STudy of Acute HIV for investiGating Eradication Strategies (STAGES): The role of IL-10 and IFN signaling - PROJECT SUMMARY/ ABSTRACT Despite over four decades of research, we still do not have an HIV cure. While antiretroviral therapy (ART) is able to suppress virus to undetectable levels, it is not a cure; virus rapidly rebounds from latently-infected cells (“the HIV reservoir”) within weeks after ART interruption. The goal of HIV cure is to accelerate the decay of the reservoir and elicit a “functional cure.” The majority of HIV cure trials to date have been unsuccessful, but these trials have largely included people treated during chronic HIV (>2 years from infection; thus, immune responses may have been exhausted and dysfunctional). Here, we propose leveraging a unique cohort of people with HIV (PWH) treated during acute infection and followed across stages of HIV to test two potential novel cytokine therapeutic targets for functional cure. For the proposed work we will determine whether enhancing the activity of interleukin (IL)-10 and type I interferons (IFNs) - which we found to strongly predict host viral control during acute and chronic HIV - could be a potential strategy for HIV functional cure. In our UCSF Treat Acute HIV cohort, we observed that IL-10 and IFN- (a type I IFN) significantly predicted faster reservoir decay immediately after ART initiation. From our chronic HIV SCOPE cohort, we found that higher plasma IL-10 was associated with both reduced reservoir transcription (HIV RNA) and a reduced reservoir size (HIV DNA). While our data from two separate clinical cohorts are in contrast to a recent SIV study (for which anti-IL10 SIV studies are underway), these data are consistent with IL-10’s known role in cancer and autoimmunity. IL-10 has been shown to reverse exhaustion and enhance functionality of antigen-specific CD8+ T cells, leading to improved tumor control, and IL-10R agonists are now being studied in phase 1 cancer trials. In autoimmunity (e.g., Crohn’s disease), loss of IL-10’s important regulatory role manifests as abnormally high mucosal damage. We hypothesize that IL-10 and IFNs work together throughout different stages of HIV to maintain functional CD8+ T cell responses, reduce aberrant inflammation, and control the reservoir. We will study 50 acute and 10 chronic PWH from our UCSF Treat Acute HIV cohort which includes PWH followed since acute (<100 days) HIV infection (AHI), ART initiation (ARTi), ART suppression (ART+), and ART interruption (ATI), and >500 existing longitudinal specimens, along with prospectively collected lymphoid tissues and post-ATI samples. We will identify the timing and frequency of immune cells expressing IL-10 and IFNs from longitudinal samples and determine whether they predict viral control across stages of HIV (Aim 1), determine whether HIV- specific T cells with enhanced IL-10 and IFN responsiveness have stem cell-like, functional phenotypes and predict viral control (Aim 2), and demonstrate causality (ex vivo validation) of the effect of IL-10 and/or IFNs on inducing functional CD8+ T cell responses and enhanced HIV-specific killing using CRISPR/Cas9 knockout (Aim 3). Findings from this work may inform the safety and timing of potential interventions involving these cytokines and provide a platform for testing additional therapeutic targets identified from studying the natural history of HIV.
