CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

vectors, which engender predominantly central memory T cell (T CM In the case of HIV infection, vaccine-induced T CM CD8+ T cell responses are at a kinetic disadvantage to the rapid pace of viral replication, thus giving rise to a scenario of an anamnestic immune response that arrives at the site of infection “too late” with “too little” magnitude to prevent irreversible establishment of the persistent viral reservoir. In contrast, accumulating evidence supports a protective role for effector memory T cell (T EM ) responses, which are fully differentiated memory T cells located directly at portals of pathogen entry, able to respond to pathogens orders of magnitude more quickly than T CM responses. Here, we present evidence for the early vulnerability of HIV to cellular immunity and discuss the rationale for inclusion of CD8+ T EM responses in prophylactic HIV vaccine design. 49 EARLY BROADLY NEUTRALIZING ANTIBODY TREATMENT LEADING TO T-CELL CONTROL MalcolmMartin , NIAID, Bethesda, MD, USA Background: Highly potent and broadly neutralizing anti-HIV 1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques and humans. To determine whether the administration of a combination of bNAbs during the acute SHIV infection of rhesus macaques might lead to long-term control of virus replication, animals challenged with SHIVAD8-EO by mucosal or intravenous routes, received a single 2-week course of 2 potent passively transferred bNAbs (3BNC117 and 10-1074). Viremia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. 4 additional animals maintained normal CD4+ T cell counts and low levels (300 to 600 Viral RA copies/ml plasma) of persistent viremia for over 2 years. The frequency of cells carrying replication-competent virus was undetectable or less than 1 per 106 circulating CD4+ T cells in the 6 elite controller macaques. Infusion of a T cell depleting anti-CD8 mAb to the elite controller animals led to a specific decline in levels of CD8+ T cells and rapid reappearance of plasma viremia. In contrast, macaques treated for 2 or for 15 weeks with combination anti-retroviral therapy (cART), beginning on day 3 after infection, experienced rebound plasma viremia shortly after treatment was interrupted. We conclude that passive immunotherapy during the acute SHIV infection differs from cART in that it facilitates the emergence of potent CD8+ T cell immunity able to durably suppress virus replication. A major focus of HIV prevention and vaccine research involves the interaction of the HIV-1 envelope protein gp120 with cell-surface receptors on CD4+ T cells. Particular attention has been devoted toward a more in depth understanding of the early events in transmission, focusing on the critical window of time when HIV first establishes infection in the host. α4β7 expressing memory CD4+ T cells are preferred targets in the earliest phases of HIV-1 infection. In mucosal tissues α4β7hi memory CD4+ T cells are metabolically activated and express high levels of CCR5, which render them highly susceptible to infection. The frequency of α4β7hi memory CD4+ T cells is directly correlated with risk of acquisition in both humans and macaques. Examination of mucosal biopsies obtained from HIV infected individuals reveals that α4β7hi memory CD4+ T cells are selectively depleted within the first weeks of infection. In a nonhuman primate model of transmission an anti α4β7 mAb protected macaques frommucosal transmission of SIV. The same mAb, when combined with ART allowed SIV infected macaques to control viremia in a durable way following treatment interruption. We determined, using an immuno-PET/CT imaging technique that anti α4β7 alone or in combination with ART alters virus distribution and preserves CD4+ T cells in later stages of infection. The precise mechanism(s) by which ART + α4β7 mAb therapy promoted virologic control remains to be defined. However, we identified a series of correlates that individually or in combination may have contributed to that control. 51 EARLY INTERVENTION THERAPIES IN HUMANS: ART, ANTIBODIES, AND VACCINES Eugène Kroon , Thai Red Cross AIDS Research Center, Bangkok, Thailand HIV cure is a desirable goal for individuals living with HIV who face stigma and life-long antiretroviral therapy (ART), while treatment costs pose a significant ) responses. 50 ANTI-ΑLPHA-4/ΒETA-7 ANTIBODY-MEDIATED CONTROL: UNDERSTANDING THE MECHANISM James Arthos , NIH, Bethesda, MD, USA

47LB ONGOING HIV MICROEPIDEMICS IN RURAL SOUTH AFRICA: THE NEED FOR FLEXIBLE INTERVENTIONS Cordelia Coltart 1 , Maryam Shahmanesh 1 , Stephane Hue 2 , Janet Seeley 2 , Till Bärnighausen 3 , Benn Sartorius 4 , Tulio de Oliveira 4 , Thembelihle Zuma 5 , Natsayi Chimbindi 5 , Anne Johnson 1 , Deenan Pillay 5 , Frank Tanser 5 1 University College London, London, UK, 2 London School of Hygiene & Tropical Medicine, London, UK, 3 Heidelberg University, Heidelberg, Germany, 4 University of KwaZulu-Natal, Durban, South Africa, 5 Africa Health Research Institute, Mtubatuba, South Africa Background: Using one of Africa’s largest HIV seronegative cohorts in KwaZulu-Natal, South Africa, we recently identified remarkable space-time variations in HIV incidence (2004-14) with the rapid emergence of a rural cluster (incidence >10% per year), near a recent coal mine development. We have undertaken a phylogenetic, epidemiological and social science investigation to understand the drivers, and guide optimal intervention, for this microepidemic. Methods: HIV incidence was measured through population-based annual surveillance. A phylogeny of 2179 HIV-1 subtype C partial pol sequences -1376 local sequences (2010-14, 15% of HIV positive population) and 803 publically available South African control sequences (2000-14) -was reconstructed by maximum likelihood inference. A dated phylogeny was inferred using Beast 2. We geo-located individuals to their residences and conducted a rapid ethnographic assessment of the HIV risk and prevention landscape in adolescents and young adults during 2017. Results: Phylogenetic reconstruction revealed a distinct monophyletic cluster (75 local sequences). The dated phylogeny suggests this emerged from a common source, with two bursts of infection (2012, 2014) and was expanding at the time of last sampling (2014). There were more males (57 vs. 43%, p<0.01) and higher employment (proportion in full-time employment: 45 vs. 18%, p<0.01) in this cluster compared to the population. Geospatial analyses revealed over 40% resided within a rural area adjacent to a mine. Another 40% of cases were located in the peri-urban area, adjacent to the main highway, previously identified as a high incidence area. The ethnographic survey found that local economic development brought money to this poor rural area, but at the cost of moving homes and bringing young men and truck drivers to the area. Whilst this did not appear to have resulted in visible sex work around the mine area, the residents described a rise in opportunities for transactional sex and access to alcohol and “places of risk” in a nearby urban area. Conclusion: Our findings highlight the continued emergence of concentrated microepidemics within an existing hyperendemic region, with the potential to fuel ongoing transmission. Rapid socioeconomic changes, such as those induced by mines and other industrial developments, that bring people and money to poor areas may have unintended health consequences. We propose that flexible HIV prevention and sexual health services are required to rapidly respond to such events. Jonah Sacha , Oregon Health and Sciences University, Portland, OR, USA HIV has proved a daunting target for vaccine development, foiling efforts to generate cellular and humoral responses capable of targeting viral vulnerabilities. While decades of research have demonstrated the critical role of CD8+ T cells in containing viral infections, the ability to elicit HIV-protective T cell responses with conventional approaches has remained frustratingly elusive. Nearly all T cell-based vaccine regimens tested to date have used non-persistent 48 MECHANISMS OF EARLY CD8+ T CELL CONTROL

Oral Abstracts

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CROI 2018