) (10). Finally, implementation of nucleic acid testing has reduced the current estimated risk of hepatitis C transmission to approx 1 in 1,500,000 units (8).

Functional and Clinical Significance of Hepatitis D Virus Genotype II Infection

Abstract Hepatitis D virus (HDV) infection is one of the important etiologies of fulminant hepatitis and may aggravate the clinical course of chronic HBV infection to cirrhosis and liver failure. HDV was classified into three genotypes. Recent molecular phylogenetic analysis of HDV suggests atleast seven major clades. The genotype I HDV is widely spread, genotype II is found in East Asia and genotype III HDV is prevalent in South America. The genomic size is 1682-1685 nucleotides (nt) for genotype II, and 1676 nt for genotype IV (IIb). The divergence in HDV nucleic acid sequences between genotype II and other genotypes varies from 13.8 to 35.3 . The divergences in the HDAg-coding region may range from 17.8 to 29.8 between genotype II and other genotypes. There is no genotypic or size restriction on the interactions of either the small or the large hepatitis delta antigens (HDAgs) between genotypes I and II, and there is also no genotypic incompatibility during co-package of HDAgs of...

Structure and Replication of Hepatitis Delta Virus RNA

Abstract While this volume covers many different aspects of hepatitis delta virus (HDV) replication, the focus in this chapter is on studies of the structure and replication of the HDV RNA genome. An evaluation of such studies is not only an integral part of our understanding of HDV infections but it also sheds new light on some

The Essential Role of the Adaptive Immune Response in HCV Clearance

In the absence of high levels of immunosuppression, HCV is a non-cytopathic virus. In the absence of an ongoing immune response, it infects and persists in target cells, predominantly hepatocytes, without inducing inflammation and damage. This has been demonstrated in both experimental chimpanzee models (Thimme et al., 2002) and in drug users or humans who were accidentally infected with contaminated needles during health care practice (Thimme et al., 2001 Timm et al., 2004). In these studies, increases in viremia were not associated with parallel increases in serum transaminase levels, thus reflecting an absence of hepatocyte damage. Furthermore, following liver transplantation, infection does not lead to liver damage for a 3-week period despite high levels of virus. The only cytopathic lesion that has been directly ascribed to HCV is the association of Genotype 3 infection with steatosis, the accumulation of lipids in hepatocytes (Pawlotsky, 2004). Although non-cytopathic, gene...

Course of hepatitis B with concurrent HIV infection

In HIV-infected patients, chronic hepatitis B has an unfavorable course compared with monoinfected patients, and the risk of liver-associated mortality is significantly increased. Data from the Multicenter AIDS Cohort Study (MACS) have demonstrated the unfavorable influence of HIV infection on hepatitis B (Thio 2002). In approximately 5,000 patients observed over a period of 14 years, the risk of liver-associated mortality was 8 times higher than in HBs antigen negative HIV patients (14.2 1,000 person-years vs. 1.7 1,000) and 15 times higher than in HBs antigen negative patients without HIV infection (14.2 1,000 vs. 0.8 1,000). Liver-associated mortality due to hepatitis B has increased significantly since the introduction of HAART in this cohort. In addition to increasing mortality, HIV coinfection accelerates the progression of hepatitis B and increases the risk of cirrhosis. Histological analysis of a series of 132 homosexual men with chronic hepatitis B, of which 65 were...

HHV6 and hepatitis

Mild elevation in hepatic transaminase levels during infection. Indeed, approximately 4 (four cases) of 89 infants with primary HHV-6 infection had signs of hepatic injury during viral infection (Asano et al., 1991a). In these cases, patients had a transient elevation in serum hepatic transaminase levels that completely resolved without any specific treatments. However, one case report described chronic hepatitis caused by HHV-6 infection in one 20 month old, otherwise healthy boy (Tajiri et al., 1997). Chronic hepatitis was confirmed by pathological analysis, and viral DNA was detected in liver tissue by polymerase chain reaction (PCR) and in situ hybridization. In these samples, HHV-6 DNA is localized to the nuclei of hepatocytes, the sinusoidal cells, and the nuclei of the epithelial cells of the intra-hepatic bile ducts. Chronic hepatitis in young children can be caused by a variety of viruses, such as hepatitis B virus, hepatitis C virus, and CMV. In addition to these viruses,...

Hepatitis B

Age-related processes play a very important role in the population dynamics of hepatitis B virus (HBV) (Medley et al., 2001). This infection has similarly been estimated to result in 1 million deaths each year, but mainly in adulthood as a result of liver cancer and cirrhosis as with measles, however, there is a safe and effective vaccine. In contrast to measles, infection with HBV can result in persistent infection over a period of decades, and additionally the probability of persistent infection is much greater if infection occurs in early childhood. The modes of transmission of HBV are similar to those of HIV (though HBV is very much more infectious), such as through sexual contacts, health interventions, intravenous drug use (IVU) or at birth from mother to child (Edmunds et al., 1996 Williams et al., 1996). These processes all have a strongly age-related or age-determined component. Also, in general, the endpoint of many persistent HBV infections, such as liver cancer or...

Hepatitis A B E

Hepatitis A is a common problem in rural areas of developing countries. There is a declining level of antibodies to hepatitis A in developed countries and adults are at special risk so 1 or 2 doses of hepatitis A vaccine should be given. If there is insufficient time a single injection of human immunoglobulin (IG) can give protection for 3 to 6 months. It is safe for all age groups but children under 8 years should not need it. A blood test for hepatitis A antibodies should be carried out to determine a person's immunity. Hepatitis B is endemic in South-East Asia, South America and other developing countries. Vaccination is recommended especially for people working in such countries, particularly those in the health care area or those who may expect to have sexual or drug contact. If patients have a 'negative' HBV core IgG titre, then vaccination would be worthwhile (3 doses 0, 1 and 6 months). Hepatitis E has a high mortality rate in pregnant women.

HDV Produces Two Forms of HDAg from the Same Gene

Hepatitis delta virus (HDV) is often compared to viroids because of the characteristic unbranched rod secondary structure formed by its RNA and the relatively small size of its genome. However, unlike viroids, HDV does contain one gene that encodes the sole viral protein, HDAg. Early analyses showed two electrophoretic forms of HDAg in liver and viral particles isolated from serum (Bergmann andGerin 1986 Bonino et al. 1981,1984,1986). (These forms were sometimes referred to by their apparent molecular weights, p-24 and p-27 they are denoted here as S-HDAg and L-HDAg for short and long, respectively.) Following the cloning of HDV cDNAs (Makino et al. 1987 Wang et al. 1986), a series of studies illuminated the functional roles of S-HDAg and L-HDAg in HDV replication S-HDAg is required for replication of HDV RNA, and L-HDAg is required for the formation of HDV particles (Chang et al. 1991 Glenn et al. 1992 Hwang et al. 1992). Early studies found that L-HDAg also inhibits HDV RNA...

Role of LHDAg Farnesylation in the HDV Replication Cycle

In the HDV packaging process, hepatitis B surface antigen (HBsAg) interacts with L-HDAg to form particles this process can occur even in the absence of HDV RNA (Hwang and Lai 1993). HBsAg is mainly localized in the endoplasmic reticulum (ER) membrane, while the localization of newly synthesized L-HDAg is very dynamic (Hourioux et al. 1998). Analyses of transiently transfected cells revealed the sequential appearance of L-HDAg in the nucleoplasm, then in the nucleolus, and finally in nuclear speckles (Shih and Lo 2001). Prenylated L-HDAg is concentrated in the nuclear speckles. Far-Western protein blotting analysis indicated a direct protein-protein interaction between HBsAg and L-HDAg (Hwang and Lai 1993). The L-HDAg isoprenylation also mediates this protein-protein interaction. When HDV particles assemble, L-HDAg must interact with HBsAg in the ER membrane. From where the prenylated ER-associated L-HDAg comes remains unknown. The protein is probably either transported from the...

