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BackgroundThe current opioid epidemic across the United States has fueled a surge in the rate of new hepatitis C virus (HCV) infections among young persons who inject drugs (PWIDs). Paramount to interrupting transmission is targeting these high-risk populations and understanding the underlying network structures facilitating transmission within these communities.MethodsDeep sequencing data were obtained for 52 participants from 32 injecting partnerships enrolled in the U-Find-Out (UFO) Partner Study, which is a prospective study of self-described injecting dyad partnerships from a large community-based study of HCV infection in young adult PWIDs from San Francisco. Phylogenetically linked transmission events were identified using traditional genetic-distance measures and viral deep sequence phylogenies reconstructed to determine the statistical support of inferences and the direction of transmission within partnerships.ResultsUsing deep sequencing data, we found that 12 of 32 partnerships were genetically similar and clustered. Three additional phylogenetic clusters were found describing novel putative transmission links outside of the injecting relationship. Transmission direction was inferred correctly for 5 partnerships with the incorrect transmission direction inferred in more than 50% of cases. Notably, we observed that phylogenetic linkage was most often associated with a lower number of network partners and involvement in a sexual relationship.ConclusionsDeep sequencing of HCV among self-described injecting partnerships demonstrates that the majority of transmission events originate from outside of the injecting partnership. Furthermore, these findings caution that phylogenetic methods may be unable to routinely infer the direction of transmission among PWIDs especially when transmission events occur in rapid succession within high-risk networks.

BackgroundHepatitis C virus (HCV), a major cause of morbidity and mortality, is common and rising among young persons who inject drugs (PWID). Reducing the level of viremia may be an intervention, yet the impact of viremia on HCV transmission is unknown.MethodsWe conducted a prospective study of injecting partnerships (Partner Study) of young adult (age < 30 years) PWID within the UFO Study, which enrolled those at risk for HCV or with seronegative viremic infection and up to 3 HCV RNA-positive regular injecting partners. We examined the level of HCV viremia and stage of infection in the HCV-positive partner in regression analyses of HCV transmission events that were corroborated via HCV phylogenetic linkage analyses.ResultsWe enrolled 69 at-risk/acutely infected PWID. There were 25 new HCV infections (incidence rate, 35.9 per 100 person-years; 95% confidence interval [CI], 24.3-53.2 per 100 person-years); 12/25 (48%) were phylogenetically linked to at least 1 partner. We found no association between the infected partner's quantitative level of HCV viremia and likely transmission in multivariate analyses (adjusted odds ratio [AOR], 0.90; 95% confidence interval [CI], 0.55-1.46); however, seronegative viremic infection in the infected partner was associated with increased transmission (AOR, 28.02; 95% CI, 5.61-139.95).ConclusionsThe HCV viremia level was not associated with increased odds of transmission, yet acute HCV infection (seronegative viremic) was. Explanations include high-risk behavior during acute infection or missed fluctuations in viremia during acute infection. Both point to the need for frequent testing to detect new infection and attempt to prevent onward transmission.

BackgroundHepatitis C virus (HCV), a major cause of morbidity and mortality, is common and rising among young persons who inject drugs (PWID). Reducing the level of viremia may be an intervention, yet the impact of viremia on HCV transmission is unknown.MethodsWe conducted a prospective study of injecting partnerships (Partner Study) of young adult (age < 30 years) PWID within the UFO Study, which enrolled those at risk for HCV or with seronegative viremic infection and up to 3 HCV RNA-positive regular injecting partners. We examined the level of HCV viremia and stage of infection in the HCV-positive partner in regression analyses of HCV transmission events that were corroborated via HCV phylogenetic linkage analyses.ResultsWe enrolled 69 at-risk/acutely infected PWID. There were 25 new HCV infections (incidence rate, 35.9 per 100 person-years; 95% confidence interval [CI], 24.3-53.2 per 100 person-years); 12/25 (48%) were phylogenetically linked to at least 1 partner. We found no association between the infected partner's quantitative level of HCV viremia and likely transmission in multivariate analyses (adjusted odds ratio [AOR], 0.90; 95% confidence interval [CI], 0.55-1.46); however, seronegative viremic infection in the infected partner was associated with increased transmission (AOR, 28.02; 95% CI, 5.61-139.95).ConclusionsThe HCV viremia level was not associated with increased odds of transmission, yet acute HCV infection (seronegative viremic) was. Explanations include high-risk behavior during acute infection or missed fluctuations in viremia during acute infection. Both point to the need for frequent testing to detect new infection and attempt to prevent onward transmission.

HIV Research for Prevention: AIDS Vaccine, Microbicide, and ARV-based Prevention Science (HIVR4P) was built on a growing consensus that effective HIV prevention requires a combination of approaches and that understanding, analyzing, and debating the cross-cutting issues that impact prevention research are all essential to combat the global HIV/AIDS epidemic. To that end, the biennial HIVR4P conference is dedicated to all biomedical HIV prevention research approaches, including HIV vaccines, microbicides, pre-exposure prophylaxis, and treatment as prevention. The HIVR4P 2016 conference was held in Chicago, Illinois (USA), on October 17-21, and included more than 700 scientific presentations and 21 satellite sessions covering the latest and most promising advances across the HIV prevention research field. The theme "Partnering for Prevention" represented the conference's commitment to breaking down silos between research disciplines as well as between researchers, program developers, care providers, advocates, communities, and funders. Delegates spanning 42 countries attended the conference. One-third of those in attendance were early career investigators, which reflects a firm commitment to emerging researchers and ultimately to the goal of developing a sustainable scientific enterprise well into the future. This article presents a concise summary of highlights from the conference. For a more detailed account, one may find full abstracts, daily summaries, and webcasts on the conference website at hivr4p.org.

HIV Research for Prevention: AIDS Vaccine, Microbicide, and ARV-based Prevention Science (HIVR4P) was built on a growing consensus that effective HIV prevention requires a combination of approaches and that understanding, analyzing, and debating the cross-cutting issues that impact prevention research are all essential to combat the global HIV/AIDS epidemic. To that end, the biennial HIVR4P conference is dedicated to all biomedical HIV prevention research approaches, including HIV vaccines, microbicides, pre-exposure prophylaxis, and treatment as prevention. The HIVR4P 2016 conference was held in Chicago, Illinois (USA), on October 17-21, and included more than 700 scientific presentations and 21 satellite sessions covering the latest and most promising advances across the HIV prevention research field. The theme "Partnering for Prevention" represented the conference's commitment to breaking down silos between research disciplines as well as between researchers, program developers, care providers, advocates, communities, and funders. Delegates spanning 42 countries attended the conference. One-third of those in attendance were early career investigators, which reflects a firm commitment to emerging researchers and ultimately to the goal of developing a sustainable scientific enterprise well into the future. This article presents a concise summary of highlights from the conference. For a more detailed account, one may find full abstracts, daily summaries, and webcasts on the conference website at hivr4p.org.

Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells.

Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic "signatures" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.