CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

that have reduced HIV incidence at a population level. These examples provide hope and a template to use when planning to scale up new technologies like PreP, as well as scaling up the use of older technologies like condoms. However for this to be successful at the frontline it will require scientists and politicians and communities and frontline implementers to sit down together, listen to each other, understand the science AND the realities of people’s lives and the systems that support them, and come up with scientifically sound and pragmatic approaches to scale up services, impact populations and measure progress. The history of HIV has many lessons for us as we look into the future. Science, even brilliant science, will not end the HIV epidemic without collaboration and synergy with a wide range of other actors, strategies and full involvement of infected and affected communities. Sharon R. Lewin , University of Melbourne, Melbourne, Australia Despite the great success of antiviral therapy (ART), treatment is life long for the majority of people living with HIV (PLWH). Antiviral treatment is simple and relatively cheap and close to 60% of PLWH have access to treatment. However, ART is still not available or secure for many, drug resistance is common globally and there are emerging toxicities from some of the most potent antivirals. Modelling studies of the cost and impact of a cure have identified that the need for frequent follow up and viral load testing after cessation of ART, unpredictable viral rebound and lack of protection from re-infection will all reduce the impact of a cure at a population level. Therefore there is now an increasing focus in the field to achieve a true cure and not HIV remission. Understanding where and how virus persists is key to the development of novel interventions to achieve a cure. Recent work has identified the significant contribution of proliferation of infected cells to HIV persistence on ART. Understanding the drivers of proliferation and clonal expansion remains a key unanswered question. In addition, multiple factors including the site of integration can influence the transcriptional activity of a virus and a deeper state of latency may reduce the chance of viral rebound off ART. Finally, the majority of viruses that persist on ART are defective and unable to replicate. A cure may therefore occur with loss of intact virus but persistence of only defective forms. New high throughput assays can now quantify intact and defective viruses more accurately and positive emission tomography and imaging can potentially identify tissue reservoirs of virus persistence. Multiple strategies to achieve a cure are being evaluated in both animal models and human clinical trials including combination immunotherapy to reduce the viral burden and enhance immune clearance. Results from recent clinical trials of newer latency reversing agents, immune checkpoint blockade and other immune adjuvants, broadly neutralising antibodies and gene therapy will be discussed. It is likely that in the next few years long acting and implantable antiretrovirals will be available and these newer modalities may address many of the current challenges of ART. Therefore, ongoing consultation is needed with PLWH and all other stakeholders to develop an acceptable target product profile for a cure that will have the greatest personal and population impact and can be implemented at scale. 18 UNIVERSAL TEST AND TREAT (UTT): LESSONS FROM THE PAST AND FOR THE FUTURE Kevin M. De Cock , US CDC Nairobi, Nairobi, Kenya This presentation discusses the four recently completed community randomized trials of “Universal Test and Treat” (UTT) in East and southern Africa and their implications. Three themes developed in parallel and led to these ambitious implementation studies: recognition of the centrality of viral load for HIV pathogenesis and HIV transmission; studies showing >90% effectiveness of “treatment for prevention”; and evolution of antiretroviral treatment guidelines that since 2015 recommend immediate treatment of all persons living with HIV. Mathematical modeling in 2008 suggested UTT, with repeated and regular HIV testing, could eliminate HIV in an epidemic of South African severity (Granich et al, Lancet, 2009). Political advocacy highlighted the concept of “Ending AIDS” while scientific debate culminated in four community randomized trials aiming to assess UTT with HIV incidence as the primary outcome in Botswana (BCPP); Kenya and Uganda (SEARCH); South Africa (TASP); and South Africa and Zambia (PopART), from 2012-2018. Primary results of the four trials were published in Lancet HIV (TASP, 2018) and NEJM (2019) and additional analyses, including on cost-effectiveness, are underway. All four trials achieved >90% knowledge of HIV serostatus but TASP yielded low linkage to treatment. The other three 17 HIV CURE FROM BENCH TO BEDSIDE

