A vigorous hepatitis C virus (HCV)-specific Th cell response is regarded as essential to the immunological control of HCV viremia. The aim of this study was to comprehensively define the breadth and specificity of dominant HCV-specific CD4(+) T cell epitopes in large cohorts of subjects with chronic and spontaneously resolved HCV viremia. Following in vitro stimulation of PBMC, HCV-specific cell cultures from each subject were screened with an overlapping panel of synthetic 20-mer peptides spanning the entire HCV polyprotein. Of 22 subjects who spontaneously controlled HCV viremia, all recognized at least one of a group of six epitopes situated within the nonstructural (NS) proteins NS3, NS4, and NS5, each of which was detected by >30% of subjects, but most subjects recognized additional, more heterogeneous specificities. In contrast, none of the most frequently targeted epitopes was detected by >5% of persons with chronic infection. The most frequently recognized peptides showed promiscuous binding to multiple HLA-DR molecules in in vitro binding assays and were restricted by different HLA-DR molecules in functional assays in different persons. These data demonstrate that predominant CD4(+) T cell epitopes in persons with resolved HCV infection are preferentially located in the nonstructural proteins and are immunogenic in the context of multiple class II molecules. This comprehensive characterization of CD4(+) T cell epitopes in resolved HCV infection provides important information to facilitate studies of immunopathogenesis and HCV vaccine design and evaluation.
CD8(+)-T-cell responses play an important role in the containment and clearance of hepatitis C virus (HCV) infection, and an association between viral persistence and development of viral escape mutations has been postulated. While escape from CD8+ -T-cell responses has been identified as a major driving force for the evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), a broader characterization of this relationship is needed in HCV infection. To determine the extent, kinetics, and driving forces of HCV sequence evolution, we sequenced the entire HCV genome longitudinally in four subjects monitored for up to 30 months after acute infection. For two subjects the transmission sources were also available. Of 53 total non-envelope amino acid substitutions detected, a majority represented forward mutations away from the consensus sequence. In contrast to studies in HIV and SIV, however, only 11% of these were associated with detectable CD8+ T-cell responses. Interestingly, 19% of non-envelope mutations represented changes toward the consensus sequence, suggesting reversion in the absence of immune pressure upon transmission. Notably, the rate of evolution of forward and reverse mutations correlated with the conservation of each residue, which is indicative of structural constraints influencing the kinetics of viral evolution. Finally, the rate of sequence evolution was observed to decline over the course of infection, possibly reflective of diminishing selection pressure by dysfunctional CD8+ T cells. Taken together, these data provide insight into the extent to which HCV is capable of evading early CD8+ T-cell responses and support the hypothesis that dysfunction of CD8+ T cells may be associated with failure to resolve HCV infections.
BackgroundHepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.Methods and FindingsWe measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r 2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).ConclusionsThese results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
The current study examined the feasibility of an HIV/STI prevention intervention for African American female adolescents. The intervention, SiHLEWeb, is a web-based adaptation of the evidence-based intervention, Sistas, Informing, Healing, Living, and Empowering (SiHLE). Participants were 41 African-American girls aged 13 to 18 years, recruited in collaboration with community partners (local high schools, Department of Juvenile Justice, child advocacy center, medical university). Results support the feasibility of recruitment, screening, and follow-up retention methods. The majority (63.4%) of recruited participants completed the intervention, taking an average of 4.5 site visits. Completers of SiHLEWeb demonstrated increases in knowledge regarding HIV/STI risks and risk reduction behavior, as well as significant increases in condom use self-efficacy. Findings provide preliminary support for the large-scale, randomized-controlled trial of the efficacy of SiHLEWeb to reduce high-risk sexual behavior among female African-American adolescents.
While similar rates of traumatic experiences exist in both rural and urban settings, mental health resources available to those living in rural areas are often scarce. Limited resources pose a problem for children and families living in rural areas, and several barriers to service access and utilization exist including reduced anonymity, few “after-hours” services, decreased availability of evidence-based treatments, few specialty clinics, and expenses associated with travel, taking time off work, and provision of childcare. As a solution, the authors discuss the utility, use, and set-up of a telemental health program through an existing community outreach program. Suggestions for establishing a telemental health clinic are presented along guidelines for the delivery of trauma-focused, cognitive-behavioral therapy (TF-CBT) via telemental health videoconferencing technology. Specific guidelines discussed include (1) establishing and utilizing community partnerships, (2) Memoranda of Understanding (MOU), (3) equipment setup and technological resources, (4) videoconferencing software, (5) physical setup, (6) clinic administration, (7) service reimbursement and start-up costs, (8) therapy delivery modifications, and (9) delivering culturally competent services to rural and remote areas.
African-American adolescent girls are at disproportionate risk for HIV infection. Although numerous evidence-based risk-reduction interventions exist, dissemination and implementation resources remain limited, and prevention services remain notably inaccessible to the very populations at highest risk for HIV infection. Internet delivery of HIV risk-reduction programming has promise as a mechanism for extending the reach of existing prevention efforts and overcoming barriers associated with traditional service delivery. This article: (1) details the development process for the creation of SiHLEWeb, a web-adapted version of an evidence-based, culturally-informed HIV prevention program traditionally delivered to female African-American adolescents via an in-person group format; and (2) presents findings from quantitative and qualitative usability testing conducted among 18 African-American girls (13–18). Results suggest that users found the website improved knowledge and learning, was helpful, efficient to use, and generally attractive. Users reported some concerns about website navigation. Implications for internet delivery of health prevention programming are discussed.
Chronic hepatitis C virus (HCV) infectionis typically characterized by a lack of virus-specific CD4 ؉ T-cell-proliferative responses, but strong responses have been described in a subset of persons with persistent viremia. One possible explanation for these responses is that they were primed by an earlier resolved infection and do not recognize the current circulating virus. We defined all targeted epitopes using overlapping peptides corresponding to a genotype 1a strain in 44 patients chronically infected with different HCV genotypes (GT). Surprisingly, more HCVspecific CD4 ؉ T-cell responses were detected in patients with chronic non-GT1 infection compared with patients with chronic GT1 infection (P ؍ .017). Notably, we found serologic evidence of a previous exposure to GT1 in 4 patients with non-GT1 infection, and these persons also demonstrated significantly more responses than non-GT1 patients in whom genotype and HCV serotype were identical (P < .
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