CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

have been followed by demonstrations of NK cell memory to viruses and viral antigens in mice, non-human primates, and most recently humans. Indeed recent work from our laboratory and others has shown that adaptive NK cells are mounted against both HIV and SIV antigens, both by infection and multiple vaccine vectors. These responses have proven to be robust, long-lived, and particularly enriched in tissues. Mechanistically, adaptive NK cell responses in humans and non-human primates largely depend on NKG2C expression and MHC-I-mediated presentation on target cells. In this presentation a current state of the field will be discussed, including multiple types of memory NK cells, how each type may mobilize against HIV and SIV infection, and how these novel phenomena could ultimately be harnessed in the context of effective vaccine and antiviral modalities. The persistence of HIV infection under ART is due to a reservoir of latently infected cells that remain indefinitely despite full suppression of virus replication. HIV latency is triggered by several mechanisms that lead to the silencing of virus expression including epigenetic DNA modification through methylation and histone deacetylation, limited availability of critical transcription factors and inefficient elongation of the nascent viral transcripts. Defining the mechanisms responsible for the establishment and maintenance of the HIV reservoir under ART has been the focus of efforts aimed at HIV eradication. Numerous studies have demonstrated that CD8+ T cells inhibit virus replication during untreated HIV/SIV infection. However, the mechanisms responsible for this antiviral effect remain poorly understood and include the direct killing of HIV/SIV-infected cells (i.e., cytotoxic T lymphocyte activity) as well as non-cytolytic mechanisms. Several studies now have shown that depletion of CD8+ lymphocytes results in increased viremia without prolonging the average in vivo lifespan of productively infected cells, thus suggesting a key role for non-cytolytic mechanisms of virus suppression. Experiments conducted in ART-treated SIV-infected rhesus macaques have demonstrated that depletion of CD8+ lymphocytes is followed by reactivation of virus production, and increased susceptibility to the latency reversal effect of an IL-15 superagonist. These results reveal an important role of CD8+ lymphocytes in cooperating with ART to maintain virus suppression and also strongly suggest that CD8+ lymphocytes function to silence HIV expression. Indeed, our recent studies employing in vitro models of HIV latency have demonstrated a CD8+ lymphocyte mediated suppression of HIV expression in CD4+ T cells that functions to induce the establishment of latency as well as maintain latency in the presence of activation signaling. Understanding the mechanisms by which CD8+ lymphocytes suppress virus transcription and ultimately promote HIV latency and persistence in ART-treated HIV-infected individuals may provide critical insight to support the design of new approaches for HIV eradication. 158 OBESITY: A GROWING PROBLEM IN ANTIRETROVIRAL THERAPY John R. Koethe , Vanderbilt University, Nashville, TN, USA Over the past two decades, the prevalence of obesity (i.e., body mass index ≥30kg/m 2 ) among persons living with HIV (PLWH) has steadily risen, which is clinically important as obesity increases the risk of diabetes, cardiovascular disease, fatty liver disease, neurocognitive impairment, and other comorbidities. Among PLWH, traditional risk factors for obesity (e.g., food insecurity, lack of readily available healthy foods, insufficient physical activity, and limited knowledge of healthy lifestyle practices) intersect with HIV-specific factors. Many PLWH experience abrupt weight gain after starting antiretroviral therapy (ART). A retrospective analysis of more than 14,000 patients starting ART found that, after three years of treatment, 22% of normal-weight individuals became overweight and 18% of overweight individuals became obese. Weight gain on ART is multifactorial and may be due, in part, to reduced inflammation and catabolism following viral suppression; increased access to health education, social support services (e.g., food assistance), smoking cessation, and treatment of depression with entry into HIV care; and effects of specific ART medications. While weight gain appears to occur with all current ART regimens, between-class and within-class differences have emerged. AIDS Clinical Trials Group (ACTG) study A5257 found a higher incidence of severe (>10%) weight gain among ART-naïve participants after starting a regimen containing the integrase strand transfer inhibitor (INSTI) raltegravir versus the protease inhibitors (PI) darunavir or atazanavir, each boosted with ritonavir. In a large retrospective analysis, ART-naïve patients starting INSTI-based regimens 157 HIV SUPPRESSION BY CD8+ LYMPHOCYTES Deanna Kulpa , Emory University, Atlanta, GA, USA

Oral Abstracts

154 TISSUE-RESIDENT MEMORY CD8+ CELLS

Michael R. Betts , University of Pennsylvania, Philadelphia, PA, USA Recent studies have established that non-recirculating resident memory CD4 + and CD8 + T cells can be found in virtually every human tissue. These cells bear a transcriptional profile of tissue retention and immediate effector function, suggesting a pivotal role in protective immunity. Resident memory CD8 + T cells specific for HIV have been found in sites of HIV persistence (gut and LN), and have been associated with viral control. This presentation will review current knowledge on resident memory T cells in humans, in the context of HIV infection. The potential relevance of resident memory T cells to HIV cure and therapeutic and prophylactic vaccine strategies will also be highlighted. Innate lymphoid cells (ILCs) play critical roles in mucosal barrier defense. HIV-1 infection is characterized by depletion of ILCs with decreased integrity of GI tract epithelium. Interestingly, ILC depletion is not a generalized feature of all viral infections. There is thus considerable interest in understanding the exact mechanisms of ILC loss in HIV/SIV infections. We find that in ARV naïve, SIV- infected nonhuman primates, distinct inflammatory and type I interferon gene signatures coincide with rapid loss of ILC3s in gut-draining mesenteric lymph nodes (MLN). Pharmacologic control of viremia with antiretroviral treatment was sufficient to reconstitute ILC3s in the MLN, and MLN ILCs were preserved in elite controller RMs with natural virologic control. To understand mechanisms underlying ILC3 loss in HIV-infection we created hallmarks of progressive HIV-1 infection with loss of CD4 T cells and/or GI barrier damage, and in healthy uninfected rhesus macaques. Experimental depletion of CD4+ T cells in combination with dextran sodium sulfate was sufficient to significantly reduce ILC frequencies in MLNs. Moreover, in HIV-uninfected subjects with durable CD4+ T cell deficiency, deemed idiopathic CD4+ lymphopenia, similar ILC deficiencies in blood were observed, collectively identifying determinants of ILC homeostasis in primates and potential mechanisms underlying their depletion in HIV/SIV infection. Jason Brenchley , National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA Natural killer (NK) cells provide rapid early responses to viral infections and thus can contribute substantially to disease modulation and potentially vaccine efficacy. Traditionally, NK cells have been considered to be nonspecific components of innate immunity, but burgeoning evidence suggests that the functional repertoire of NK cells is far more diverse and can include adaptive features and memory recall. Some of the first evidence that NK cells respond in an antigen-specific fashion came from experiments revealing that subpopulations of murine NK cells could respond to a specific MCMV protein, and that in the absence of T and B cells, murine NK cells also mediated adaptive immune responses to a secondary challenge with specific haptens. These data

155 MECHANISMS UNDERLYING LOSS OF ILCs IN HIV/SIV-INFECTED INDIVIDUALS

156 MEMORY NK CELLS AS NOVEL EFFECTORS AGAINST HIV AND SIV R. Keith Reeves , Harvard Medical School, Boston, MA, USA

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CROI 2019