Characterization of HCV-specific Patr class II restricted CD4+ T cell responses in an acutely infected chimpanzee

Woollard, David John; Grakoui, Arash; Shoukry, Naglaa H.; Murthy, Krishna K.; Campbell, Katherine; Walker, Christopher M.

doi:10.1053/jhep.2003.50478

Cited by 38 publications

(34 citation statements)

References 24 publications

(47 reference statements)

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“…Immune responses to the six mapped epitopes (Table II) were monitored by IFN-␥ ELISPOT analysis on cryopreserved PBMCs collected at different time points during primary infection. In addition, we monitored the immune response to a Patr-DRB5*0310-restricted epitope identified in another animal and designated NS3 1380 (1380-YGKAIPLEVI-1389) (31). Similar to what we and others have reported previously, there was a marked delay in the generation of HCV-specific immune responses despite robust virus replication (16,17,23,26).…”

Section: Tracking the Development Of Helper Responses During Primary supporting

confidence: 54%

Conserved Hierarchy of Helper T Cell Responses in a Chimpanzee during Primary and Secondary Hepatitis C Virus Infections

Shoukry¹,

Sidney

Sette

et al. 2004

The Journal of Immunology

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Control of hepatitis C virus (HCV) infection could be influenced by the timing and magnitude of CD4+ T cell responses against individual epitopes. We characterized CD4+ T cells targeting seven Pan troglodytes (Patr) class II-restricted epitopes during primary and secondary HCV infections of a chimpanzee. All Patr-DR-restricted HCV epitopes bound multiple human HLA-DR molecules, indicating the potential for overlap in epitopes targeted by both species. Some human MHC class II molecules efficiently stimulated IL-2 production by chimpanzee virus-specific T cell clones. Moreover, one conserved epitope designated NS31248 (GYKVLVLNPSV) overlapped a helper epitope that is presented by multiple HLA-DR molecules in humans who spontaneously resolved HCV infection. Resolution of primary infection in the chimpanzee was associated with an initial wave of CD4+ T cells targeting a limited set of dominant epitopes including NS31248. A second wave of low-frequency CD4+ T cells targeting other subdominant epitopes appeared in blood several weeks later after virus replication was mostly contained. During a second infection 7 years later, CD4+ T cells against all epitopes appeared in blood sooner and at higher frequencies but the pattern of dominance was conserved. In summary, primary HCV infection in this individual was characterized by T cell populations targeting two groups of MHC class II-restricted epitopes that differed in frequency and kinetics of appearance in blood. The hierarchial nature of the CD4+ T cell response, if broadly applicable to other HCV-infected chimpanzees and humans, could be a factor governing the outcome of HCV infection.

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Section: Tracking the Development Of Helper Responses During Primary supporting

confidence: 54%

Conserved Hierarchy of Helper T Cell Responses in a Chimpanzee during Primary and Secondary Hepatitis C Virus Infections

Shoukry¹,

Sidney

Sette

et al. 2004

The Journal of Immunology

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“…It defines the development of T helper 1 (Th1) cells and is critical for host defense against a variety of intracellular pathogens, including HCV. IFN-␥ efficiently inhibits HCV replication in the replicon system in vitro (6) and the intrahepatic level of IFN-␥ appears to be associated with viral clearance in the chimpanzee model (7). The human IFN-␥ gene on chromosome 12q24.1 spans Ϸ5.4 kb and contains four exons that encode a 146-aa protein.…”

mentioning

confidence: 99%

A functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection

Huang

Yang

Borg

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

105

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Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-γ gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received IFN-α-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-γ promoter region next to the binding motif of heat shock transcription factor (HSF), −764G, was significantly associated with sustained virological response [ P = 0.04, odds ratio (OR) = 3.51 (confidence interval 1.0–12.5)]. The association was independently significant in multiple logistic regression ( P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [ P = 0.04, OR = 3.51 (1.0–12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-γ promoter SNP −764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients.