The Effect of HDV Infection on the HBV Life Cycle

Since HDV is directly dependent on HBV for propagation, it can be transmitted concomitantly with HBV to an individual who has no history of prior HBV infection, this is referred to as a coinfection pattern - or it can be transmitted to an HBV chronic carrier, this is referred to as superinfection. Coinfections are often acute and self-limiting, and they result in a concomitant replication of both HBV and HDV, whereas superinfections cause severe acute and chronic type D hepatitis in 70 of cases. They also lead to the inhibition of HBV replication during the acute phase of HDV infection. This phenomenon has been describedinbothhumansand experimentallyinfectedchimpanzees, but it remains poorly understood (Chen et al. 1988 Sureau et al. 1989 Wu et al. 1991). It could result from a direct suppression of HBV replication exerted by the coexpressed HDV proteins, RNA or RNPs, or could be the consequence of an indirect interfering mechanism driven by inflammatory cytokines. The suppressive...

HDV Genetic Distances and Geography

Similar to HCV (Morice et al. 2001) and HBV (Ganne-Carrie et al., 2006), the delta viruses characterized in Paris (France) showed a wide African distribution. For example, the six full-length viral RNA sequences were obtained from five patients from Western or Central sub-Saharan African countries (Cameroon, Guinea, Ivory Coast, Mali, and Republic of Congo) and from an adult Polish woman who had lived in Cameroon for 3 years. To determine whether the geographic distribution of the HDV isolates was correlated with their levels of sequence divergence, we compared the Kimura-2-parameter pairwise distances between full-genome sequences with the relative geographic distances matrix of the capitals of the countries where the patients had been infected. To compare two quantitative continuous variables, we decided to calculate the correlation coefficient to evaluate the degree of proportionality of data sets. When the ubiquitous type-I sequences were removed, a significant statistical...

Influence of Replication and Genotypes of HBV

Smedile et al. reported that HBV replication modulates pathogenesis of HDV in chronic hepatitis D 16 . Wu et al. also reported that persistent replication of HBV or HDV are associated with elevated serum transaminase levels 14 . Based on an intergroup divergence of 8 or more in the complete nucleotide sequence, HBV can be classified into eight genotypes A-H 47 . Genotypes andcorepromotermutations ofHBVhavebeenreportedtobeassociatedwith time of HBeAg seroconversion, HBV DNA levels, treatment response to interferon and long-term outcomes 47-62 . Because chronic hepatitis D patients still have underlying chronic hepatitis B, replication status, genotypes and mutations of HBV may also influence clinical course and outcomes of chronic HDV infection. In a recent study in our laboratory, persistent replication of HBV or HDV was associated with higher adverse outcomes (cirrhosis, HCC or mortality) compared to those who cleared both viruses from sera 63 . HBV genotype C is also a significant...

CD4 T Cells in Chronic Infection

Chronic infections are characterized by a permanent, almost complete, loss of HCV-specific CD4+ T cells in the blood (Figure 2). PBMC harvested from patients infected for many years with HCV failed to proliferate and or produce IFN-y or exhibited oligoclonal diversity (Gerlach et al., 1999 Lechner et al., 2000 Schirren et al., 2000 Day et al., 2002 Rosen et al., 2002 Ulsenheimer et al., 2003 Wertheimer et al., 2003). The relative lack of circulating HCV-specific CD4+ T cells has recently been confirmed more directly using MHC class II tetramers (Day et al., 2003b). Although CD4+ T cells are hard to detect in the blood, they are not totally absent, however. Following HCV-specific stimulation, a very low percentage of CD4+ T cells that upregulated expression of the alpha chain of the IL-2R (CD25), an early marker of activation, was detected among PBMC from chronically infected subjects (Ulsenheimer et al., 2003). Furthermore, it has been possible to derive some CD4+ T cell lines...

WoodchuckHDV Inoculum Derived from a Molecular Clone Analysis of Genetic Changes Occurring During Acute and Chronic

The determinants of the outcome of HDV superinfection are not known. Analyses of the viral genetics of hepatitis C virus have indicated that progression to chronic infection is correlated with sequence changes and increased sequence diversity in the hypervariable region of the envelope protein (Farci et al. 2000). Previous studies of genetic changes that occur during the course of HDV infection have either analyzed sequence modifications that occur over time in HDV RNA isolated from the sera of chronically infected patients (Chao et al. 1994, Imazeki et al. 1990, Lee et al. 1992), or from the liver of an infected woodchuck at the end of several serial passages (Netter et al. 1995). However, none of these studies addressed the role of viral genetic changes in the establishment of chronic infection. One of the more interesting observations of the genetic changes occurring during the course of infection was that in nearly all animals, a limited number of modifications had occurred in the...

Vaccine Strategies for HDV

Responses are not protective against HDV infection (Karayiannis et al. 1990) is not particularly surprising given that HDAg is not exposed on the surface of the virion. However, it appears that some form of immunity follows acute, self-limiting infection because hepatitis B carrier chimpanzees superinfected with HDV were resistant to rechallenge with HDV 6 months later (Purcell et al. 1987). Most likely, the alteration of the course of infection by some vaccines is due to the ability to elicit appropriate cell mediated immune responses. However, there appears to be no correlation between vaccine efficacy and antiHD T-cell proliferative responses (Fiedler et al. 2001). Perhaps, cytotoxic T lymphocyte activity is the more important contributor to clearance of virally infected cells. Future vaccine studies may benefit from measurement of cytotoxic T lymphocyte activity induced by vaccines and or HDV infection.

Mechanisms of Interferon Action

Our understanding of interferon action against the hepatitis C virus is possible due to the availability of HCV cell culture models. Work on this area began almost 10 years ago by Shimizu (1992, 1993, 1996), where HCV replication models were developed in lymphoid cell lines. Subsequently, full-length chimpanzee infectious clones for HCV were developed by the laboratories of Dr. Charles Rice, Rockefeller University (Kolykhalov et al., 1997), and Dr. Jens Bukh of NIH (Yanagi et al., 1997). An initial attempt to establish HCV replication models in hepatic cells was made using full-length RNA transfection (Yoo et al., 1995 Dash et al., 1997). The levels of HCV replication in these models remained low and required the RT-PCR method to detect HCV replication. These technical difficulties have demanded the development of a more reliable cell culture system for HCV. A significant advance in this area took place after development of a subgenomic replicon-based model by Lohmann and...

The SHBsAg Protein and the Assembly of HDV Particles

It is worthy of note that the members of the Hepadnaviridae family closest to HBV, namely the Woodchuck hepatitis virus (WHV) and the Woolly monkey hepatitis B virus (WMHBV), can assist in HDV propagation because their small envelope proteins (S-WHsAg and S-WMHBsAg, respectively) are competent for HDV RNP envelopment (Barrera et al. 2004 Ponzetto et al. 1984 Ryu et al. 1992). Experimental transmission of HDV has been achieved in woodchucks, and this animal model has been useful to study the interactions between HDV and the helper Hepadnavirus. In contrast, the envelope protein of a more distantly related Hepadnavirus, namely the Duck hepatitis B virus (DHBV), is unable to package the HDV RNP (O'Malley and Lazinski 2005). Therefore, determinants that are specific for HDV maturation on the S-HBsAg

Secretion of Soluble MICA into Serum in HCC and NKG2D Expression in NK Cells

In order to examine the importance of sMICA in liver disease, we conducted ELISA quantitation of serum sMICA from healthy donors and patients with chronic HBV HCV and HCC (Jinushi et al., 2005). Only a small amount of sMICA was detected in a small number of cases of healthy donors and patients with chronic hepatitis, while notably larger amounts of sMICA were detected in some patients with HCC. We also conducted the test according to the HCC stage and observed that the number of sMICA positive cases was notably more frequent for advanced HCC than for early HCC. We conducted FACS analysis of NKG2D expression in CD56-positive cells from healthy donors and patients with HCC (sMICA positive negative) and chronic HCV. The results showed that the level of NKG2D expression in patients with hepatitis or HCC (sMICA negative) was the same as that in healthy donors, while the level of NKG2D expression in patients with HCC (sMICA positive) was decreased. Next, in order to examine whether sMICA is...

