Hcv Infection 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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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

Evolutionary Dynamics of HCV Envelope Genes

HCV can be classified into six genetically distinct genotypes and further subdivided into a large number of subtypes, of which the six major genotypes differ by approximately 30 and the subtypes differ by 20 -25 at the nucleotide level (Simmonds et al. 2005). A significant challenge for vaccine and immunotherapeu-tic development is the identification of protective epitopes conserved in the majority of viral genotypes and subtypes. This problem is compounded by the fact that the envelope E1E2 proteins, the natural targets for the Vn response, are two of the most variable proteins (Bukh et al. 1995). The error-prone nature of the RNA-dependent RNA polymerase together with the high HCV replicative rate in vivo (Neumann et al. 1998) results in the production of viral quasispecies (Martell et al. 1994 Bukh et al. 1995). Quasispecies can respond to and overcome a variety of selective pressures including host immunity (Cooreman and Schoondermark-Van de Ven 1996 Cooreman and Schoondermark-Van...

Human Immunodeficiency Virus And Viral Hepatitis Infection

The viral infections which are of interest to clinicians, and especially surgeons, are human immunodeficiency virus (HIV) and hepatitis B and C viruses (HBV and HCV). This stems from their transmission risk from patient to healthcare worker or vice versa. Guidelines for reducing the risk of transmission of HIV, HBV and HCV are available for healthcare workers. Their main objective is to minimize exposure of any individual to blood and body secretions regardless of infective status of the second individual involved. Routine serological testing for HIV is not recommended. The debate over testing has not been made easier by the finding that prior knowledge of HIV status does not decrease the risk of transmission. In addition, a negative test does not exclude HIV infection as a seroconversion window exists which may last up to 3 years and during which a person may have circulating antigen but has not yet produced the antibody. If testing is required, consent must be obtained and, if...

Virus Neutralization with HCVRetroviral Pseudoparticles

A robust means to analyze Vn potency and breadth is the infectious HCV retroviral pseudoparticle (HCVpp) system, whereby infection by retroviral particles containing an appropriate reporter gene is mediated by HCV E1E2 envelope proteins (Bartosch et al. 2003b Bartosch et al. 2003c Hsu et al. 2003). These HCVpp preferentially infect human hepatocytes and hepatocellular cell lines, and the E1E2 present in these particles has been shown to represent the functional and antigenic noncovalent E1E2 heterodimer formed by their recognition by a panel of conformation-dependent E2-specific HMAbs (Op De Beeck et al. 2004). All E2 HMAbs to conformational epitopes were able to immunoprecipitate HCVpp, suggesting their expression on the HCVpp surface (Keck et al. 2004a). Studies with HCVpp have provided important insights into the early stages of virus entry (Bartosch et al. 2005, 2003c Goffard et al. 2005 Lavillette et al. 2005 Voisset et al. 2006). With genotype 1b HCVpp infection on Huh-7 cells,...

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.,...

CoInfection with Hepatitis C

Hepatitis C is a blood-borne infection, transmitted through contaminated blood, injection drug use equipment, and, less efficiently, through sexual intercourse. Prevalence of hepatitis C among the HIV-infected population is about 30 worldwide, but can vary from 10.4 in an Asian Pacific cohort (TREAT Asia HIV Observational Database) (20) to 51 in a largely injection drug use population in Columbia, Canada (21). In the United States and Europe, estimates are that 25 of HIVpositive individuals have hepatitis C infection as well. More recently, acute hepatitis C outbreaks are being reported among men who have sex with men (21, 22). Hepatitis C infection has emerged as an important cause of morbidity and mortality concomitant with the decline in HIV-related morbidity and mortality associated with effective antiretroviral treatment.

Virus Neutralization with Cell Culture Infectious HCVVirions

Three groups recently developed full-length HCV RNA genomes that are able to replicate efficiently and produce infectious viral particles when transfected into human hepatoma cells (Huh-7) (Lindenbach et al. 2005 Wakita et al. 2005 Zhong et al. 2005). The availability of these and other cell-cultured infectious HCV virions (HCVcc) should greatly accelerate studies of HCV biology (Cai et al. 2005 Lindenbach et al. 2005 Pietschmann et al. 2006 Wakita et al. 2005 Yi et al. 2006 Zhong et al. 2005). Another group reported that stable human hepatoma cell lines containing a chromosomally integrated cDNA of HCV genotype 2a (JFH1) RNA constitutively secrete HCVcc into the medium (Cai et al. 2005). Employing this source of HCV virions, HMAbs to three distinct immunogenic domains on HCV E2 to neutralize HCVcc were tested (Keck et al. 2007). Vn was determined by measuring the levels of HCV NS3 protein expression by Western blot analysis. Figure 6 shows the inability of each domain A HMAb and the...

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

HCV Infection of B Cells Induces Ig Hypermutation Altering B Cell Immunity

Besides chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, HCV infection is also frequently associated with B lymphocyte proliferative disorders, including mixed cryoglobulinemia, a disorder characterized by oligoclonal proliferation of B cells, and non-Hodgkin's B cell lymphoma (Silvestri et al. 1997). These B cell diseases may be the result of infection of B cells by HCV or the activation of B cells by HCV envelope proteins. The HCV envelope proteins E1 and E2 are type I transmembrane proteins, with N-terminal ectodomains and C-terminal hydrophobic anchors. It has been suggested that HCV infects human cells through the interaction of E2 with a tetraspanin molecule CD81. CD81 is thought to be a cellular receptor for HCV, based on its ability to bind E2 (Pileri et al. 1998 Hsu et al. 2003 McKeating et al. 2004 Zhang et al. 2004). CD81 is a member of the tetraspanin family and is a component of the multimeric B cell antigen receptor complex (Levy et al. 1998). It 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...

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

Adventitious Agents Hepatitis B and Avian Leucosis Viruses in 17D Chick Embryo Vaccine

Early manufacturing procedures for yellow fever 17D vaccine included the addition of nonimmune human serum to the tissue culture fluid and to the final vaccine as a stabilizer. As early as 1937, Findlay and McCallum noted the occurrence of acute hepatitis occurring 2-7 months after 17D yellow fever vaccination 72 . Similar cases were reported in Brazil by Soper and Smith 73 . There were lessons from history transmission of hepatitis by human blood had been described as early as 1885, caused by smallpox vaccine prepared from human lymph 74 , and in the 1930s, there was an outbreak of jaundice among recipients of human measles and mumps-convalescent plasma 75 . However, with the advent of World War II, large numbers of military personnel were immunized with vaccine prepared in New York with pooled human serum. In 1942, a massive outbreak of jaundice occurred, with approximately 28,000 cases and 62 deaths from fulminant hepatitis 78 . Investigation into this outbreak was coordinated by...

