CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

large-scale datasets; conversely global, unbiasedly collected datasets helps inform the more mechanistic studies. Recently, we have been studying the host-pathogen interface using a series of proteomic and genomic approaches, which has revealed insight into global mechanisms of pathogenesis but has also uncovered important specific insight into the how specific pathogenic proteins re-wire the host during infection. Effort is now ongoing to connect this information to clinical data especially to sequence information from relevant cohorts. Recent progress in these areas will be discussed. 172 Molecular Basis of T-Cell Exhaustion E. JohnWherry University of Pennsylvania, Philadelphia, PA, US T cell exhaustion is common during chronic infections in animal models and in humans as well as in cancer and can prevent optimal immunity. Exhausted T cells are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity and poor survival following antigen stimulation. In addition, it has become clear that exhausted T cells co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at re-invigorating exhausted T cells. We have used genomic and systems biology approaches to define transcriptional networks of T cell exhaustion revealing key molecular pathways, modules and central “hub” genes involved in this state of T cell dysfunction. Recent work has focused on the role of centrally involved transcription factors, including T-bet and Eomesodermin (Eomes). T-bet and Eomes control a proliferative hierarchy necessary to maintain exhausted T cell populations during chronic infection where these subsets of exhausted T cells exert partial ability to contain, but not control chronic viral replication. Moreover, our studies revealed unique context-specific functions for T-bet and Eomes since these transcription factors are associated with different roles in functional memory T cells. Additional studies are focusing on the role of other transcription factors as well as the molecular and systems biology signatures of reversal of T cell exhaustion. Ultimately, a more precise molecular understanding of T cell exhaustion should lead to novel and more robust clinical interventions to reverse or prevent exhaustion in settings of persisting infections such as HIV. 173 A Systems Biology Approach to Identify Targets and Mechanisms of HIV Latency and HIV Eradication Rafick P. Sekaly Case Western Reserve University, Cleveland, OH, US There is intense interest in developing safe and scalable curative interventions for Berlin patient has paved the way to identify therapeutic interventions that can lead to eradication of HIV. This goal can only be achieved by identifying the cellular localization of the HIV reservoir, the molecular mechanisms that result in the establishment and maintenance of latent infection and host determinants that dictate who might or might not respond to curative interventions. We have used an unbiased system biology approach to identify signal transduction pathways and transcriptional nodes that can predict the size of the HIV reservoir—as estimated by integrated HIV DNA levels—in a large cohort of long-term antiretroviral-treated adults. We show that distinct intracellular pathways associated with cell metabolism, activation and differentiation predict the estimated size of the reservoir. We found that upregulation of TGF-beta was associated with higher reservoir size, and validated the importance of the TGF-beta pathway in vitro using a primary T cell model of HIV latency. Finally we have shown that a specific subgroup of subjects who fail to reconstitute their immune system after ART (immune non-responders) have significantly higher levels of HIV replication competent latent HIV . We show using integrated OMICs approaches that the balance between FOXO3A and IRF-7 is a correlate of immune reconstitution and the size of the reservoir. System biology approaches have proven an essential tool in providing highly relevant clues that could lead to the identification of novel curative interventions. This work was funded by grants from the NIH U19 AI096109, Merck Research Laboratories, and the Fasenmayer Foundation. Khader Ghneim, Jessica Brehm,Aarthi Talla, Slim Fourati, Deanna Kulpa Nicolas Chomont,Daria Hazuda, Steve Deeks and Michael Lederman. Case Western Research University, Merck Research Laboratories, Universite de Montreal, VGTI Florida and University of California, San Francisco 174 Translating Anti–HIV-1 Immune Mechanisms Into Clinical Interventions Sallie R. Permar Duke University, Durham, NC, US HIV-1 transmission occurs in a complex in vivo setting, with innate and adaptive immunity, host genetics, and virus diversity all contributing to the risk of virus acquisition. As we expand our repertoire of techniques to measure HIV-1-specific immune responses and viral and host factors, we have both sharpened our ability to dissect the protective role of HIV-1-specific immune responses, as well as clouded the picture through measurement of immune responses and host factors with overlapping functions and roles. Thus, novel methods are needed to probe immune mechanisms that underlie the measured immune responses with overlapping, redundant, and correlated functions to make predictions about the unmeasured immune phenomenon that may contribute to interrupting HIV-1 transmission in vivo . Maternal antibody is known to protect the infant against acquisition of microbial pathogens, yet the role of maternal antibody in protection against mother to child transmission of HIV-1 remains unclear. In this talk, I will discuss our application of multivariable immune correlate analysis to cohorts of HIV-1-transmitting and non-transmitting women and the insights gained on the role of both the measured immune responses that associated with reduced transmission risk and the underlying immune mechanisms on vertical HIV-1 transmission. Moreover, I will discuss strategies to further probe the hypotheses generated by these immune correlate analyses in both nonhuman primate and human studies. Insights gained from detailed analysis of immune correlates and studies of their underlying mechanisms combined with strategies for hypothesis testing can inform the next generation of immune-based interventions to prevent or treat HIV-1 infection.

Oral Abstracts

Session S-8 Symposium

Room 6D

4:00 pm– 6:00 pm Scale-Up of Interventions 175 From Equipoise to Efficacy to Millions ReachedWith Voluntary Medical Male Circumcision for HIV Prevention Jason B. Reed US Department of State, Office of the Global AIDS Coordinator, Washington, DC, US

Data from three randomized controlled trials in sub-Saharan Africa demonstrated voluntary medical male circumcision (VMMC) reduces males’ risk of HIV acquisition by approximately 60%, making it one of the most effective HIV prevention interventions. VMMC also reduces the risk of several sexually transmitted infections (STI) in males and their female partners, and reduces females’ HIV risk as their probabilities of encountering HIV-infected male sexual partners decrease. In 2011, WHO and UNAIDS set a target of reaching 80% circumcision coverage among males aged 15-49 years in 14 priority countries in east and southern Africa, equivalent to over 20 million VMMCs by the end of 2016. According to mathematical models, this could avert 3.4 million new HIV infections within 15 years and save up to US$16.5 billion in HIV care and treatment costs. Through the end of U.S. fiscal year 2014, PEPFAR had supported more than 6.5 million VMMCs in the priority countries.

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