Natural History of the Clinical Course of HDV Infection

HDV infection in patients shows two courses of disease. HBV and HDV coinfection induces a disease similar to the classical acute HBV hepatitis with a cellular immune response to HBV resulting in a downregulation of HBV replication by cytokines and an elimination of infected cells by cytotoxic cells (Chisari and Ferrari 1995 Guidotti et al. 1996b). Neutralizing antibodies against HBsAg prevent hepatocytes from reinfection with HBV and HDV. The humoral immune response to HDV in this mode of infection is characterized by low titers of anti-HDV, which disappear soon after infection (Rizetto 1981, 1984). A specific immune response against HDV may not be required in the context of HBV clearance because HDV, as a helper-dependent virus, essentially needs HBV envelopes to form complete particles.

Comparison Between Genotypes I and II HDV

It hasbeenreportedthatgenotypeIIHDV infectionisrelativelylessfrequently associated with fulminant hepatitis at the acute stage and less unfavorable outcomes (cirrhosis or HCC) at the chronic stage as compared to genotype I of the same area 18 . This study was composed of symptomatic inpatients and asymptomatic outpatients for regular check up. In a longer follow-up for more than 15 years, about 45 of patients with chronic genotype I HDV infection survived, while more than 75 of patients with chronic genotype II HDV infection remained alive 63 . The difference is statistically significant. The long-term prognosis of patients with chronic genotype II HDV infection seems better than that reported previously in western countries where only genotype I HDV is currently found 10,11,17 . All the patients in the study by Ivaniushina et al. had a history of chronic liver disease, and all except two presented with grave liver disease or cirrhosis 26 . It is not surprising that there was no...

Attractive Features of Prenylation Inhibition Based Antiviral Therapy

It is worth emphasizing that prenylation inhibition-based antiviral therapy has implications for other viruses besides HDV which are found to have similarly prenylated proteins. Indeed a CXXX box motif is present in proteins of numerous other medically important viruses, as well as in agents with a potential for bioterrorism (Elazar and Glenn 2005). The precise role played by prenylation, however, may differ in each case and need not be restricted to mediating assembly as in HDV. For example, the polymerase proteins of hepatitis A virus and foot and mouth disease virus have a conserved CXXX box. Because the replication of these positive single-strand RNA viruses is thought to occur in intimate association with intracellular membranes, prenylation of these proteins may provide a membrane anchoring function for the catalytic subunit of the respective replication complexes. On the other hand, the UL32 gene product of herpes simplex virus (HSV), which is thought to be involved in virus...

Therapy for HDV Based on Inhibition of the Helper Hepadnavirus

There is currently no generally accepted effective therapy for type D hepatitis (see Niro et al. 2005 for a review), and liver transplantation is the only option for the associated end-stage liver disease (Wright and Pereira 1995). The dependence of HDV on HBV could suggest that successful treatment of HDV infection would follow successful treatment of the supporting HBV infection. Unfortunately, this does not always appear to be the case. Although treatment of chronic HBV carriers with lamivudine (b-L-2',3'-dideoxy-3'-thiacytidine, 3TC) leads to decreased levels of HBV in serum and improved liver histology (Dienstagetal. 1995 Laietal. 1998 Nevensetal. 1997),in patients with chronic delta hepatitis prolonged lamivudine therapy neither lowers HDV RNA levels nor ameliorates disease activity, even though HBV viremia is reduced (Lau et al. 1999 Wolters et al. 2000). Similarly, treatment with famciclovir was not effective against HDV infection (Yurdaydin et al. 2002). The most likely

CD8 T Cells in Acute Infection

CD8+ T cells have been investigated extensively in HCV infections. This has been facilitated by the availability of MHC class I tetramers. Studies in infected chimpanzees and humans using both functional methods of CTL identification and MHC class I tetramers have demonstrated that increases in serum transaminase levels and clearance of the virus during the acute phase are generally associated with the emergence of a strong CTL response in the blood and the liver 1 to 3 months after infection (Cooper et al., 1999 Thimmeet al., 2001,2002 Shoukry et al., 2003 Cox et al., 2005a) (Figure 2). Up to 8 of the blood CD8+ T cells can be specific for a single HCV epitope at the peak of the acute response (Klenerman et al., 2002). Viral clearance follows the entry and accumulation of HCV-specific IFN-y-producing T cells within the liver (Thimme et al., 2002). Consistent with this observation, a poor CD8+ T cell response is associated with viral persistence (Cooper et al., 1999) (Figure 2). The...

TCell Immune Responses

Negro et al. demonstrated that rechallenge with HDV of chimpanzees, which had apparently recovered from a first HDV infection, resulted in the reappearance of HDV replication, sometimes associated with hepatitis (Negro et al. 1989). However, only low levels of viremia were detected and ALT elevations, when present, were mild. This finding suggests that at least a partial immunity against HDV can be raised.

Structure of HDV and Hdv Rna

HDV is a small RNA virus consisting of spherical particles of about 36 nm in diameter. The virion itself is comprised of a short (1.7 kb) single-stranded, circular RNA that exists as a ribonucleoprotein complex with the only HDV-encoded protein, hepatitis delta antigen (HDAg). Together these form a roughly spherical core structure that is enveloped by hepatitis B surface antigen (HBsAg). There are approximately 70-200 HDAg molecules per RNA molecule (Ryu et al. 1993 Gudima et al. 2002). Fig. 1 Genome organization of HDV RNA. Numbering is based on that of Wang et al. (1986). G, genomic HDV RNA AG, antigenomic HDV RNA S-HDAg, small hepatitis delta antigen L-HDAg, large hepatitis delta antigen

Sensitivity to Ribavirin

Some years ago it was shown that ribavirin could block the replication of HDV in primary woodchuck hepatocytes (Choi et al. 1989 Rasshofer et al. 1991). Recent studies confirm that this occurs in cell lines undergoing HDV replication (Chang et al. 2006). Moreover, this inhibition can be achieved with 30 M ribavirin, a dose low enough to avoid cell toxicity. In contrast to this, others have cited that ribavirin treatments for HDV-infected patients are not effective (Hoofnagle 1998). However, given that ribavirin treatment is demonstrably selective for HDV replication in cultured cells, further studies in patients maybe warranted. What might seem a possible hindrance to patient studies is that a side effect of ribavirin treatment can be anemia (Galban-Garcia et al. 2000). However, such side effects can be controlled, as judged by the current acceptance of ribavirin (combined with pegylated interferon) as part of a treatment for chronic hepatitis C virus infection. Also, ribavirin might...

Mechanisms of Interferon Resistance

The nucleotide sequences of HCV genomes isolated from patients from different parts of the world are quite heterogeneous. Six major genotypes of HCV virus show 30-50 variation in their nucleotide sequences (Simmonds, 2004). More than 50 subtypes of HCV have also been described, showing 15-30 difference in their nucleotide sequences. Isolates of HCV from a single patient can show a 1-5 difference in their nucleotide sequences (Hoofnagle, 2002). The sequence variability suggests that the HCV genome mutates frequently during replication and circulates in the serum as a population of quasispecies. Interferon therapy, usually in combination with ribavirin, is the standard treatment for chronic HCV infection throughout the world. HCV genotype is the most important predictor of treatment outcome. Sustained virologic responses can be achieved in up to 82 of patients infected with genotypes 2 and 3, whereas a substantially lower response rate, around 4050 , is achieved in patients with...

Immunization with HDV Protein

Recently, the same HDAg expressed in yeast was used in another study for vaccination and challenge of eight woodchucks (D'Ugo et al. 2004). Four animals were immunized with HDAg using CFA IFA as adjuvant, the other four with HDAg using MF59 as adjuvant. MF59 is an oil mineral-water emulsion which has been shown to augment the antigen-specific humoral immune response and to induce a Th-cell response that is more type 2-like in nature (Verschoor et al. 1999). The humoral immune response was detected earlier and at higher titers in the woodchucks immunized with HDAg CFA vs. those immunized with HDAg MF59. The Th-cell immune response was already described (see Sect. 3.3.3). After challenge HDV RNA was detected at 2-4 weeks in all animals, indicating that neither of the vaccines was able to protect from superinfection despite the presence of anti-HDV and a Th-cell immune response to HDAg. However, differences were observed in peak serum HDV RNA levels and persistence namely, the HDAg CFA...