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...

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).

Is the Neurocognitive Profile of HAND Changing and What Are the Effects of Age HCV and Gender

However, direct cohort comparison is potentially fraught with difficulty in interpretation. Some authors argue that the interpretation of a difference may be due to unknown factors. Nevertheless, because of the intrinsic complexity of the disease, historical cohort comparisons should remain a potential strategy coupled with prospective studies in the HAART era. Factors, such as rapidly evolving treatment, significant changes in demographic characteristics of the HIV epidemic including more women and more minorities, aging, and HCV coinfection render the interpretation of HAND profile change in longitudinal data in the HAART era very complex as well.

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. The probability of transmission from needlestick injuries after exposure to HCV-contaminated blood is 2-8 , compared to only 0.3 after exposure to HIV-contaminated blood. In contrast, sexual transmission of HCV occurs significantly less frequently than HBV or HIV. As a result,...

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 (about 15 times). Following the decrease in HIV mortality, an increase of liver-associated mortality has been observed (Thio 2002, Konopnicki 2005). In addition to increasing mortality, HIV coinfection accelerates the progression of hepatitis B and increases the risk of cirrhosis. Despite the worsening described, initially the clinical course is usually more benign in HIV-positive patients, although viral replication is increased. This seems contradictory at first, but can be explained by the impairment of cellular immunity, which may lead to an increase in viral replication, but at the same time also reduces hepatocyte damage. Therefore, transaminases in HBV HIV-coinfected patients are frequently only mildly increased. In contrast, HBV DNA, as a marker for viral replication, is higher than in immunocompetent...

The Potential Additive Effect of HCV and HIV on the Brains

There is evidence that approximately 30 of HCV+ individuals with mild liver disease present at least mild neuropsychological dysfunction that is independent of substance use and other comorbid factors such as depression and fatigue (107). From a series of six studies (104, 108-112), it appears that the most robust cognitive dysfunction was found in domains of sustained attention and complex attention as well as motor functions compatible with fronto-striatal models of neurocognitive impairment (113). An additive or synergistic effect of HCV in HIV-infected individuals has been hypothesized and there is an emerging evidence that coinfected subjects are more likely to be neuropsychological impaired, (104, 114) particularly in tests of executive functions (111, 115) and psychomotor speed (114).

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...

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...

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...

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...

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...

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...

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...

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...

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...

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 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 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...

Acute Hepatitis C

During recent years a constantly growing number of cases of acute hepatitis C has been observed in homosexual men. These mainly had had contacts with high risk of infection (e.g. use of sex toys, fisting). As HCV-antibodies are produced only long time after infection, diagnosis of acute hepatitis C is made according to history, elevated transaminases (ideally normal before) and positive HCV-RNA. The optimal management of acute hepatitis C remains unclear. Data available so far show an improved response rate of about 60 (up to 80 in genotype 2 3) if treatment is initiated early (Vogel 2005). These data support early treatment even in the presence of HIV coinfection. On the other hand spontaneous clearance after acute infection might be better than previously expected. The following aopproach might be feasible In case of symptomatic acute hepatitis C (especially jaundice), patients are followed for 12 weeks in order to await possible spontaneous clearance. Patients with asymptomatic...

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 Virus

HBV is a partially double-stranded DNA virus that is transmitted by direct contact with infected bodily fluids (Hollinger and Liang 2001). In normal individuals, hepatitis B will generally induce a self-limited hepatitis, but it has the capacity to establish a chronic active state that can eventually lead to cirrhosis or hepatocellular carcinoma. In the United States, hepatitis B immune globulin (HBIG) is prepared from a small number of donors hyperimmunized with the HBsAg vaccine (Terrault and Vyas 2003). The main three categories of use for HBIG are (1) post-exposure prophylaxis for nonimmune contacts, (2) inhibition of vertical transmission of the virus at birth, and (3) prevention of relapse in HBV-positive patients following orthotopic liver transplantation. Following a suspected infected needle-stick or fluid exposure, HBIG is recommended to be administered in combination with the HBsAg vaccine (CDC 1984). Maternal-fetal transmission can be inhibited by administration of HBIG...

Hepatitis B and C

Electrophysiological measures have mainly been used to assess the side effects of interferon treatment on cognitive and psychological function in patients with hepatitis B and C (Tanaka et al, 2004). In one of the earliest reports of this kind, hepatitis C patients who were treated with interferon-alpha had higher delta, theta-1, and theta-2 power values, and lower alpha-2 and beta power values as measured by EEG (Kamei et al, 2002). These changes were recorded when comparing baseline values to those obtained during the course of treatment. Another study compared baseline EEG recordings and psychological functioning to that assessed at various time points during interferon treatment in hepatitis B and C patients, abnormal EEG activity (e.g., general slowing of the basic rhythm and of the alpha wave) was associated with increased incidence of various psychological symptoms including mania, depression, and sleep disorders (Tanaka et al, 2004). This association appeared to be independent...

History of Hepatitis

Hepatitis is an apt subject for discussions of the history of vaccination, since it is clearly an example of recognizable diseases of ancient recorded history, as well as of clinical diseases of diverse and multiple etiologies. Hepatitis, with its distinguishing yellow jaundice, must have been a recognizable feature for an illness of human beings ever since the species discarded its hairy overcoat in favor of the buff. Table l Brief history of hepatitis Yellow fever vaccine and dirty synage cause serum hepatitis Definitive experimentation Hepatitis A and B named History records the occurrence of icteric disease as early as 400 bc (Table 1) 1, 2 . The concept of contagiousness was evolved during the millennium from 700 to 1700 ad. This was followed by two centuries of endless and illiterate argument about the causation of the disease, in spite of compelling examples of epidemics of campaign jaundice in the military that indicated its infectious nature. Infectious etiology was well...