trials met the UNAIDS 90:90:90 targets, achieving 74-88% population-level viral suppression. Treatment guidelines changed over the studies’ course, resulting in some erosion of differences between intervention and control communities. BCCP and one of PopART’s two intervention arms showed 30% reduction in HIV incidence compared to control communities, while no significant differences were found in the other studies. Despite the successful achievement of 90:90:90 targets, HIV incidence in intervention communities (6-22.3/1000/year) remained well above an arbitrary definition of HIV elimination of <1/1000/year. Knowledge of HIV serostatus and early treatment are essential for individual and the public health, but UTT alone will not lead to HIV elimination. Priorities include expansion in scale and scope of HIV testing to reduce the diagnostic and treatment gap in generalized epidemic settings, addressing needs of key and underserved populations (including youth and men), and scale-up of highly effective interventions such as voluntary medical male circumcision and PrEP. Greater focus on measuring HIV incidence and mortality is required to better understand epidemic trends in the face of combinations of preventive interventions. 19 MECHANISMS OF PSGL-1 AND CD43 RESTRICTION OF HIV INFECTION OF CD4 T CELLS Yajing Fu 1 , Yuntao Wu 1 , Sijia He 1 , Abdul A. Waheed 2 , Deemah Dabbagh 1 , Hong Shang 3 , David N Levy 4 , Eric O. Freed 5 1 George Mason University, Fairfax, VA, USA, 2 NIH, Frederick, MD, USA, 3 China Medical University, Shenyang, China, 4 New York University College of Dentistry, New York, NY, USA, 5 National Cancer Institute, Frederick, MD, USA Background: PSGL-1 (P-selectin glycoprotein ligand-1) and CD43 are surface glycoproteins that are expressed on blood CD4 T cells to bind to selectins for T cell tethering, rolling, and migration into inflamed tissues. PSGL-1 is primarily expressed on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of the endothelium for migration into inflamed tissues. Recently, PSGL-1 has also been identified as an INF-γ-regulated anti-HIV-1 restriction factor that inactivates virion infectivity. However, the mechanisms of PSGL-1-mediated anti-HIV activity remain to be elucidated. Methods: We studied PSGL-1 and CD43 restriction of HIV-1 virion infectivity by co-expression of PSGL-1 or CD43 DNA with HIV-1 DNA in virion producer cells, and then quantified virion infectivity in an HIV Rev-dependent GFP indicator cell. We also studied virion incorporation of PSGL-1 by gradient ultracentrifugation and western blot detection of PSGL-1 in virion particels. In addition, we examined virion proteins of PSGL-1 imprinted particles. We also performed mapping studies to identify functional domains of PSGL-1 necessary for blocking virion infectivity. Furthermore, we performed HIV-1 entry and attachment assays to study the interaction of PSGL-1 imprinted virion particles with target cells. Results: We found that the expression of PSGL-1 in virus-producing cells inhibits virion infectivity by inhibiting virion attachment to target cells. Mapping studies show that the extracellular, N-terminal domain of PSGL-1 is necessary for its anti-HIV-1 activity, and the PSGL-1 cytoplasmic tail contributes to inhibition. In addition, we demonstrate that the PSGL-1 related monomeric E-selectin binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or expression of either Vpu or Nef, downregulates PSGL-1 from the cell surface; expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1-mediated restriction. Finally, we found that PSGL-1 inhibits the infectivity of other viruses such as murine leukemia virus and influenza A virus. Conclusion: These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a novel mechanism of action. Further elucidation of PSGL-1 and CD43 interaction with HIV-1 and other viruses may offer new therapeutic strategies for targeting viral infections. 20 STRUCTURAL ANALYSES OF A BOUND ANTI-CD4 ADNECTIN INHIBITOR OF HIV-1 David Wensel 1 , Shawn William 2 , David P. Dixon 3 , Paris Ward 2 , Patti McCormick 2 , Nestor Concha 2 , Eugene Stewart 2 , Xuan Hong 2 , Shreya Pal 1 , Charles Maxxucco 1 , Bo Ding 1 , Mark Krystal 1 1 ViiV Healthcare, Branford, CT, USA, 2 GlaxoSmithKline, Collegeville, PA, USA, 3 GlaxoSmithKline, Uxbridge, UK Background: GSK3732394 is a multi-specific biologic inhibitor of HIV entry currently under clinical evaluation. A key component of this molecule is an

Oral Abstracts

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CROI 2020