Viral Genetics of HBVand HDV

Despite an effective vaccine, infection with hepatitis B virus (HBV) is mainly transmitted through the mother-to-neonate route in endemic countries. In most cases, chronic infection results and the transmission will therefore occur from generation to generation. HBV could be considered as an indirect marker of population migration. Transmitted from the mother, it might be considered as an alternate to mitochondrial DNA (mtDNA) (Ingman et al. 2000). MtDNA analyses indicate that around 59,000-100,000 years before present, earth colonization might have occurred from Africa to the Middle East, Asia then to Australia, Europe and to Americas. Several hypothesis have been proposed to link the HBV to human evolution and dispersal around the globe (reviewed in Simmonds 2001). (1) The existence of Hepadnaviridae in other primates, mammals and birds makes possible a co-speciation of HBVs during evolution. (2) The higher divergence of the South American HBV genotype F strains (HBV F) could have...

CD8 T Cells in Chronic Infection

Between the acute and chronic phases of HCV, the number of HCV-specific CD8+ T cells declines dramatically. Recent studies (Cox et al., 2005a) in which 23 infected patients were sampled monthly during this transition have revealed that the breadth of the response was set early in infection and that early responses became unde-tectable, while no new responses were formed. Despite early reports based on IFN-y production or CTL activity suggesting that CD8+ T cells were not detected in the blood of chronically infected patients, CD8+ T cell clones specific for HCV can be derived from the liver of humans and chimpanzees in which the virus persists (Koziel et al., 1992, 1993, 1995 Kowalski et al., 1996 Nelson et al., 1997 Wong et al., 1998 Eckels et al., 1999). The presence of anti-HCV-specific CTLs have been confirmed using MHC class I tetramers. This powerful immunological tool has demonstrated that the liver contains a higher frequency of HCV-specific T cells than the blood (He et al.,...

Control of DC Function by NK Cells

Next, we examined DC maturation and functional activation resulting from co-culture with hepatoma cells and NK cells using NK cells from patients with HCV instead of those from healthy donors. The stimulation of IM-DCs using the supernatant of a 24-hour co-culture of NK cells from HCV patients with hepatoma cells resulted in suppressed DC maturation and allostimulatory capacity compared with the case in which we used NK cells from healthy donors. In order to examine whether NKG2A signals from HLA-E during a mixed culture of hepatoma cells and NK cells are involved in this inhibition of DC maturation and activation, we conducted an inhibition experiment by adding anti-NKG2A antibody during the mixed culture. DC maturation and activation resulting from culture supernatant stimulation were enhanced by adding anti-NKG2A antibody either in the case of NK cells from healthy donors or in the case of those from patients with HCV. However, DC maturation and activation were more notably...

IsHDVaCytopathic Virus

Both small and large HDAg and expressing these proteins in the liver do not develop any form of liver disease. Hence, the hepatitis in humans may be induced rather by the immune response than by HDV itself (Guilhot et al. 1994). The issue of the cytotoxicity of HDV itself has been investigated in different in vitro systems and yielded conflicting results. More recently, Wang et al. studied this issue extensively (Wang et al. 2001). When cells transfected with replication-competent HDV-cDNA were followed, a progressive decline in viral RNA replication and a steady decrease in the cells expressing HDAg were found. However, in transient transfection assays, no evidence was found to link HDV replication to apoptosis or cell cycle arrest. Thus, HDV does not appear to be acutely cytotoxic. In dividing cells, however, HDV replication was associated with a slight growth disadvantage. The authors discuss that this may not cause hepatitis in vivo but might contribute to impaired liver...

HDV Genetic Variability and Clinical Patterns

The wide radiation of HDV we describe might contribute to the spectrum of pathologies associated with HDV. For example, specific liver lesions, including morula cells, have been observed in severe hepatitis in African and Amazonian patients (Casey et al. 1993 Parana et al. 1995). It is therefore considered that the association of HDV-3-HBV F leads to severe acute hepatitis. By contrast HDV-2 and HDV-4 have been typically associated with less severe hepatitis disease than Type I-associated infections (Wu et al. 1995). However, a recent study among the Miyako island strains suggests that the HDV-4 Okinawa subgroup (labelled IIb-M in the original paper) induces a greater progression to chronic hepatitis and to cirrhosis (Watanabe et al. 2003). Type-I viruses have a wide spectrum of pathologies, ranging from severe fulminant hepatitis in Sweden (Hansson et al. 1982 Zhang and Hansson 1996), Russia (Flodgren et al. 2000) and Taiwan (Wu et al. 1995) to very mild disease in the town of...

Isoprenylation of LHDAg

HDV isolates are classified into three genotypes I, II and III based on the differences in their nucleotide sequences. The CXXQ motif in genotype III is CTQQ and is less efficiently farnesylated than other genotypes (O'Malley and Lazinski 2005). During the early phase of HDV replication, the small form of hepatitis delta antigen (S-HDAg) is more abundant than L-HDAg, and the L-HDAg S-HDAg ratio increases when replication progresses. The level

The Virion Structure

Hepatitis Delta Envelope

The HDV virions are heterogeneous in size with an average diameter of 36 nm and a buoyant density of 1.25 g cm3 in CsCl (Fig. 1), and they display a chimerical structure consisting of an outer lipid membrane in which the HBV envelope proteins are anchored, and an inner ribonucleoprotein (RNP) made of HDV-specific elements (Bonino et al. 1984 He et al. 1989 Rizzetto et al. 1980b). The RNP includes a 1,700-nucleotide single-stranded RNA genome associated with approximately 200 copies of the HDAg protein (Gudima et al. 2002). This protein appears as two isoforms the small form (S-HDAg) of 195 amino acid residues and the large form (L-HDAg), which is 19 amino acids longer. The difference in size arises as a consequence of an RNA editing event that occurs on a replication intermediate of the viral genome and is copied onto the HDAg mRNA (see the chapter by J.L. Casey, this volume). The examination of the RNP by electron microscopy reveals a spherical, core-like structure, with no apparent...

Interferon System

Ifn Gamma Ifn Alpha Beta Signalling

It is believed that the interferon system is transcriptionally activated intracellularly within a few hours of virus infection through a cascade of signaling pathways that involve NF-kB, ATF2-c-Jun, and interferon-regulatory factors (IRF 3) and IRF-7 (Kawai & Akira, 2006). In humans, Type I interferons are encoded by 14 functional genes that form the interferon-alpha family. Single genes encode for interferon-beta and -omega, and three genes encodes for interferon-lambda (Sen, 2001 Bekisz et al., 2004). The biological significance of having multiple genes for interferon-alpha and only one for interferon-beta is not clear. The genes for different Type I interferons are all located together on human chromosome 9 (Diaz et al., 1994), and the Type II interferon gene is located on chromosome 12 (Schroder et al., 2004). The commercially available recombinant interferon used against HCV is interferon-a2a, interferon-a2b, or a consensus interferon (Blatt et al.,...


The studies summarized in this chapter demonstrate that the WHV wood-chuck model of experimental chronic hepatitis infection can be applied to the analysis of aspects of the natural history of HDV infection, the development of HDV vaccine strategies, and therapeutic studies of chronic HDV superinfection. The relatively rapid progression to hepatocellular carcinoma in WHV-infected woodchucks does pose challenges for the use of this model for evaluating drug efficacy against chronic HDV disease. Further, HDV infection appears to increase the risk of hepatocellular carcinoma in patients with compensated cirrhosis type B (Fattovich et al. 2000) and the influence of chronic HDV on progression of end-stage liver disease in the woodchuck model has not been established. Indeed, many of the woodchucks in the clevudine study progressed to hepatocellular carcinoma, which precluded post-treatment follow-up studies. Perhaps these limitations can be overcome by the use of younger WHV-carrier...