Hepatitis A

The history of hepatitis A research and the development of the vaccine is identifiable principally in the pioneering work carried out in our laboratories since 1969 2 . An effective vaccine has also been developed by others, at the SmithKline Beecham Laboratories in Belgium 19 . Research studies in our laboratories on hepatitis A are separable into two time periods (Table 3) the marmoset era and the vaccine era 2 . The initial success was the isolation of the Costa Rican CR326 strain of hepatitis A in marmosets and its establishment as the cause of the human disease 7, 20 . Table 3 Historic evolution of hepatitis A vaccine Table 3 Historic evolution of hepatitis A vaccine More specifically, serum neutralization, complement fixation, and immune adherence tests were developed for assay of hepatitis A antigen and antibody 21-25 . Appearance and persistence of specific antibody followed hepatitis A infection, and there was no serologic relationship to hepatitis B. Seroepidemiologic...

Hepatobiliary Malignancies

Physicians and physician assistants in the GI Tumor Center at M. D. Anderson evaluated more than 900 new patients with primary or metastatic hepatobiliary tumors in 2002. Patients with primary liver cancer include those with hepatocellular carcinoma (HCC), gallbladder cancer, and intrahepatic or extrahepatic cholangiocarcinoma. Patients with liver metastases from other organ sites, most commonly colorectal adenocarci-noma, and with disease confined to the liver may be considered for surgery, tumor ablation, regional chemotherapy, or systemic chemotherapy. The initial screening evaluation of new patients includes a thorough review of outside medical records, pathologic assessment of any surgical or needle-biopsy specimens, and review of prior diagnostic CT scans and plain radiographs. Once again, a thorough history and physical examination are mandatory. In patients with liver metastases, recent assessment of the primary site of disease, such as colonoscopy for colorectal cancer, is...

HIV nucleic acid testing NAT

Qualitative testing for viral genome serves as a marker of infection. It supplements antibody testing for the diagnosis of HIV infection in special situations (suspected primary infection absence of antibodies during the diagnostic window newborn of infected mother presence of maternal antibodies - also see below). The quantitative detection of HIV RNA in plasma (viral load testing) is used as a prognostic marker, to monitor antiretroviral therapy and to estimate infectiousness (Berger 2002). Ultra-sensitive tests detect as few as 50 copies per millilitre of plasma. Both as a prognostic and as a therapeutic marker, viral load testing is today an indispensable clinical tool. Unfortunately, though, many developing countries cannot afford the currently available assays (Drosten 2006, Fiscus 2006). The risk of HIV transmission through blood transfusion has decreased enormously through careful selection of donors - to exclude people with potential risk factors for blood-borne viral...

Special case occupational HIV exposure see also chapter on PEP

If the index patient is known, he or she should be tested - after relevant counseling and with consent - for HIV and HCV antibodies and for HBsAg. According to the circumstances (e.g. weekend), the use of a rapid assay should be considered (see above). As any delay in instituting HIV post-exposure prophylaxis (HIV PEP) reduces its chances of success (Puro 2004, Panlilio 2005) If there is any doubt, the first one or two doses of HIV PEP (hopefully always readily available as a so-called starter pack) should be taken and later discontinued once a negative test result becomes available

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)...

Human Subjects Research in the United States after World War

A number of studies cited by Beecher became notorious on their own. In a study of immunity to cancer at the Jewish Chronic Disease Hospital (New York), investigators injected live cancer cells into human subjects without obtaining informed consent. Another study involved the deliberate induction of infectious hepatitis (to understand better the natural history of the disease) in mentally impaired children who were residents at the Willowbrook State School for the Retarded (New York). The ethical concerns raised by this study were the

Materials And Methods

And DU-PAN-2 Glycoproteins 136 CCND1 136 Cyclooxygenase-2 136 Glypican-3 137 Hepatitis B XAntigen 137 HER-2 neu 138 Carcinoma 142 Hepatitis B Virus 142 Hepatitis C Virus 143 Risk Factors 143 Treatment of Hepatocellular Carcinoma 153 Natural History of Hepatocellular Carcinoma 154 Chronic Hepatitis 155 Cirrhosis 155 Phenotypic Alterations and Dysplasia 156 Emergence and Progression of Hepatocellular Carcinoma 156 Etiology of Hepatocellular Carcinoma in Humans 156 Hepatitis Viruses 157 Aflatoxins 157 Introduction 207 Epidemiology of Liver Cancer 207 Hepatitis, Liver Cirrhosis, and Liver 11 Role of Hepatitis B Surface Antigen in Hepatocarcinogenesis 229 Introduction 229 Hepatitis B Virus and Hepatocellular Carcinoma 229 Hepatitis B Virus Integration and Hepatocarcinogenesis 229 Role of Hepatitis B Surface Antigen and Hepatocellular Carcinoma 230 Detection of Hepatitis B Surface Antigen in Hepatocellular Carcinoma 230 MATERIALS 230 Immunohistochemistry 230 Southern Blot Analysis 231...

Interoperating With Other Organizations

FIGURE 5.7 Health Alert Network. a, Screenshot of an official Pennsylvania Health Advisory related to the hepatitis A outbreak described in Chapter 2. This was distributed only to Pennsylvania clinicians and alerted clinicians about an immune globulin clinic and reminded them of their need to report hepatitis A cases (CDC, 2005f). FIGURE 5.7 Health Alert Network. a, Screenshot of an official Pennsylvania Health Advisory related to the hepatitis A outbreak described in Chapter 2. This was distributed only to Pennsylvania clinicians and alerted clinicians about an immune globulin clinic and reminded them of their need to report hepatitis A cases (CDC, 2005f).

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 may be 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...

What should be clarified beforehand

The risk of developing severe hepatotoxicity on nevirapine or ritonavir is highest in patients with a history of liver disease and chronic hepatitis (Den Brinker 2000, Sulkowski 2000). Caution is also required with boosted PIs. However, one study conducted in over 1,000 patients found no difference between lopinavir ritonavir and an unboosted PI such as nelfinavir in patients co-infected with hepatitis C (Sul-kowski 2004). In co-infections with HBV, 3TC or FTC (not simultaneously ) in combination with tenofovir should ideally be used. Active hepatitis B Active hepatitis C Potential additive toxicities should also be considered in the choice of therapy. If other myelotoxic drugs (valganciclovir ) are necessary, caution is required with AZT. The same is true for dapsone and co-trimoxazole. When treating hepatitis C

Health Care And Governmental Public Health

In addition, the workflow processes related to detection and characterization of outbreaks would be distributed optimally across both domains to maximize the efficiency and speed of the biosurveillance process. Most clinicians are capable, for example, of making observations needed to complete a case-investigation form, but at present this is a task conducted by a health department. Considerable efficiency and speed-up may be possible if IT were to enable a physician to elicit and record more epidemiologically relevant data about a patient with hepatitis A at the time the patient presents in the office setting. This level of integration is many years in the future and requires a rethinking of current systems that takes into account the potential of IT to enable conceivable, but previously impossible, configurations of organizations and workflows.

