CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

vaccines. Vaccination with the yellow fever vaccine causes a systemic acute viral infection and thus provides an attractive model to study innate and adaptive responses to a primary viral challenge. Vaccination with the live attenuated influenza vaccine causes a localized acute viral infection in mucosal tissues and induces a recall response, since most vaccines have had prior exposure to influenza, and thus provides a unique opportunity to study innate and antigen- specific memory responses in mucosal tissues and in the blood. Vaccination with the inactivated influenza vaccine offers a model to study immune responses to an inactivated immunogen. Studies with these and other vaccines are beginning to reunite the estranged fields of immunology and vaccinology, yielding unexpected insights about fundamental mechanisms of immune regulation. 154 DECODING THE TRANSCRIPTIONAL INFLAMMATORY CASCADES THAT MAINTAIN HIV RESERVOIR Susan Pereira Ribeiro , Case Western Reserve University, Cleveland, OH, USA Antiretroviral therapy (ART) has improved the quality of life of HIV-infected subjects. However, the persistence of long-lasting viral reservoir poses a major obstacle for viral eradication. Early HIV infection is characterized by a cascade of inflammatory cytokines followed by a negative feedback loop of anti-inflammatory cytokines, such as IL10, in order to reestablish homeostasis. Interestingly, viruses have evolved mechanisms that exploit the immunoregulatory function of IL10 for immune evasion, suppression, and tolerance to promote their own survival. As a result, some viruses, as HIV, can persist for life in infected hosts. HIV persists in a small pool of long-lived latently infected quiescent CD4 T cells and molecular mechanisms that maintain the survival of productively infected cells is not completely understood. In a cohort of ART-treated HIV aviremic subjects, IL10 was increased in blood and lymph nodes as compared to healthy controls. IL10 producing cells, including T cells, macrophages and B cells were in close proximity to cells with viral DNA in lymph nodes of infected subjects. Importantly IL10 triggered several cellular processes that promoted HIV persistence including the survival of infected cells, the upregulation of several co-inhibitory receptors (Co-IRs) which are involved in the establishment of HIV latency and immune dysfunction; confirming the ex vivo and in vitro gene signatures we also have shown that IL-10 is a potent regulator of TFH differentiation, a major HIV reservoir. Genetic manipulation i.e in vitro knockout of STAT3, the transcription factor downstream of IL10/IL10R engagement, or functional inactivation of this pathway through the use of a neutralizing antibody to IL10, led to decreased T cell survival, downmodulation of Co-IRs expression and decreased TFH frequencies, and consequently led to a significantly lower frequency of HIV infected cells in vitro. These data confirm the role of IL-10 as a trigger for HIV persistence. In vivo blockade of the IL10 pathway in aviremic chronically infected Rhesus macaques, using an anti-IL10 antibody, led to reversion of all the pathways observed in humans as associated to HIV reservoir maintenance, and resulted in significant decrease on SIV provirus. The NHP pre-clinical data confirmed the safety of this intervention which could be targeted for HIV Cure in humans. 155 DISSECTING THE DRIVERS OF CHRONIC INFLAMMATION Krystelle Nganou , NIH, Bethesda, MD, USA Immune recovery during HIV infection is profoundly influenced by inflammation, with chronic inflammation being consistently associated to disease progression and poor prognosis. In addition, numerous studies have shown that antiretroviral therapy (ART) does not resolve inflammation. Therefore, understanding the drivers of chronic inflammation is of considerable interest. This presentation will review current knowledge on the factors known to influence inflammation during ART; such as the HIV reservoir, microbial translocation and co-infections with other viruses. Recent studies on the microbiome will be presented in an effort to clarify whether changes in the microbiome are a cause or consequence of chronic inflammation. Moreover, we will describe howmetabolic factors and health risk behaviors also contribute to chronic inflammation in persons living with HIV. Finally, the use of multi-omics approaches and state-of-the-art methodologies will be highlighted as means to unravel the mechanisms underlying chronic inflammation in HIV infection and, ultimately, to identify optimal therapeutic targets. 156 DEFINING TREATABLE PATHWAYS IN INFLAMMAGING: IS IT NICE TO FOOL WITH MOTHER NATURE? Michael M. Lederman , Case Western Reserve University, Cleveland, OH, USA