HDV Ribozymes

Abstract The self-cleaving RNA sequences, or ribozymes, in the genomic and antige-nomic strands of hepatitis delta virus (HDV) RNA fold into structures that are similar to each other but distinct from those of small ribozymes associated with the RNA repli-cons that infect plants. HDV ribozymes have provided a tractable system for studying the mechanism of catalytic RNA, and results of biochemical and structural studies on the HDV ribozymes, from a number of labs, have enhanced our understanding and expanded our thinking about the potential for catalytic roles of RNA side chains. The results of these studies are consistent with models suggesting that both an active-site cytosine and a divalent metal ion have catalytic roles in facilitating the cleavage reaction in the HDV ribozymes. Despite recent advances, details about the catalytic mechanism of the HDV ribozyme continue to be debated, and these ribozymes should serve as a good system for further study.

HDV Disease Burden

It has been estimated that at least 15 million of the over 300 million people infected with hepatitis B virus (HBV) also harbor a hepatitis delta virus (HDV) infection and such infections can be found throughout the world (Gerin et al. 2001 Rizzetto et al. 1991). The clinical course associated with HDV is typically more severe than for HBV infection alone. Unfortunately, current therapies are largely ineffective against HDV. The study of HDV molecular virology, however, has revealed exciting new avenues for potential therapeutic intervention. After a brief review of the basic HDV virion composition and life cycle(coveredinmoredetailinother chapters in this volume),thischapter will focus on a special post-translational modification of a key HDV protein. This modification reaction, termed prenylation, turns out to be both a mechanism exploited by the virus to mediate its assembly, and the basis for an exciting new form of antiviral therapy. HDV can be viewed as a 'parasite virus' of...


Phosphorylation of S177, acetylation of K72 and methylation of R13 of S-HDAg could all modulate the replication of HDV genomic RNA from antigenomic RNA but not replication of HDV genomic RNA from antigenomic RNA. These results suggest that PTMs of S-HDAg play critical roles for its functions to facilitate the replication of HDV genomic RNA. The different requirements of S-HDAg for the replication of genomic and antigenomic RNA are also consistent with the previous suggestion that rolling circle replication of hepatitis delta virus RNA is carried out by different cellular RNA polymerase machineries (Macnaughton et al. 2002 see also the chapter by T.B. Macnaughton

Concluding Remarks

HCV infection and subsequent hepatocarcinogenesis and HCC progression can be summarized from the perspective of receptor expression in NK cells as follows. HCV patients show increased NKG2A expression, and patients with advanced HCC display decreased NKG2D expression under the influence of sMICA. There is a link between the staged change of NK-cell phenotypes and the decreased cytotoxic activity of NK cells to HLA-E positive MICA positive hepatoma cell lines. This might have a disadvantageous effect on a living body in the ablation of transformed liver cells or the growth of tumor. It appears that apart from well-known factors from the virus viewpoint and the inflammation viewpoint, the modulation of innate immunity like this is involved in the high rate of hepatocarcinogenesis and the following progression in patients with HCV (Figure 5). In vivo, DCs are the most potent APC to activate naive T cells, but to initiate adaptive immunity in this manner, DCs should be mature and...

Closing Notes

HDV superinfection of chronically HBV-infected patients results in acute, sometimes severe, hepatitis and in a high frequency of persistence of both viruses. The disease could be triggered by a HDV specific CTL response, although no data on the cellular immune response in acute HDV infection has been reported so far. Cellular immune responses (Th cells and CTLs) were found in patients with resolved HDV superinfection (without detection of HDV RNA), but not in chronically HDV-infected patients. Although these results were seen only in a small number of patients, one might conclude that a proper T-cell response seems to be the prerequisite for the elimination of HDV. This mechanism was shown for chronic HBV infection a higher frequency of HBV-specific CD8+ T-cells was detected in patients with a low level of HBV replication than in those with a high level of HBV replication (Webster et al. 2004). The HBV-specific CD8+ T-cell response was overall weak in the blood of patients with...


Between January 1999 and February 2005, 391 samples, collected from HDV infected patients that were positive in a routine search of HDV RNA detection in serum, were analysed. In the first part of the study (Radjef et al. 2004), we selected 25 patients whose preliminary examination suggested that the HDV viral strains varied from previously described HDV genotypes. Indeed, we selected the 25 samples for which (1) HDV cDNA could not be amplified using previously described primers 6A and 6S (Deny 1994) even though HDV serology was positive or (2)) the RO-DNA amplicon restriction pattern was atypical (Gordien et al., unpublished results, see Fig. 2). Interestingly, 22 samples were obtained from patients from Africa or who had travelled to Africa. The male to female ratio was 0.8 and the mean age was 35 years (range, 15-53 years). Most patients had chronic active hepatitis or cirrhosis and only one patient, aged 33 years, had acute HDV superinfection.

Subject Index

HDAg interaction 173, 178, 179 HDV assembly 122,123 HDV infectivity 124-126 hepatitis B surface antigen (HBsAg) 114 hepatitis B virus (HBV) 114-126, 152, 156, 164-167 hepatitis delta antigen (HDAg) 27-39,92,97-102 hepatitis delta antigen long form (L-HDAg) 68,69,71,74,75, 77-80, 82-84 histone acetyltransferase (HAT) 101, 103 L-HBsAg 115-119,124-126 lamivudine 138,220,221 large hepatitis delta antigen (L-HDAg) 114, 117, 120-124, 126 linear RNA 3-5,10-12,17 small hepatitis delta antigen (S-HDAg) 114,115,120,121, 124, 162, 166, 167 subcellular localization 96, 101-103 woodchuck hepatitis virus (WHV) 212-214,221,222


We discussed the progress made in our understanding of the mechanisms of interferon action and interferon resistance from basic research on HCV. Chronic hepatitis C virus infection is the major cause of liver cirrhosis and liver cancer in the United States and in many developed nations. The most effective way of preventing HCV-associated liver cancer is to eradicate chronic hepatitis C virus infection from the human population by developing effective antiviral strategies. Interferon therapy is a highly effective first line of treatment available against hepatitis C virus infection. The most challenging task is to cure those chronically infected patients not responding to interferon-based therapy. Research in this area will increase our understanding of the mechanisms of interferon resistance and develop alternative strategies to treat chronic HCV infections that are IFN nonresponders.

Michael A Morse MD Timothy M Clay PhD and H Kim Lyerly MD

In general, vaccines approved for clinical use in the United States are applied as prophylaxis against infectious pathogens, such as hepatitis B virus and pneumococcus. Generally, these vaccines must be administered prior to the onset of an infection (as primary prophylaxis) in order to be effective, although there are rare exceptions such as the treatment of rabies (in which both specific immunization and immune globulin are administered to achieve postexposure prophylaxis). In contrast, cancer immunotherapy vaccines presently are aimed at the eradication of either a microscopic or, more commonly, macroscopic burden of tumor cells.

Animal Models For The Analysis Of Innate Immune And Inflammatory Responses To Systemically Applied Ad

After systemic administration have shown that within the first minutes of intravenous virus delivery in mice, more than 99 of the infectious particles are removed from the circulation (27a,88a). Although the kinetics of virus clearance from the blood in primates (and humans) is somewhat slower than in mice, the liver remains the predominant organ in the body transduced with Ad after systemic application (2,27a,88a,140). Upon intravenous Ad administration, serum levels of IL-6 and TNF-a are increased with similar kinetics in both mice and humans (60a,141). Moreover, hepatic injury plays a key role in the pathogenesis of systemic Ad toxicity observed in mice (60a,131). It is important to note that immune responses to Ad vary significantly among different mouse strains and between different species (142). Whereas Ad-induced hepatitis following systemic vector application has been observed in all species, the dose of virus that resulted in severe toxicity (calculated as particles kg)...

TABLE 5 Extraglandular Manifestations in Primary SS

Autoimmune hepatitis primary biliary cirrhosis Diagnosis of SS also requires exclusion of other conditions that can mimic it. These include previous radiation therapy to the head and neck, amyloidosis, sarcoidosis, lymphoma, graft versus host disease, hepatitis C virus infection, HIV-diffuse infiltrative lymphocytosis syndrome, medication-induced dryness, and uncontrolled diabetes mellitus.