Infections in Human Populations

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

Toxicity Associated With Traditional Use by Native Populations

A healthy 14-year-old adolescent girl developed nausea, vomiting, general malaise, and weight loss. Several days later she became icteric and was admitted to hospital with acute hepatitis. Drug history revealed no alcohol use two kava products and occasional ibuprofen had been used over the preceding 4 months. The packaging of the kava products was unavailable for identification purposes. Liver biopsy revealed active fulminant hepatitis with extensive necrosis and tests for viral hepatitis were negative. She underwent a successful liver transplantation and was able to return to normal activity upon recovery (34). Unfortunately, no information was provided indicating that acetaminophen toxicity had been ruled out, and the observed toxic effect could also have been associated with a large, undiagnosed acetaminophen ingestion. A 33-year-old woman took 210 mg of kava extract for 3 weeks and discontinued the product. After 2 months, she resumed taking the same product for an additional...

Changing Demography And Its Impact

The age distribution of infection is governed by the intrinsic transmissibility of the infection, by contact patterns between age groups, and by the age distribution of immunity from past infection. Thus, changes in age distribution of the population itself will impact upon the transmission dynamics of infection, perhaps in complex ways, and these in turn will impact upon the future age distribution of infection and disease and of susceptibility and immunity the ''echoes'' of such perturbations in the dynamics of infection have the potential therefore to persist for a number of years (Williams and Manfredi, 2004). The processes of infection and disease are often strongly age related, so that changes in age at infection may have important consequences for the number of deaths or cases of serious disease. Well-known examples are rubella, mumps, and poliomyelitis in which infection of young children is likely to have few long-term consequences, but infection of young adults may have...

Within Hostimmune System Models

The compartmental differential equation models described earlier are also adaptable to the study of the dynamics of the immune system in response to infection. Such models can provide novel and useful insights into the observed time course of quantitative clinical measures of infection within the human host and how these might relate to the probable course which may be taken by the infection by providing explanations for observed dynamical changes in such measures they also offer the prospect of illuminating some of the reasons why response to infection appears to differ between hosts. Useful examples of such work may be found in work on HIV by Nowak and Bangham (1996) and Nowak et al. (1997), and on viral hepatitis by Bocharov et al. (2004).

Importance Of Anatomy And Animal Research

Likewise, animal research has been fundamental for much of the progress made in medicine. Most, if not all, of what we know about the human body and biology in general has been initially made possible through animal research. A1989 American Medical Association publication, cited in ref. 2, listed medical advances that had emanated from animal research, including studies on acquired immunodeficiency syndrome (AIDS), anesthesia, cardiovascular disease, diabetes, hepatitis, and Parkinson's disease, to name only a few.

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

Antibodies to Linear Epitopes

While Vn E1 antibodies have been described (Keck et al. 2004a Dreux et al. 2006 Pietschmann et al. 2006), the majority of antibodies in natural infection are targeted to the E2 protein. Antibodies that demonstrate broad Vn capacity described to date generally tend to be directed against conformational epitopes within E2 (Habersetzer et al. 1998 Ishii et al. 1998 Allander et al. 2000 Hadlock et al. 2000 Bugli et al. 2001). However, Vn antibodies that recognize linear epitopes within HCV E2 have also been reported. Farci et al. (1996) first described a rabbit hyperimmune serum directed against HVR1 of E2 that was able to neutralize virus in vitro and thus protect chimpanzees in experimental infections. Subsequently, Zibert et al. (1995, 1997) showed that patient antibodies to HVR1 as well as a rabbit immune serum to that region were able to specifically block virus binding to cells. More recently, antibodies targeting this region have been shown to inhibit binding of E2 to cells...

The Natural Immune Response to Htlvi Infection

Several successful viral vaccines have been devised that have prevented significant disease morbidity and mortality throughout the world. These include vaccines for polio, small pox, measles, and the world's first genetically engineered vaccine the recombinant hepatitis B virus vaccine. In all of these cases, the vaccines have been successful because they were designed to prevent only the appearance of disease and because the target viruses are intrinsically genetically stable. In contrast, there are many other viral infections for which vaccines have been only partially successful, such as for influenza viruses and herpes simplex virus, or are difficult to develop, as with HIV-1 and hepatitis C virus. With the latter viruses, issues such as high genetic variability, viral integration into the host genome, viral latency, the need for mucosal immunity, and or a requirement for long-lasting sterilizing immunity need to be addressed. HTLV-I vaccine prospects most closely resemble those...

The risks resistance clinical problems AIDS

The sharp increase in viral load that may often occur can present as a retroviral syndrome. The symptoms are similar to acute HIV infection, with lymphadenopa-thy, fever, asthenia and malaise (Colven 2000, Kilby 2000, Zeller 2001, Ruiz 2004). Thrombocytopenia has also been described during interruptions (Ananworanich 2003). The blood count needs to be monitored, especially in patients with a previous history of thrombocytopenia. Finally, attention should also be paid to patients who are co-infected with hepatitis B virus. If the HBV treatment with 3TC, FTC or tenofovir is interrupted, HBV rebound can result in fulminant and life-threatening hepatitis (Sellier 2004). It is therefore advisable to look after these patients very carefully and monitor the liver enzymes at least every two weeks.

Mechanisms of Virus Neutralization

HCV is a member of the family Flaviviridae and is composed of three structural proteins, capsid, two envelope proteins, E1 and E2, and six nonstructural proteins (Robertson et al. 1998 Lindenbach and Rice 2001 McLauchlan et al. 2002). Similar to other flaviviruses, virus entry is thought to be mediated by envelope proteins, which are responsible for virus attachment and receptor-mediated endocytosis where a low pH environment in the endosomes triggers conformational structural changes leading to virus envelope fusion with the endosomal membrane (Bartosch et al. 2003c Hsu et al. 2003 Op De Beeck et al. 2004). Antibody binding to E1 or E2 epitopes on virion surface should then lead to Vn by a number of mechanisms (Smith 2001 Fig. 9). First, HCV antibodies may mediate aggregation of virus particles, leading to a reduced number of infectious virions, the pentameric status of IgM therefore being associated with increased neutralization potency. Second, the prevailing view for some viruses...