Sweden, 5 Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Background: The impact of low-level viremia (LLV) during ART is unclear. We explored the associations between LLV and mortality, AIDS, and serious non-AIDS events (SNAE) using a population-based cohort. Methods: All adults in the nationwide Swedish InfCare HIV register who started combination ART (cART) 1996-2017 were included if ≥2 viral load results (VL) were available ≥6 months after cART initiation. Participants were grouped into 3 categories: virologic suppression (<50 c/mL), LLV (50-999 c/mL), and high-level viremia (HLV, ≥1000 c/mL). Viremia was handled as a time-varying covariate; reclassification was only possible to a higher viremia stratum. In a separate analysis, LLV was divided into 2 subcategories: LLV 50-199 c/mL and 200-999 c/mL. Cox proportional-hazard models were fitted to determine the associations between viremia category and all-cause death, first AIDS condition, and first SNAE (cardiovascular disease, non-AIDS cancer, thromboembolism, pulmonary hypertension, renal and liver disease). The multivariable analysis included sex, age at start of cART, CD4 count and VL before ART, country of birth, injection drug use, exposure to mono and/or dual ART prior to cART, treatment interruptions, and an interaction term between viremia category and time. Results: In total, 6,956 participants were included, with a median follow-up of 5.7 years (49,986 person years). LLV occurred in 953 (14%) subjects; at the end of follow-up, 4,177 (60%) had virologic suppression, 339 (5%) had LLV 50-199 c/mL, 258 (4%) had LLV 200-999 c/mL, and 2,182 (31%) had HLV. LLV was associated with increased all-cause mortality compared to virological suppression, adjusted hazard ratio (aHR) 2.2 (95% confidence interval [CI] 1.3-3.6). When analyzed separately, LLV 50-199 c/mL had an aHR of 2.2 (95% CI 1.3-3.8) and LLV 200-999 c/mL of 2.1 (95% CI 0.95-4.7). All-cause mortality was also independently associated with higher age, male sex, lower CD4 counts, injection drug use, and treatment interruptions. Overall, LLV was not linked to increased risk of AIDS and SNAE, but in a subanalysis, LLV 200-999 c/mL was significantly associated with SNAE, aHR 2.1 (95% CI 1.2-3.8). Conclusion: In conclusion, patients with LLV during cART were at increased risk of death. LLV 200-999 c/mL was associated with SNAE when compared to virologic suppression. Our study adds to mounting evidence that persistent LLV may be associated with increased risk of adverse events.

Oral Abstracts

153 USING SYSTEMS BIOLOGY TO UNDERSTAND THE MECHANISMS OF VACCINE EFFICACY Bali Pulendran , Emory University, Atlanta, GA, USA For more than a century, immunologists and vaccinologists have existed in parallel universes. Immunologists have for long reveled in using 'model antigens', such as chicken egg ovalbumin or nitrophenyl haptens, to study immune responses in model organisms such as mice. Such studies have yielded many seminal insights about the mechanisms of immune regulation, but their relevance to humans has been questioned. In another universe, vaccinologists have relied on human clinical trials to assess vaccine efficacy, but have done little to take advantage of such trials for studying the nature of immune responses to vaccination. The human model provides a nexus between these two universes, and recent studies have begun to use systems biological approaches to study the molecular profile of innate and adaptive responses to vaccination in the human model. Such 'systems vaccinology' studies are beginning to provide mechanistic insights about innate and adaptive immunity in humans. Here, we present an overview of such studies, with particular examples from studies with the yellow fever and the seasonal influenza

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CROI 2020