Picornaviruses Poliovirus

Poliovirus (PV) is a nonenveloped, positive-stranded RNA virus, which is responsible for causing poliomyelitis. PV RNA is composed of a 5'-nontranslated region that contains an internal ribosomal entry site (IRES) which directs the synthesis of a single polypeptide that is subsequently processed by viral proteases into structural and nonstructural proteins (75). Polioviruses tropism is restricted to cells expressing CD155, a member of the Ig superfamily, which is prevalent on lower motor neurons resident within the spinal cord and brainstem (138). The IRES elements encode strong cell-type specific restrictions and probably play a key role in the neurovirulent behavior of the virus. It subsequently became apparent, that other viruses, such as hepatitis C virus (HCV) or rhinoviruses also contain IRES elements. Experiments into the importance of the IRES elements lead to creation of a poliovirus chimera (referred to as PV1) (139), which contained the human rhinovirus type 2 IRES element....

New nucleoside analogs

Since the development of the guanosine analog DAPD came to a halt, hopes are now focused mainly on cytidine analogs. The most promising substances are currently elvucitabine, reverset and SPD-754. Mitochondrial toxicity seems to be low, and most are effective against hepatitis B. One problem with cytidine analogs could be the combination with the cytidine analog 3TC, where a loss of efficacy seems possible. ACH-126,433 (Elvucitabine) is a nucleoside analog developed by Achillion Pharmaceuticals. It is an enantiomer of DPC 817, with the chemical name beta-L-d4FC, and is effective against HIV and HBV. In vitro studies show potency even in the presence of numerous nuke resistance mutations (Fabrycki 2003). It is also of interest as it seems to have low mitochondrial toxicity, and because of its very long halflife (Dunkle 2001). Phase II studies are underway in HIV-infected patients and in patients with hepatitis B. A small, double-blind study showed a reduction in viral load between 0.7...

Viiiclinical Considerations

Viral hepatitis is a term used to describe infection of the liver by a group of viruses that have a particular affinity for the liver, which include rhe following. 1. Hepatitis A virus is a self-limiting disease that does not lead to chronic hepatitis or fulminant hepatitis. It is commonly referred to as infectious hepatitis. 2. Hepatitis B virus leads to acutc and chronic hepatitis, fulminant hepatitis, and hepatocellular carcinoma. It is transmitted by transfusions, dialysis, and intravenous drug abuse. It is commonly referred to as serum hepatitis. 3. Hepatitis C virus leads to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. It may be the leading cause of chronic hepatitis in the Western world. 4. Hepatitis D virus leads to hepatitis only in the presence of hepatitis R virus. 5. Hepatitis E virus is a self-limiting disease that does not lead to chronic hepatitis or fulminant hepatitis. It is transmitted through water.

From the anticonvulsant hypersensitivity syndrome to the DRESS

The systemic manifestations of the anticonvulsant syndrome were first described by Chaiken (Chaiken et al., 1950) with dilantin. The authors reported a case of hepatitis with jaundice, fever, and exfoliative dermatitis. The phenytoin syndrome was later described in 1979 by Haruda (1979). Rashes were the most frequent manifestation, followed by fever, pharyngitis, lymphadenopathy, eosinophilia, hepatitis, and hematological abnormalities. It was observed that this adverse reaction was delayed in onset after drug initiation. This reaction was then reported with phenobarbital and carbamazepine (McGeachy and Bloomer, 1953 Pellock, 1987 Shear and Spielberg, 1988). c. Hepatitis (alanine aminotransferase x normal values)

Histamine2receptor blockers H2Bs

These drugs are generally well tolerated by older adults, however, there are concerns about adverse effects and drug-drug interactions do exist. The overall incidence of adverse events is 3-5 , with most being mild 2 . Cardiovascular events occur most often with cimetidine, and include bradycardia and hypotension. Mental confusion has been reported with cimetidine, with associated factors including high dose, old age, decreased renal function, and cerebral impairment 74 . Other central nervous system effects include delirium, hallucinations, depression, and dyskinesia, seen mostly with the intravenous formulation 31 , 74 . Cimetidine causes a reversible decrease in creatinine clearance in 26 , but does not worsen existing renal failure. Cimetidine also causes a transient increase in serum aminotransferases. Other less common effects include rash, myalgia, and neutropenia with cimeti-dine, and hepatitis, arthralgias, rash, and bone marrow suppression with ranitidine.

Psychiatric and physical complications

Medical complications, sometimes fatal, often arise from the intravenous injections of opiates and other drugs. They include infections (abscesses, phlebitis, septicaemia, hepatitis, endocarditis, pneumonia, and HIV) and arterial occlusions leading to gangrene of limbs. Drug misuse in pregnancy may be teratogenic, and lead to complications with the pregnancy or birth. Poor diet and poor hygiene in drug misusers lead to various impairments of health.

Complications Of Hepatic Arterial Infusion Therapy And Their Management

Chemotherapy-associated complications include gastrointestinal toxicities (gastroduodenal inflammation or ulceration, and pancreatitis), chemical hepatitis, and sclerosing cholangitis. Gastroduodenal and pancreatic toxicities usually results from inadvertent perfusion and drug delivery to these organs. Persistent epigastric pain in patients on HAI therapy mandates prompt cessation of therapy and endoscopic evaluation. Methylene blue can be infused via the side port during upper endoscopy if blue staining of the ulcer appears, an angiogram to identify and possibly embolize the aberrant vessel is warranted (26). Chemical hepatitis with elevation of liver enzymes or bilirubin is a unique toxicity associated with HAI using FUDR, occurring in 42 of patients in early randomized trials (25). In some cases, progressive biliary sclerosis develops, which resembles idiopathic sclerosing cholangitis radiographically (65). Significant biliary sclerosis documented by endoscopic retrograde...

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...

Preferred Automation Compatible

In a general sense enzyme assays have an inherent advantage over simple binding assays that make them easier to automate. Enzymes catalytically turn over multiple molecules of substrate into product. This inherent amplification improves the sensitivity of enzyme assays over stoichiometric binding assays. Chromo-genic and fluorogenic enzyme assays that use appropriately labeled substrates are very amenable to HTS, as they are often homogeneous mix-read or mix-stop-read, requiring very few operations. There are multiple examples of assays and commercially available labeled substrates suitable for many fluorescent and colorimetric-based signal detection and generation technologies. Colorimetric, chemiluminescent, fluorescence resonance energy transfer (FRET), homogeneous time-resolved fluorescence (HTRF), and fluorescence polarization (FP) assays have been described. There are FRET 69,70 and colorimetric 71 assays for HCV protease. FRET assays have been reported for metalloproteases...

Biomedical Importance

Knowledge of the biochemistry of the porphyrins and of heme is basic to understanding the varied functions of hemoproteins (see below) in the body. The porphyrias are a group of diseases caused by abnormalities in the pathway of biosynthesis of the various por-phyrins. Although porphyrias are not very prevalent, physicians must be aware of them. A much more prevalent clinical condition is jaundice, due to elevation of bilirubin in the plasma. This elevation is due to overproduction of bilirubin or to failure of its excretion and is seen in numerous diseases ranging from hemolytic anemias to viral hepatitis and to cancer of the pancreas.

Stable Gene Transfer Vectors

Vectors derived from murine leukemia virus (MuLV), myeloproliferative sarcoma virus (MPSV), spleen focus-forming virus (SFFV), and other oncoretroviruses have been generated (1-4). Extensive characterization of these vectors has revealed both positive and negative regulatory elements that affect transgene expression in primitive hematopoietic cells (4-7). Exogenous sequences have also been inserted into these vectors to improve transgene expression levels. In this regard, scaffold attachment regions (8,9) and insulator elements (10-12) reduce silencing and positional effects, whereas post-transcriptional regulatory elements (PREs), such as that from the Woodchuck hepatitis virus, improve expression levels by increasing transcript export and stability (13). The cell division requirement for retroviral integration and the quiescent nature of HSCs has limited retrovirus-based transduction efficiencies. However, insight into the roles specific cytokines play in hematopoiesis has led to...

