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(2009)Journal ArticleBACKGROUND: Circumcision status was examined as an independent risk factor for sexually transmissible infections (STIs) in the Health in Men cohort of homosexual men in Sydney. METHODS: From 2001 through 2004, 1427 initially human immunodeficiency virus (HIV)-negative men were enrolled and followed up until mid-2007. All participants were offered annual STI testing. The history of STIs was collected at baseline, and information on sexual risk behaviors was collected every 6 months. At annual face-to-face visits, participants reported STI diagnoses received during the previous year. RESULTS: Circumcision was not associated with prevalent or incident herpes simplex virus 1, herpes simplex virus 2, or self-reported genital warts. There was also no independent association of circumcision with incident urethral gonorrhea or chlamydia. Being circumcised was associated with a significantly reduced risk of incident (hazard ratio, 0.35 [95% confidence interval, 0.15-0.84]) but not prevalent (odds ratio, 0.71 [95% confidence interval, 0.35-1.44]) syphilis. The association was somewhat stronger among men who reported predominantly insertive unprotected anal intercourse (hazard ratio, 0.10 [95% confidence interval, 0.01-0.82]). CONCLUSIONS: These are the first prospective data obtained from homosexual men to assess circumcision status as a risk factor for STIs. Circumcised men were at reduced risk of incident syphilis but no other prevalent or incident STIs. Circumcision is unlikely to have a substantial public health impact in reducing acquisition of most STIs in homosexual men.
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(2018)ThesisThe CD8+ T cell responses play a pivotal role in controlling viral replication during HCV infection. HCV evades the immune system by rapid viral evolution affording escape from immune selection pressure including at MHC-I restricted epitopes. However, some CTL epitopes remain conserved well past the time of establishment of chronic infection, implying additional mechanisms immune failure exists. CD8+ T cells exhibiting an exhausted phenotype have been extensively reported during the chronic stage of illness for chronic viral infections, such as HCV and HIV. Additionally, impaired differentiation and trafficking of CD8+ T cells is known to be associated with immune escape and exhaustion of CTLs, but the timing and mechanisms and expression patterns of inhibitory receptors as wells as impairments in differentiation during primary HCV infection remains unclear. HCV-specific CD8+ T cell responses against the transmitted founder virus identified via ELISpot. Immune escape was observed in the NGS data set in ~33% of all ELISpot identified epitopes. The majority of HCV-specific CD8+ responses identified via IFN- ELSPOT in chronic progressors were also characterised by a dominant population of terminally differentiated effector memory cells (CCR7lowCD45ROhighKLRG1highCD127low), and elevated expression of co-inhibitory markers (PD-1 and 2B4) targeting both conserved as well as escaped HCV variants at the peak of immune response (as early as 70-90 days post infection). However, evidence of long-term central memory subpopulations with moderate IFN-γ production was identified in a subset of responses. There was an association of viral escape with the magnitude (IFN- production) of the response, suggesting ongoing evolution of CTLs in response to prolonged viral exposure. Analysis of T-bet expression revealed that T-bet expression on HCV-specific CD8+ T cell was not associated with clearance. Immuno-phenotyping of liver showed that, liver was enriched with T cells expressing the chemokine receptors CCR2, CCR5, CXCR3, and CXCR6. Additionally, the studies revealed preferential expression of CXCR3 on HCV-specific CD8+ T cells in both chronic and acute HCV infection suggesting a key role for CXCR3 in regulation of HCV-specific CD8+ T cell trafficking to the site of infection in the liver. Taken together the studies in this thesis provide both consistent findings with more limited studies in HCV and comparable contexts in HIV, and clear contrasts with previous reports in murine LCMV models. The findings offer novel insights into our understanding of the immunopathgenesis of primary HCV and into HCV vaccine design.