PROJECT SUMMARY/ ABSTRACT The goal of HIV cure research is to induce “antiretroviral therapy (ART)-free” remission by eliminating persistent HIV to overcome the need for lifelong ART and improve clinical outcomes associated with persistent HIV (increased inflammation- and aging-associated diseases). However, HIV cure trials have thus far failed to demonstrate a clinically meaningful reduction in the HIV reservoir size or lead to sustained ART-free viral control. The goal of the proposed work is to address a critical need – to determine host in vivo mechanisms that drive HIV reservoir decay and sustain long-term viral control, identifying potential novel therapeutic candidates for HIV cure. We recently demonstrated that class II cytokines (specifically, IL-10 and type I and III interferons) exhibited ongoing fluctuations and predicted faster HIV reservoir decay during the first 24 weeks of ART. These data support prior work demonstrating a dynamic and temporal role of type I interferons in controlling HIV/SIV infection and two recent studies that showed a critical role for IL-10 in the maintenance of the HIV/SIV reservoir. However, these other studies did not specifically evaluate the role of host cellular drivers of class II cytokine-mediated viral control across HIV stages: acute HIV infection (AHI), ART initiation (ARTi), ART suppression (ART+), and ART interruption (ATI). Our central hypothesis is that class II cytokines dynamically control virus at different stages of HIV. We aim to identify the host cellular drivers of class II cytokine-mediated viral control across HIV stages from 50 participants from our UCSF Treat Acute HIV cohort (diagnosed and initiated ART <100 days from infection), which includes monthly biospecimen sampling as well as optional tissue sampling (gut, lymph node) and ATI sub-studies. Host viral control will be measured as (1) HIV reservoir decay and (2) post-ATI control (time-to-viral- rebound [TTVR]). Since there is no “gold standard” for measuring the HIV reservoir, we will leverage several HIV reservoir assays currently being performed in our cohort, using additional funded grants. We hypothesize that across longitudinal blood timepoints (Aim 1), class II cytokine-mediated cellular responses exert robust innate antiviral effects (e.g., after HIV transmission), enhance adaptive/cell survival responses during long-term ART+, and re-induce innate responses at ATI. We hypothesize that these cellular responses are more robust in tissues than in blood (Aim 2) since several class II cytokines (IL-10, IFN λ/IL 29) act as antiviral defenses specifically at mucosal barrier tissue sites. Finally, we hypothesize that plasma metabolic signatures will predict class II cytokine-driven viral control, priming their use in future HIV cure clinical monitoring (Aim 3). Targeting class II cytokines represents a promising interventional strategy, but given their complex host-viral temporal dynamics, a deeper understanding of the natural t...