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“…Serum alanine aminotransferase (ALT) levels have been used in HCV studies to assess hepatocyte destruction by CD8 ϩ cytotoxic T cells (14,20,29,33). ALT levels were not elevated in marmosets M839 and M848 following infection (15), indicating that noncytolytic mechanisms may have been responsible for the control of viral replication.…”

Section: Discussionmentioning

confidence: 99%

“…HCV infection studies with chimpanzees have shown that virus-specific T-cell responses are associated with viral clearance (9,31,33) and are able to respond rapidly to viral antigen when an animal is rechallenged (2,14,29). The duration and magnitude of viremia in the secondary infection are reduced in comparison to those of the primary infection and are associated with the rapid induction of memory CD4 ϩ and CD8 ϩ T cells (29).…”

Section: Reinfection Of Marmosets With Gbv-bmentioning

confidence: 99%

Virus-Specific T-Cell Immunity Correlates with Control of GB Virus B Infection in Marmosets

Woollard

Haqshenas

Dong

et al. 2008

J Virol

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GB virus B (GBV-B) is a hepatotropic virus that is closely related to hepatitis C virus (HCV). GBV-B causes acute hepatitis in infected marmosets and tamarins and is therefore a useful small-animal model for the study of HCV. We investigated virus-specific T-cell responses in marmosets infected with GBV-B. Gamma interferon (IFN-␥) enzyme-linked immunospot (ELISPOT) assay responses in the peripheral blood of two marmosetswere assessed throughout the course of GBV-B infection. These T-cell responses were directed against the GBV-B nonstructural proteins 3 (NS3), 4A (NS4A), and 5B (NS5B), and their appearance was temporally associated with clearance of viremia. These marmosets were then rechallenged with GBV-B at least 3 months after clearance of the primary infection to determine if the animals were protected from reinfection. There was no detectable viremia following reinfection, although a sharp increase in T-cell responses against GBV-B proteins was observed. Epitope mapping of T-cell responses to GBV-B was performed with liver and blood samples from both marmosets after rechallenge with GBV-B. Three shared, immunodominant T-cell epitopes within NS3 were identified in animals with multiple common major histocompatibility complex class I alleles. IFN-␥ ELISPOT responses were also detected in the livers of two marmosets that had resolved a primary GBV-B infection. These responses were high in frequency and were directed against epitopes within GBV-B NS3, NS4A, and NS5B proteins. These results indicate that virus-specific T-cell responses are detectable in the liver and blood of GBV-B-infected marmosets and that the clearance of GBV-B is associated with the appearance of these responses.A major impediment in the development of antiviral agents and vaccines against hepatitis C virus (HCV) has been the lack of a convenient small-animal model to test their efficacy. The chimpanzee is the only animal model that supports virus replication and has been used in studies examining vaccine efficacy (12, 26), but due to the high cost involved in their enrollment and care and their endangered status, these animals are beyond the reach of most research groups. Consequently, protective or immunosuppressive regions of the HCV polyprotein that should be incorporated into or excluded from vaccine design are still unknown. A potential small-animal model for studying HCV immunity is the common marmoset (Callithrix jacchus). These animals are relatively inexpensive, are not endangered, and are easily kept in captivity. Furthermore, marmosets are often relatively inbred, which facilitates the study of major histocompatibility complex (MHC)-restricted T-cell immunity. Marmosets develop acute hepatitis following infection with GB virus B (GBV-B) (4, 19), but there have been reported cases of persistent infection with similar pathological and virologic changes to those seen with persistent HCV infection (21). Infection of marmosets with GBV-B produces a peak viremia ranging from 10 7 to 10 9 genomic equivalents/ml (GE/ml) for a period of...

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Characterization of HCV-specific Patr class II restricted CD4+ T cell responses in an acutely infected chimpanzee

Cited by 38 publications

References 24 publications

Conserved Hierarchy of Helper T Cell Responses in a Chimpanzee during Primary and Secondary Hepatitis C Virus Infections

Conserved Hierarchy of Helper T Cell Responses in a Chimpanzee during Primary and Secondary Hepatitis C Virus Infections

A functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection

Virus-Specific T-Cell Immunity Correlates with Control of GB Virus B Infection in Marmosets

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