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Background: Detectable HCV-specific cellular immune responses in HCV antibody and RNA negative people who inject drugs (PWID) raise the question of whether some are resistant to HCV infection. Immune responses from people who have been exposed to hepatitis C virus (HCV) and remain anti-HCV negative are of interest for HCV vaccine development; however, limited research addresses this area. Conclusions: This study demonstrated the detection of HCV-specific IFN-γ responses in HCV antibody and RNA negative individuals, with a tendency for HCV-specific IFN-γ responses to be associated with HCV exposure. The potential role of HCV-specific IFN-γ responses in those who remained HCV RNA negative is of value for the development of novel HCV therapeutics. Objectives: In a cohort of HCV antibody and RNA negative PWID, we assessed whether the presence of HCV-specific IFN-γ responses or genetic associations provide any evidence of protection from HCV infection. Patients and Methods: One hundred and ninety-eight participants were examined longitudinally for clinical, behavioral, social, environmental and genetic characteristics (IFNL3 genotype [formally IL-28B] and HLA type). Sixty-one of the 198 participants were HCV antibody and RNA negative, with 53 able to be examined longitudinally for HCV-specific IFN-γ ELISpot T cell responses. Results: Ten of the 53 HCV antibody and RNA negative participants had detectable HCV-specific IFN-γ responses at baseline (18%). The magnitude of IFN-γ responses averaged 131 +/- 96 SFC/106 PBMC and the breadth was mean 1 +/- 1 pool positive. The specificity of responses were mainly directed to E2, NS4b and NS5b. Participants with (10) and without (43) HCV-specific IFN-γ responses did not differ in behavioral, clinical or genetic characteristics (P > 0.05). There was a larger proportion sharing needles (with 70%, without 49%, P = 0.320) and a higher incidence of HCV (with 35.1 per 100 py, 95% CI 14.6, 84.4, without 16.0 per 100 py, 95% CI 7.2, 35.6, P = 0.212) in those with IFN-γ responses, although not statistically significant. Half the participants with baseline IFN-γ responses became HCV RNA positive (5/10), with one of these participants spontaneously clearing HCV. The spontaneous clearer had high magnitude and broad Th1 responses, favorable IFNL3 genotype and favorable HLA types. Refereed/Peer-reviewed

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has detrimental effects on HCV disease progression, including increased HCV RNA levels, promotion of viral persistence in primary infection, and faster progression to cirrhosis and hepatocellular carcinoma [1]. HIV/HCV coinfection has also been associated with a significant reduction in the response to HCV antiviral treatment [2]. Individuals with primary HCV infection who undergo spontaneous clearance have an initial robust CD4+ helper cell response, whereas those who develop viral persistence have a poorer response, which diminishes overtime [3]. However, studies addressing the impact of coinfection on the effector function of HCV-specific T cells in acute HCV infection are limited. A small study by van den Burg et al reported a valuable role for HCV-specific CD4+ T-cell responses targeting HCV nonstructural (NS) proteins in reduction of HCV RNA (n = 2) and resolution of HCV (n = 1) in subjects with acute HIV/HCV coinfection [4]. Schnuriger et al demonstrated a similar finding, wherein HCV-specific proliferative responses (particularly against NS4) were associated with lower HCV RNA levels and spontaneous clearance of HCV in HIV/HCV-coinfected subjects [5]. Interestingly, IFN-γ responses were not associated with HCV clearance or with CD4+ T-cell counts [5]. More recently Thomson et al reported a trend for spontaneous clearance of acute HCV infection, in HIV-positive men, associated with higher CD4+ T-cell counts and stronger T-cell responses within the first 3 months of HCV infection [6]. Even fewer studies, have directly compared acute HCV-specific T-cell responses between HIV/HCV coinfection and HCV monoinfection. Danta et al demonstrated a lower frequency of HCV-specific IFN-γ production in HIV/HCV-coinfected subjects compared with internationally recruited HCV-monoinfected controls, although there was no difference in the magnitude of IFN-γ production between the cohorts [7]. These studies raise the question of whether the detrimental effects of HIV/HCV coinfection on HCV clearance could be attributed to a lack of CD4+ T-cell help, which is important in the generation and maintenance of CD8+ T-cell responses [8], to an altered cytokine environment, or both. Our objective was to determine whether the magnitude and breadth of the HCV-specific cellular immune responses in acute HCV infection is affected by HIV/HCV coinfection by directly comparing HCV-specific T-cell responses in subjects with acute HCV infection with or without HIV infection, recruited simultaneously within the Australian Trial in Acute Hepatitis C (ATAHC).