Biological Processes Linking Positive Well Being and Health

The cross-sectional single measure approach has demonstrated some important associations between the activation of health-related biological pathways and positive well-being. For instance, we carried out a study of 2873 healthy men and women in which in an inverse relationship between the positive affect and the inflammatory markers, C-reactive protein and IL-6, was observed. These affects were independent of age, ethnicity, socioeconomic position, body mass, smoking, and depressed mood (Steptoe et al, 2008a). However, they were found in women only and not in men. Interestingly, low IL-6 was also related to high ratings on measures of eudaimonic well-being in a sample of older women in Wisconsin (Friedman et al, 2007). Positive affect has also been linked with functional immune measures such as heightened antibody responses following vaccination for hepatitis B, independently of age, gender, health behavior, and negative affect (Marsland et al, 2006).

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....

Mechanisms of Immune Escape

The mechanisms of viral escape include mutational escape from humoral (see Sect. 2, Evolutionary Dynamics of HCV Envelope Genes) and cellular immunity, and viral infection of immune cells that leads to the induction of Ig hypermutation. The latter phenomenon is associated with a reduction in binding affinity and Vn activity of antibodies that are specific for HCV envelope proteins. Furthermore, antibody-dependent enhancement of infection and potential roles of lipoproteins and glycans to modify antibody binding to epitopes mediating Vn have been described (Voisset et al. 2006 Nielsen et al. 2006 Germi et al. 2002).

Mutational Escape from Cellular Immunity

The relationship between cell-mediated immunity and the outcome of HCV infection has been established by numerous studies. Memory CD8+ cytotoxic T cells (CTL) are required for protection against persistent HCV infection at the same time, durable intrahepatic memory is likely established during acute HCV infection, since T cells recognizing HCV antigens have been recovered from the livers of chimpanzees several years after spontaneous clearance of infection (Shoukry et al. 2004). Consequently, the outcome of HCV infection may be dictated by escape mutations in the epitopes targeted by CTL (Erickson et al. 2001). On this issue, one report demonstrated that CTL escape mutations occurred in persistent HCV infection (Cox et al. 2005). A second report described that divergent and convergent virus evolution after a common-source outbreak of HCV affected disease outcome (Ray et al. 2005). Immune evasion leading to persistent infection, in contrast to recovery from viral infection, after acute...

Antibody Dependent Enhancement of Infection

Complement-mediated enhancement of antibody function for neutralization of pseudotype virus containing HCV E2 chimeric glycoprotein has been reported (Meyer et al. 2002). Significant increases in the neutralization titers of E2 HMAbs and rabbit antiserum to HVR1 mimotopes have been observed upon addition of guinea pig complement. Complement activation occurred primarily by the classical pathway, since a deficiency in the C4 component led to a significant decrease in the level of Vn. During infection, HCV E2 glycoprotein induces a weak Vn antibody response these antibodies can be measured in vitro by the surrogate pseudotype virus plaque reduction assay, and the neutralization function can be augmented by complement (Meyer et al. 2002). Therefore, it is possible that complement activation enhances infection, and lipoproteins and glycans can modify antibody binding to epitopes mediating Vn.

Applications of Adenoviral Vectors in Gene Expression

Hepatitis B virus surface antigen (HBsAg) has been produced from Ad-infected cells using a wide variety of strategies. In one case the HBsAg gene, driven by the MLP either with or without inclusion of TPL sequences, was inserted in place of the Ad5 El region (Davis et al., 1985), and addition of the TPL resulted in approximately a 70-fold increase in protein synthesis. As expected for expression driven by late viral regulatory elements, the appearance of HBsAg in the medium was observed at late times (10-20 hr

Analytical epidemiology

In an experimental or interventional study, individuals are randomly allocated to be included in a study group, which is exposed to a factor under study or allocated to a non-exposed control group. Such studies offer the most direct and conclusive method of establishing a causal relationship between a risk factor and a cancer. Although the introduction of a suspected risk factor may happen opportunistically, as in irradiation following the atomic bombs in Japan, the introduction of harmful measures (or withdrawal of beneficial ones) from random sections of the population is not ethical. Although this study design is standard for assessing the effects of treatment, it is applicable only to epidemiological studies of primary or secondary prevention for example vaccination against hepatitis B or screening for breast cancer. Such large and expensive population studies will become more frequent as chemoprevention becomes a reality.

Potential Roles ofLipoproteins and Glycans to Modify Antibody Binding to Epitopes Mediating Vitus Neutralization

Lipoproteins, high-density lipoproteins (HDL), low-density lipoproteins (LDL), and very low-density lipoproteins (VLDL) could potentially reduce the neutralizing effect of the HCV-specific antibodies by promoting HCV entry (Voisset et al. 2006). In studies on HCVpp, HDL inhibits HCV Vn antibodies by stimulating cell entry via activation of the scavenger receptor BI (SR-B1). SR-B1 mediates lipid transfer and is proposed as a cell entry cofactor of HCV (Dreux et al. 2006). HDL interaction with the SR-BI has been shown to strongly reduce Vn of HCVpp by Vn MAbs and HMAbs (Dreux et al. 2006). For serum and liver HCV virions, it is probable that VLDL LDL are involved in virus entry (Nielsen et al. 2006). The majority of serum and liver HCV RNA can be precipitated by antibodies to apolipoprotein B and apolipoprotein E. As to the site of lipoprotein linkage to virions, a study on intracel-lular infectious HCVcc and extracellular infectious HCVcc suggests that acquisition of lipoproteins might...

Clinical Manifestations

Oral hairy leukoplakia, a collection of hairy or corrugated white lesions located on the lateral surface of the tongue, is common. Sometimes splenomegaly or mild hepatitis may develop. Uncommon manifestations include heart problems, jaundice, pneumonitis, blood dyscrasia, and cerebritis (2). In patients with HIV infection, infection of epithelial cells by EBV is often represented by oral hairy leukoplakia.