Removal Of Cornea For Transplantation

At the time of writing, the EBAA has a list of absolute contraindications that includes HIV, hepatitis B and C (social conditions that put the donor at risk for these entities are also considered contraindications), Creutzfeld-Jakob disease, ocular and intraocular inflammation, rabies, malignant tumors of the anterior segment, leukemia, lymphoma, and retinoblastoma.

Suggested Readings

Abdalla EK, Barnett CC, Doherty D, et al. Extended hepatectomy in hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg 2002 137 675-680. Ahmad SA, Bilimoria MM, Wang X, et al. Hepatitis B or C virus serology as a prognostic factor in patients with hepatocellular carcinoma. J Gastrointest Surg 2001 5 468-476. Izzo F, Cremona F, Ruffolo F, et al. Outcome of 67 hepatocellular cancer patients detected during screening of 1,125 patients with chronic hepatitis. Ann Surg 1998 227 513-518.

Practical tips for management of treatment

As HIV coinfection accelerates the course of hepatitis C and increases the risk of hepatotoxicity after initiation of HAART, the indication for treatment should be determined in every patient with diagnosed HIV HCV coinfection. The algorithm in Figure 1 can be used as a guide. In particular, treatment should be discussed for cases with a bioptically confirmed fibrosis of grade F2-F4. Extra-hepatic manifestations of hepatitis C are also an indication for treatment (vasculitis, glomerulonephritis, systemic cryoglobulinemia). The following factors are associated with a more favorable response to treatment HCV RNA 2 million copies ml HCV genotype 2+3 HCV antibodies HCV antibodies HCV RNA HCV RNA HCV genotype and viral load ALT FO+F1 F2-F4 HCV-RNA Figure 1 Hepatitis C treatment algorithm If possible, HCV should be treated before HIV. Reasons for this include the increased hepatotoxicity of HAART with concurrent hepatitis C possibly, impaired immune reconstitution resulting from hepatitis C...

Cholangiocarcinoma General Considerations Epidemiology

The incidence of bile duct tumors in large autopsy series varies from 0.01 to 0.2 and may constitute about 2 of all reported cancers (2). It is an uncommon cancer with an incidence of 1-2 per 100,000 in the United States (3). The majority of patients are more than 65 years, and the peak incidence occurs in the eighth decade of life (3). Cholangiocarcinomas are generally classified according to their site of origin within the biliary tree (Fig. 1), with those involving the biliary confluence, or hilar cholangiocarcinoma, the most common and accounting for approximately 60 of all cases (4-7). Twenty to thirty percent of cholangiocarcinomas originate in the lower bile duct, while approximately 10 arise within the intrahepatic biliary tree and will present as an intrahepatic mass (8-10). Less than 10 of patients will present with multifocal or diffuse involvement of the biliary tree (11). Recent reports have documented rising incidence and mortality rates associated with intrahepatic...

Posttranslational Processing Affects The Activity Of Many Proteins

Some animal viruses, notably poliovirus and hepatitis A virus, synthesize long polycistronic proteins from one long mRNA molecule. These protein molecules are subsequently cleaved at specific sites to provide the several specific proteins required for viral function. In animal cells, many proteins are synthesized from the mRNA template as a precursor molecule, which then must be modified to achieve the active protein. The prototype is insulin, which is a low-molecular-weight protein having two polypeptide chains with interchain and intrachain disulfide bridges. The molecule is synthesized as a single chain precursor, or prohormone, which folds to allow the disulfide bridges to form. A specific protease then clips out the segment that connects the two chains which form the functional insulin molecule (see Figure 42-12).

General Immune Enhancement

The largest was a 3-year study of 20,847 people that showed that substituting conventional table salt with table salt fortified with sodium selenite significantly reduced the incidence of viral hepatitis compared with controls provided with normal table salt (Yu et al 1989).

Differential Diagnosis

Patients usually present with radiological evidence of a solitary, intrahepatic tissue mass, often with satellite lesions. Percutaneous needle biopsy will demonstrate adenocarcinoma. Patients should be investigated for evidence of a primary tumor elsewhere gastrointestinal (GI) tract, lung, breast , since the most common diagnosis for adenocarcinoma in the liver is metastatic disease. In addition, hepatitis serology panel and serum a-fetoprotein levels should be drawn to rule out a poorly differentiated hepatocellular carcinoma. In the absence of an extrahepatic primary site, patients with biopsy proven adenocarcinoma in the liver should be considered to have an IHC. Immunohistochemical staining of the biopsy specimen may suggest a lesion of pancreaticobiliary origin, further supporting this diagnosis.

Characterizing the virally encoded 3Clike serine protease motif

Alignment of the astrovirus 3C-like serine protease motif with those of other viruses. The predicted 3C-like serine protease motif of human astrovirus serotypes 1 3 ( HAST1, 2 and 3 , GenBank accession numbers L23513, Z25771 L13745 and AR141381) were aligned with the 3C-like protease motifs of avian astroviruses (turkey astrovirus TAST , AF206663 avian nephritis virus ANV , protein accession number BAA92848), hepatitis C virus (HCV, P26664), tobacco etch virus (TEV Nia, P04517), murine hepatitis virus (MHV, 453423), hepatitis A virus (HAV, p26580), and human rhinovirus type 14 (HRV14, P03303) using the Pileup program. Motifs with Ser in the catalytic triad are shown in the upper panel and those with Cys (instead of Ser) are shown in the lower panel. Asterisks indicate residues that are conserved in all motifs compared. A filled circle indicates the amino acids (also shown in bold) predicted to form the catalytic triad, an inverted triangle represents...

Potential Side Effects

In order to predict any potential toxicity to patients, proper preclinical toxicology testing is critical. However, the currently available preclinical models do not fully reflect clinical settings. In addition, because the latent period of the insertional muta-genesis in patients was more than 2 yr, long-term safety evaluation, which is not always practical for preclinical testing, needs to be improved. Furthermore, a large proportion of cancer patients have other comorbid diseases that might affect the biodistribution and toxicity of these gene therapy agents. Patients with liver function impairment (e.g., liver cirrhosis and or chronic hepatitis) might have an impaired hepatic clearance of viral vectors in contrast, pulmonary uptake might be increased in these patients, as shown in animal models (45). It is also unknown whether patients with chronic viral infection (hepatitis B virus HBV , Epstein-Barr virus EBV , etc) will have acute exacerbation resulting from activation by viral...

Areas Of Promising Research

The impact of comorbidities on cancer survival must be explored. The incidence of various comorbidities varies within different ethnic groups. Knowing which co-morbidities affect each group and developing interventions that target specifics groups will enhance survival for all cancer patients. Oncology health care providers must be cognizant of what issues affect each particular racial ethnic group. A prime example of this is the atypical cancer burden suffered by Asian Americans. As opposed to other racial ethnic groups, cancer rather than heart disease remains the leading cause of death in Asian Americans.34 Coupled with the fact that this group also has an increased incidence of cancer caused by infectious agents such as cervical cancer and HPV, hepatocellular cancer and hepatitis B infection, interventions targeted to this group should be focused to address these particular causes.

Preoperative Imaging For Curative Resection Of Hepatocellular Carcinomamm

Recent progress in imaging techniques has facilitated the recognition of early HCC as a principal tumor in at-risk subjects who undergo regular medical check-ups for chronic viral hepatitis or cirrhosis (18). Both dynamic CT and dynamic MRI are highly sensitive methods that are useful for detecting hypervascular HCC (19,20). The recent development of multi-detector-row CT may further increase the sensitivity of this modality.

Disorders Of Fibrinogen

Appropriate levels of fibrinogen are necessary to maintain hemostasis and to cause platelets to aggregate. The reference range for fibrinogen is 200 to 400 mg dL. Fibrinogen is an acute-phase reactant, meaning that there will be a transient increase in fibrinogen during inflammation, pregnancy, stress, and diabetes and when taking oral contraceptives. Therefore, a careful patient history is necessary when evaluating a problem involving fibrinogen. For the most part, decreases in fibrino-gen result from acquired disorders such as acute liver disease, acute renal disease, or disseminated intravascular coagulation. Acquired increases in fibrinogen may be demonstrated in hepatitis patients, pregnant patients, or those with atherosclerosis.3 The inherited disorders of fibrinogen are afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia. These conditions are rare and are marked by hematomas, hemorrhage, and ecchymoses depending upon severity.