Background Hepatitis C virus (HCV) infection is common in prisoner populations, particularly those with a history of injecting drug use (IDU). Previous studies of HCV incidence have been based on small case numbers and have not distinguished risk events in prison from those in the community. Methods HCV incidence was examined in a longitudinal cohort of 488 Australian prisoners with a history of IDU and documented to be seronegative within 12 months prior to enrolment. Inmates were tested for anti-HCV antibodies and viremia, and interviewed about demographic and behavioral risk factors for transmission. Results The cohort was predominantly male (65%) with high rates of prior imprisonment (72%) and tattooing (73%), as well as longstanding IDU (mean 8.5 years). Ninety-four incident HCV cases were identified (incidence 31.6 per 100 person years). Independent associations were observed between incident infection and prior imprisonment (p = 0.02) and tattooing (p = 0.03), and surprisingly also with methadone maintenance treatment (MMT) (p < 0.001). Conclusions High rates of new HCV infection were found in this prisoner cohort reflecting their substantive risk behavior profile, despite having remained uninfected for many years. The association with MMT is challenging and highlights the need for better understanding of prison-specific HCV transmission risks, as well as the uptake and effectiveness of prevention programs.

Background & Aims HCV patients who fail conventional interferon-based therapy have limited treatment options. Dendritic cells are central to the priming and development of antigen-specific CD4 + and CD8 + T cell immunity, necessary to elicit effective viral clearance. The aim of the study was to investigate the safety and efficacy of vaccination with autologous dendritic cells loaded with HCV-specific cytotoxic T cell epitopes. Methods We examined the potential of autologous monocyte-derived dendritic cells (MoDC), presenting HCV-specific HLA A2.1-restricted cytotoxic T cell epitopes, to influence the course of infection in six patients who failed conventional therapy. Dendritic cells were loaded and activated ex vivo with lipopeptides. In this phase 1 dose escalation study, all patients received a standard dose of cells by the intradermal route while sequential patients received an increased dose by the intravenous route. Results No patient showed a severe adverse reaction although all experienced transient minor side effects. HCV-specific CD8 + T cell responses were enumerated in PBMC by ELIspot for interferon-γ. Patients generated de novo responses, not only to peptides presented by the cellular vaccine but also to additional viral epitopes not represented in the lipopeptides, suggestive of epitope spreading. Despite this, no increases in ALT levels were observed. However, the responses were not sustained and failed to influence the viral load, the anti-HCV core antibody response and the level of circulating cytokines. Conclusions Immunotherapy using autologous MoDC pulsed with lipopeptides was safe, but was unable to generate sustained responses or alter the outcome of the infection. Alternative dosing regimens or vaccination routes may need to be considered to achieve therapeutic benefit.

Background HIV-specific cellular immune responses have been detected in some uninfected infants born to HIV-infected women, indicating transient virus exposure or replication has occurred. Small quantities of maternal blood pass into the infant's circulation during childbirth, termed “microtransfusion”, potentially facilitating viral exposure. We sought to determine the occurrence of microtransfusion and HIV-specific immune responses as an indicator of viral exposure in a cohort of uninfected infants born to HIV-infected women, in the context of interventions.

Compelling evidence now suggests that αβ CD8 cytotoxic T lymphocytes (CTL) have an important role in preventing human immunodeficiency virus (HIV) infection and/or slowing progression to AIDS. Here, we describe an HIV type 1 CTL polyepitope, or polytope, vaccine comprising seven contiguous minimal HLA A2-restricted CD8 CTL epitopes conjoined in a single artificial construct. Epitope-specific CTL lines derived from HIV-infected individuals were able to recognize every epitope within the construct, and HLA A2-transgenic mice immunized with a recombinant virus vaccine coding for the HIV polytope also generated CTL specific for different epitopes. Each epitope in the polytope construct was therefore processed and presented, illustrating the feasibility of the polytope approach for HIV vaccine design. By simultaneously inducing CTL specific for different epitopes, an HIV polytope vaccine might generate activity against multiple challenge isolates and/or preempt the formation of CTL escape mutants.

Fifteen T-cell clones were derived from BALB/c or DBA/2 mice immunized with a synthetic peptide corresponding to the C-terminal 24 residues (residues 305 to 328) of the HA1 chain of H3 subtype influenza virus hemagglutinin. All of the clones proliferated when the peptide was presented in association with I-Ed. By using shorter homologs, it was shown that the T-cell response was focused predominantly on the region at the N-terminal end of the peptide encompassed by residues 306 to 319. Individual clones recognizing this region differed in their absolute requirements for residues at the extremities of the site and also in their patterns of efficiency of recognition of shorter homologs. One particular clone defined another site of T-cell recognition within residues 314 to 328. The response of the clones to peptide analogs identified certain residues within the sites that were critical for recognition, with the substitution Gln-311----Ser having a differential effect on clones responding to the N-terminal site. Only one of the clones responded well to influenza virus itself. This clone also required relatively low concentrations of the parent peptide for optimum stimulation and was suppressed by higher concentrations. The data demonstrate striking heterogeneity in the T-cell response even to a short synthetic peptide, with different T-cell clones recognizing slightly different but overlapping areas of the molecule.