Heat Shock Proteins As Vaccine Vehicles

The class B SR subfamily contains the CD36, SR-B and lysosomal integral membrane proteins 2 (LIMP-2) genes. The SR-B gene encodes two proteins resulting from alternative splicing of the transcript, SR-BI (CLA-1) and SR-BII (Acton et al., 1994 Murao et al., 1997 Webb et al., 1997). Class B SR are type III (multiple transmembrane domains) membrane glycoproteins. CD36 and SR-BI can form dimers and multimers (Reaven et al., 2004 Thorne et al., 1997). A leucine-isoleucine motif within the C-terminal cytoplasmic tail determines lysosomal localization of LIMP-2. CD36 is expressed on monocytes, macrophages, endothelial cells and platelets. SR-BI expression is restricted to liver, adipocytes, macrophages and DC. Class B SR recognize several non altered and altered self ligands such as native LDL, OxLDL, high density lipoproteins and very low density lipoproteins, collagen, thrombospondin and apoptotic cells (Acton et al., 1996 Calvo et al., 1998 Puente Navazo et al., 1996 Rigotti et al., 1995...

Complications And Prognosis

Splenomegaly, palatal petechiae, and hepatomegaly develop in another 10 of infected patients. The main serious complication is enlarged spleen and its possible rupture. Less common complications include hemolytic anemia, thrombocytope-nia, aplastic anemia, myocarditis, hepatitis, rash, and neurologic complications, such as Guillain-Barre syndrome, encephalitis, and meningitis.

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...

Some Effects of Drug Abuse in the Brain Mimic Those of HIV

Drug abuse is clearly a confounding factor in assessing the effects of HIV in the brains of pre-symptomatic and some AIDS subjects, and the influence of drug abuse on the CNS must be considered together with HIV in this context. The problem of drugs as possible co-factors for AIDS progression has been explored in animal models and in vitro (52). Drug abuse is known to cause mild activation of microglia, possibly adding to the neuroinflammatory response observed in pre-symptomatic subjects (5). Axonal injury as shown by expression of pAPP is also evident in the brains of HIV-negative drug abusers (53, 54). A number of studies have demonstrated other neuronal and dendritic damage in HIV-negative drug abusers (53-56). Some of this CNS damage is undoubtedly hypoxic ischaemic in origin. Intravenous drug abusers are at risk of co-infection with hepatitis B or C. Liver dysfunction, particularly cirrhosis, can cause hepatic encephalopathy, contributing to cognitive problems in this group of...

Neuropathological Findings in the PostHAART

The introduction of HAART has resulted in a marked improvement in the prognosis for HIV-infected subjects, with HIV becoming a chronic disease in those who are compliant with long-term HAART. AIDS defining illnesses are no longer the major cause of death in HIV. Instead other factors such as hepatitis C infection are becoming important in HIV-related mortality. Drug abuse continues to contribute to mortality in these circumstances. The benefits of HAART are apparent not just in the systemic organ systems, but also in terms of CNS disorders despite the poor penetration of The success of HAART in reducing mortality rates has meant that opportunities for autopsy-related study of the effects of HIV on the brain have become much less common. Nevertheless small cohorts of clinically well characterised, HAART-treated subjects have been examined at post-mortem by a number of groups in the US and Europe. It is important to note that the cause of death in these cases may not be directly...

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...

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 (Bergmannand Gerin 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...

How safe is blood transfusions

In the UK, most of the information about the safety of blood transfusions comes from the Serious Hazards of Transfusion (SHOT) scheme, which is a national reporting system for serious complications of blood transfusion. The Sixth Annual Report was published in July 2003. Data from SHOT provides great evidence about the risks of transfusions. In the UK each donated unit of blood is tested for HIV, Hepatitis B and C, syphilis, and red blood cell typing for ABO and RH(D) antigens is performed. A donated unit of blood can either be transfused whole (e.g. for babies) or split into several components that can be transfused to different patients. A request for group and save results in the patient's blood being typed for ABO and RH(A) antigens, and the plasma being tested for antibodies that could lyse red cells at 37 C. A request for a blood product results in a full cross-match between the patient's blood and the unit of blood product to be transfused (Fig. 11.12).

RNAi In Clinical Cancer Therapy

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

Integration of Expression Vectors into the P pastoris Genome

An alternative integration strategy is available with P. pastoris expression vectors that contain an additional fragment derived from sequences 3' of the AOX1 gene (Fig. 2) (Cregg et al., 1987). These vectors can be cut with selected restriction enzymes that release the expression cassette (i.e., the fragment containing the promoter, foreign gene, and terminator) and HIS4 gene on a DNA fragment flanked by AOX1 5' and 3' terminal sequences. Approximately 10-20 of His+ transformation events with these vector fragments are the consequence of a gene replacement event in which the AOX1 gene is deleted and replaced by the expression cassette and HIS4 gene (Fig. 4B). The resulting strains are forced to rely on the transcriptionally weak AOX2 gene for growth on methanol and, as a result, metabolize methanol at a greatly reduced rate. These gene replacement strains are easily identified among His+-transformed colonies by replica plating them to methanol and selecting those with reduced ability...

Transfusiontransmitted infections

The chance of receiving an infected unit from a British donor is now as low as 1 in 30 million for hepatitis C, 1 in 8 million for HIV and 1 in 260 000 for hepatitis B. Since 1995 only 16 cases of viral transmission was reported to SHOT, and no confirmed transmissions have been reported in the last 2 years. Reduction of the risk depends on exclusion of donors with lifestyle markers indicating a high risk for viral infection and serological testing (PCR-based detection of viral nucleic acid).

Lymphatic and hematopoietic system see also chapters 14 and

HHV-6 infects endothelial cells of the aorta, umbilical vein and capillaries (Wu and Shanley, 1998 Rotola et al., 2000 Takatsuka et al., 2003). It may induce thrombotic microangiopathy or large vessel arteritis (Wu and Shanley, 1998 Toyabe et al., 2002 Takatsuka et al., 2003). There are single reports relating HHV-6 infection to leukocytoclastic vasculitis and to Kawasaki's disease (Hagiwara et al., 1993 Luka et al., 1995 Drago et al., 1999 Yoshikawa et al., 2003). HHV-6 genomic material was found in coronary arteries of heart allografts suggesting virus reactivation at this site. Finally, a case of fulminant myocarditis was described in a patient receiving steroid therapy for hepatitis. HHV-6 antibodies showed a fourfold increase in this patient, and HHV-6 DNA was demonstrated by PCR in liver and heart tissue (Fukae et al., 2000).