Current Status and Future Directions

Because of concerns of transmissible spongiform encephalopathies, animal sourced proteins and amino acids are currently under scrutiny. However, it should be kept in mind that the expression system described in this chapter is the mammary gland. Given the safety of milk and milk products in combination with the quality and regulatory precautions described, there is every reason to consider that proteins derived from transgenic animals should be safe with respect to possible virus and prion transmission. Many of the proteins that are expression targets today are currently available as human plasma derivatives, which have a measurable degree of risk for the transmission of HIV, hepatitis, parvo-, and other viruses, and Creutzfeld-Jakob disease.

Arathi Rao md Maria Mileno md

Table 1 refers to recommended childhood and adolescent immunization schedules. It represents the standard of care for immunizations beginning with newborn individuals. The range of ages considered for those who are on schedule are depicted with an extended arrow. Catchup immunization schedules are marked with a cui. Preadolescent assessment should be done ideally between ages 11 and 12, and recommended vaccines for this age group are depicted with an X. If a vaccine series is not completed during this age range, they can be administered at the next opportunity. Certain populations may also require Hepatitis A vaccine. Examples include travelers to endemic regions, healthcare workers, and HIV-, Hepatitis B-, and Hepatitis C-infected individuals. Table 2 refers to recommended immunizations for adults. Hepatitis B Hepatitis B Hepatitis A Hepatitis B Hepatitis A Hepatitis B Routine Hepatitis A Hepatitis B Hepatitis Hepatitis B Hepatitis A and B (combined) Exposure or anticipated...

Initial Postexposure Management

Healthcare workers sustaining blood or body fluid exposures should enact basic first aid practices to prevent infection. For percutaneous injuries, the sharp object should be removed and the injured body part washed with clean or sterile water. Hydrogen peroxide, povidone iodine, bleach, or alcohol solutions are generally harmful in wound management so should not be used. Soap solutions may be of benefit in cleaning the wound but likely do not mitigate the risk of transmission. Apply direct pressure to bleeding wounds with sterile bandages. A topical antibiotic may help reduce bacterial contamination and speed wound healing. Cutting wounds or expressing blood from wounds is not advised, as it will likely not reduce the risk of infection and will only cause further damage and risk of another percutaneous injury. Although there are no data on this subject for HIV- and hepatitis-contaminated wounds, closure of lacerations after proper irrigation should not increase the risk of HIV or...

Clinical Manifestations

The lesions are usually tender and the patient is usually unable to eat or drink. Patients with SJS appear acutely ill and may have generalized lymphadenopathy or even hepatosple-nomegaly. Arthralgias, hepatitis, nephritis, myocarditis, and gastrointestinal bleeding are occasionally seen.

Practical Issues of Peptide Immunization Assessed in Early Human Clinical Trials

One of the first considerations addressed in initial clinical trials of peptide-based vaccines was the route of administration. The primary routes of administration that have been used are the intramuscular, subcutaneous, and intradermal routes. The dose and volume of the vaccine itself, the choice of adjuvant, and the desired immune response have largely determined immunization route. There have been few human clinical peptide vaccine studies comparing the routes of administration. For example, one reported study used both an intramuscular and subcutaneous route for vaccination but did not have the power to detect a statistically significant difference in immune response (47). Early vaccine studies with peptide and protein subunit vaccines primarily used an intramuscular approach, based on the model of vaccination for infectious diseases (48-50). Most studies demonstrated evidence of antigen-specific antibody production, and one study showed evidence of a concomitant Th response...

Antigenantibody AgAb Complex Type Iii Reactions

Signs and symptoms include fever, a pruritic rash, lymphadenopathy, and joint pain. C. Incidence. This condition is rare because the use of serum is restricted to the treatment of a few diseases (e.g., hepatitis, tetanus) and immunosuppression. 3. Polyarteritis nodosa is characterized by continuous insult of arteriolar walls by the deposition of circulating Ag-Ab complexes, causing thrombosis and obliteration of blood flow. Frequently, hepatitis B-antibody complexes are involved.

Examples Of Economic Analyses In Biosurveillance

The study demonstrated not only that the outbreak had a substantial economic impact (in Milwaukee, 96.2 million) but that decreased worker productivity represented the largest economic consequence of the outbreak ( 64.6 million), a finding confirmed by studies of outbreaks of other diseases such as severe acute respiratory syndrome (SARS) (Achonu et al., 2005) and hepatitis A (Sansom et al., 2003). One implication of these studies for biosurveillance economic analyses is that any cost-of-illness study that fails to include productivity losses may seriously underestimate the potential impact of an outbreak. Outbreaks can be devastating to not only the health care system and directly affected individuals but also many businesses and the economy. This result, if further developed, may perhaps persuade individuals and organizations initially uninterested in biosurveillance to reconsider their stance. In fact, the Milwaukee study actually underestimated productivity costs by not accounting...

Reactive Lymphocytosis In Common Disease States

Reactive Lymphocytes Pics

In most cases, viral disorders affect the CBC in a similar pattern. Most have an increased white count with a depressed number of segmented neutrophils and an increased lymphocyte count. Conditions such as cytomegalovirus and hepatitis A, B, and C viruses may show reactive lymphocytes of a morphology similar to infectious mononucleosis. Cytomegalovirus (CMV) is a virus that is endemic worldwide. A member of the herpes family, this virus discovered in 1957 is similar to EBV. The virus has been isolated from respiratory secretions, urine, semen, and cervical secretions, but it also found in transplanted organs and donor blood. Indeed,

HIV and HBV coinfection Introduction

The hepatitis B virus is one of the most common human pathogens worldwide. Up to 95 of all HIV-infected patients have been infected with hepatitis B, and approximately 10-15 have chronic hepatitis B, with considerable variation among geographical regions and risk groups. It is estimated that around 100,000 HIV-infected patients in the USA suffer from chronic hepatitis B. Sexual transmission is the most frequent route of contraction. Transmission via the bloodstream is more probable than for HIV following a needlestick injury contaminated with HBV-infected blood, the risk of infection is around 30 (HCV approx. 2-8 HIV ap-prox. 0.3 ). Primary HBV infection leads to chronic hepatitis in 2-5 of immunocompetent adults, whereas HIV-infected patients experience chronification about five times more often. A possible reason for this is the HIV-associated T-cell defect. A polarization to a Th2-type response could result in the inhibition of specific cellular defense mechanisms (e.g....

Programs for Special Populations

Since special populations - for example, ethnic minorities, poor immigrants, and injection drug using (IDU) populations are concentrated in cities, the urban health services research literature includes many studies of programs for these groups (Solomon, et al., 1991 Juday, et al., 2003). Such programs include those for people with tuberculosis and HIV AIDS (Ryan White) as well as needle exchange and other programs for IDU populations. Infectious diseases like hepatitis, tuberculosis, and HIV AIDS spread rapidly in densely populated areas and cities are viewed as breeding grounds, as well, for social pathologies, e.g., drug use (New York Academy of Medicine, 2001). Some of this literature explores the prevalence of these conditions and identifies the risk factors for infection, but most studies examine the availability, use and performance of health care and social programs for specific subpopulations. Even broad-based interventions such as the RW Johnson's Urban Health Initiative,...

Combined Ocular Motor Nerve Palsies

Hepatitis, Epstein-Barr virus, Campylobacter jejuni, coxsackie virus, and nonspecific upper respiratory infections. Two of these, varicella103,521 and acute Epstein-Barr virus infection,184 precede or accompany the onset of Guillain-Barre syndrome with noteworthy frequency in children and young adults. Paresthesias, often painful, commonly appear early in the course, and signs of meningeal irritation may also appear early in children. Although a rise in CSF protein levels without pleocytosis is the rule, it generally does not occur for several days to weeks after the onset of symptoms and, in a small percentage of patients, is not observed at all. The patient should be referred to a neurologist for management in a hospital setting with materials for tracheostomy and mechanical ventilation readily available.