Partially Attenuated Live Vaccines and Sero Immunization

Theiler knew that Pasteur had modified the virulence of rabies virus by serial passage in rabbit brains, and he believed that smallpox virus had been attenuated naturally, probably by passage through an unusual (bovine) host. He therefore undertook a series of sequential brain-to-brain passages of yellow fever virus in mice in an attempt to attenuate its pathogenicity. At the 29th and 42nd passage levels, the monkeys inoculated with the mouse brain material survived infection without developing yellow fever hepatitis. Moreover, they had developed immunity, as illustrated by resistance to challenge with virulent virus 20 . Theiler also noted that sequential passage of the virus in mice led to an increase in its neurotropism, suggesting that, with further passage, the virus might eventually become fixed in its neurovirulence for mice, in the same way that rabies virus had after sequential passage in rabbit brain. The implications for preparation of a vaccine were clear The French virus...

Development and Initial Field Trials of Yellow Fever 17D Vaccine

After 100 passages in chick embryo without nervous tissue (i.e., at the 176th passage since initiating in vitro culture), Smith noted a decrease in the neurovirulence of the virus, with mice surviving or developing nonlethal paralysis. Theiler and Smith confirmed that this virus induced minimal viremia and no hepatitis in rhesus monkeys after subcutaneous inoculation and, most importantly, that it had a markedly diminished neurovirulence for mice 50 (Table 2). The loss of neurovirulence for monkeys diminished between the 89th and 114th passage subcultures, and Fatal hepatitis Fatal hepatitis

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)

Clinical spectrum and systemic manifestations

Usually, high and spiking fever begins this syndrome (Knowles et al., 1999 Begon and Roujeau, 2004). Fever precedes or is concomitant to the onset of the cutaneous manifestations. Fever and skin eruption are the most common clinical manifestations. Skin manifestations are usually a maculopapular exanthema with facial edema (periorbital), which may progress to an exfoliative dermatitis (erythroderma) (Fig. 1). Sometimes pustulosis, blistering, or oral ulceration may occur. Rarely, more serious conditions mimicking Stevens-Johnson syndrome or toxic epidermal ne-crolysis may develop. But these other serious adverse cutaneous reactions must be considered as a differential diagnosis. Involvement of mucous membranes is uncommon in DRESS. There is no correlation between the severity of cutaneous involvement and the systemic symptoms. Hepatitis involvement is frequently asymptomatic (cytolytic hepatitis or cholestasis) but jaundice, hepatic failure, and fulminant hepatitis may occur. Other...

DRESS and HHV6 the first reports

Lymphocytes, hepatitis, and renal dysfunction. Lymphocyte population was mainly T-cell lymphocytes (52.6 CD8). CD19 and CD20 lymphocytes' levels were very low, 0.8 and 0.6 , respectively. The skin biopsy analysis demonstrated a diffuse infiltration with atypical lymphocytes in the dermis. HHV-6 infection was demonstrated by serial changes in titers of antibody against HHV-6 associated with an HHV-6 viremia. HHV-6 DNA was demonstrated in serum samples collected on days 10 and 13.

Animal Models of Wilsons Disease and ICC

There are two proven rodent models of WD, the Long-Evans Cinnamon (LEC) rat and the toxic milk (tx) mouse. The LEC rat accumulates high levels of hepatic copper in the first few months after birth (78) and this excess copper is the likely the cause of early-onset hepatitis. A deletion of the 3' portion of ATP7B has been reported thus demonstrating the LEC rat is a true model of WD (79). Recent experiments have used this rat model to study the possibility of gene correction in WD (80).

HHV6 reactivation in DRESS innocent bystander or causal agent of systemic symptoms

Reactivation and viremia appeared very early in the development of DRESS. In a case of minocycline-induced DRESS we detected very high copies of HHV-6 (16 million copies ml) on the first serum at the admission (Descamps et al., 2003b). This quantitative PCR was performed on a serum sample drawn at day 6 after the beginning of the DRESS clinical manifestations (fever, rash, lymphadenopathy). Detection of viremia was concomitant of the exanthema and mononucleosis syndrome and preceded the development of hepatitis, eosinophilia, and the increase in anti-HHV-6 IgG antibodies (Fig. 2a). The copy number of HHV-6 in the serum decreased rapidly it was only 8400 copies ml 11 days later. That may explain the reason why this viremia is not always demonstrated when patients are admitted, at a hospital at distance, after the beginning of the DRESS. In another case (ethambutol-induced DRESS) HHV-6 viremia was not demonstrated at admission while an increase of anti-HHV-6 IgG antibodies was...

Combined Immunization

A few other studies have been conducted on the simultaneous administration of other bacterial and viral vaccines with yellow fever 17D. In the early 1970s, several workers reported the unexplained antagonism of whole cell cholera and yellow fever vaccines 95, 96 . In 1986 Yvonnet et al. studied infants given yellow fever simultaneously, but at different sites, together with DPT, hepatitis B, and measles or with DTP and measles 97 . Both groups had a satisfactory and similar sercon-version rate to yellow fever (> 91 ), but the mean neutralizing antibody titer to tallow fever was significantly lower in infants that had received hepatitis B vaccine. In a recent study, yellow fever and a purified typhoid vaccine were injected simultaneously at the same or in separate site(s) 98 . In this case, the bacterial antigen (the VI capsular polysaccharide of Salmonella typhi) appeared to have an adjuvant effect, so that higher neutralizing titers were found in subjects receiving both vaccines...

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

Clinical Presentation Of Ghad

Sometimes, GHAD will first be suspected when there is severe neonatal hypoglycemia or other signs of hypopituitarism (hypothyroidism, small phallus in male babies, or neonatal hepatitis). During early childhood, children with GHAD are detected when they demonstrate short stature and subnormal rates of growth. Often these children will have proportionally small limbs, increased body fat, and a cherubic appearance.

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 Role of Tissue Culture in Vaccine Development

Within only 4 years of the initial publication from the Enders laboratory, both Jonas Salk and Albert Sabin were able to report success with two differing approached to immunization against poliomyelitis, a formalin-inactivated preparation of the three virus types (Salk's IPV) and three attenuated live variants of poliovirus (Sabin's OPV) 9, 10 . Drs Beale and Melnick will discuss these at greater length in their articles. Moreover, in the succeeding years a host of new virus vaccines were developed exploiting the cell culture techniques that stemmed from the work of the Enders group. These have included measles, mumps, rubella, adenoviruses, varicella-zoster, rabies, hepatitis A, rotavirus, cytomegalovirus and others still under research and development (Table 1). None of these was easy, but the barriers has been eliminated and the pathway illustrated by their work 11 . No longer was it necessary to prepare vaccines on calf skin, in the brain or spinal cord of various species, or in...

[2 Phenotype Changes of Fut8 Knockout Mouse Core Fucosylation Is Crucial for the Function of Growth Factor Receptors

GDP-l-Fuc N-acetyl- -d-glucosaminide a1,6-fucosyltransferase (Fut8, E.C.2.4.1.152) catalyzes the transfer of a fucose residue from GDP-fucose to position 6 of the innermost GlcNAc residue of hybrid and complex types of N-linked oligosaccharides on glycoproteins to form core fucosylation in mammals, as shown in Fig.1A. Fut8 is the only core FucT in mammals, but there are core a1,3-Fuc residues in plants, insects, and probably other species. The Fut8 gene is expressed in most rat organs with a relatively high level expression in brain and small intestine (Miyoshi et al., 1997). a1,6-Fucosylated glycoproteins are widely distributed in mammalian tissues and are altered under some pathological conditions. For example, the level of core fucosylation is elevated in both liver and serum during the process of hepatocarcinogenesis (Hutchinson et al., 1991). The presence of core fucosylation of a-fetoprotein, a well-known tumor marker for hepatocellular carcinoma (HCC), is known to distinguish...

Immune Responses to HIV1 and Potential Correlates of Protection 221 Humoral Responses

Antibodies are important in preventing susceptible cells from becoming infected by blocking pathogen binding and or entry into target cells. The humoral arm of the immune system has provided protective responses in several successful viral vaccines. For example, the quantitation of serum-neutralizing activity in recipients of polio or influenza vaccines has been shown to correlate with the efficacy of the vaccine in preventing disease following later exposure to the pathogen. In addition, vaccines against viral diseases such as rabies and hepatitis B have produced high-titer neutralizing antibodies, which have been correlated with vaccine efficacy. Several prospective vaccines using this immunological measure are being tested in animal models using HIV, simian immunodeficiency virus (SIV), and S HIV immunogens.

Sites Of Rnaaminoglycoside Interactions

Aminoglycoside antibiotics, as discussed in the preceding section, interact with RNA. Ribosome is the target for this class 10-12,148 , and the antibiotics exert their antibacterial effects by binding to ribosomal RNA (rRNA) in the A site, causing misreading of the genetic code and inhibiting the process of translocation 149,150 (see above). Aminoglycoside antibiotics also interact with a variety of other biologically relevant RNA molecules. These include mRNA from human immunodeficiency virus (HIV-1), transactivation response element (TAR) 151 , group I self-splicing introns 152 , the hammerhead region of rRNA 153,154,155 , and the hepatitis delta virus (HDV) ribozyme 156 . Next, we discuss recent developments in the binding of aminoglycoside antibiotics to RNA.

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...

Interstitial pneumonia in not overtly immunocompromised persons

There are only very limited case reports of HHV-6 infection causing interstitial pneumonia, and most of these patients can hardly be considered immunologically normal'' (Cone, 1995). Russler and co-workers (1991) reported a case of pneumonitis in a young healthy man caused by coinfection with HHV-6 and Legionella pneumophila. He suffered from severe pulmonary, renal, hepatic and CNS dysfunctions. Legionella organisms were cultured from his lungs, yet specific antibiotic therapy produced no response. HHV-6 was isolated from the patient's blood cells, and the virus was also shown in lung biopsies with pneumonitis. Highdose corticosteroid therapy suppressed the inflammatory reaction, inhibited the HHV-6 replication and supported the clearance of the Legionella infection. It was thought that HHV-6 may have worked synergistically with Legionella in causing the severe pneumonitis. Another coinfection of HHV-6 and Pneumocystis carinii was associated with interstitial pneumonitis in a patient...

Summary and Future Research

Despite the advances in MRI and the many important findings in HIV-infected patients to date, improvements can be made in several key areas. One significant improvement in future research studies might be in participant selection. Generally, HIV-infected patients present with additional neurological risks that might be better controlled through patient selection and or the addition of supplementary control groups with different conditions. As already illustrated, Pfefferbaum Sullivan have demonstrated the significant contribution of alcohol abuse among commonly presenting HIV-infected populations. Much has also been written about other subpopulations within HIV-infected cohorts such as drug abuse (71, 121, 122), hepatitis C (HCV) coinfection (75, 123, 124), etc. The use of more controlled research designs will not only broaden our understanding of the neurological effects of these additional factors, but will improve our understanding of the specific mechanisms of HIV-associated CNS...

Current Risks Of Platelet Transfusions

The risks for transfusion-transmitted diseases are estimated to be at an historically low rate (Table 2) (6). Nucleic acid testing has substantially decreased the risk of viral infection by shortening the window of infectivity for the hepatitis C virus and the human immunodeficiency virus (HIV). Infections Viral Hepatitis B Hepatitis C HIV Bacterial Red cells Platelets

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...

Twin studies and adoption studies

The first formal evidence that genetics is important in susceptibility to infectious disease was gained in the 1930s through work on twins with tuberculosis (Diehl and Von Verschuer, 1936) and twin studies have been carried out subsequently for a number of infectious diseases such as malaria (Sjoberg et al., 1992 Jepson et al., 1994), tuberculosis (Kallmann and Reisner, 1942 Comstock, 1978), leprosy (Chakravarti and Vogel, 1973) and hepatitis B (Lin et al., 1989). These studies all demonstrated a substantial role for genetics in host susceptibility because monozygotic twins were more likely to have concordant disease states than dizygotic twins. Another useful study design for the investigation of genetic effects is the adoptee study, where risk of disease in an adoptee is analyzed according to the characteristics of their biological and adoptive parents. Like the twin study,

Details on individual vaccines

Hepatitis B All HIV patients seronegative to HBV should be vaccinated as the combination vaccine with hepatitis A is advantageous with regard to price and possibly immunogenicity (Van der Wielen 2006), indication for hepatitis A vaccination should be considered in this context. The vaccination response rate and durability, being generally reduced in HIV patients, correlate with CD4+ T-cell counts thus, vaccination should be performed early after HIV diagnosis (Laurence 2005). Immuno reconstitution under ART increases vaccination response (Wonk 1996) as does viral load suppression (Overton 2005). In patients with isolated anti-HBc, a constellation occasionally observed in HIV patients, an HBV vaccine should be given (Gandhi 2005) if after the first vaccine dose anti-HBs is detectable, a prior hepatitis B infection should be assumed and the vaccination cycle does not need to be completed. Hepatitis A This infection is common among HIV patients (Fonquernie 2001). The vaccine is indicated...