Distinct cellular reservoirs of replication competent HIV/SIV that are not eliminated by ART are concentrated in lymph node (LN) B cell follicles (BCF) and T cell zones. Optimizing antiviral activity in lymphoid tissues is of critical importance for HIV eradication/remission strategies; however, tightly regulated immune cell trafficking render this challenging. Cytolytic effector T cells are typically excluded from LNs by relative lack of LN and BCF homing receptors and they fail, once entering, to remain as they move into systemic circulation drawn by a concentration gradient of sphingosine-1 phosphate (S1P). To counteract these mechanisms, we recently showed that treatment of ART-suppressed, SIV-infected rhesus macaques (RMs) with the S1P receptor modulator fingolimod is safe and retains cytolytic immune cells in LN. Furthermore, we showed that administration of heterodimeric interleukin-15 (hetIL-15) to uninfected and SHIV-infected RMs promotes expansion of cytolytic CD8+ T cells and NK cells, and promotes their migration to the BCF where infected T follicular helper cells persist. Fingolimod is FDA approved for multiple sclerosis and hetIL-15 is in clinical trials for cancer and HIV. Our findings have provided rationale for two upcoming clinical trials in acute HIV infection, testing the safety of fingolimod or hetIL-15 administration as monotherapies at ART initiation. We propose to move the field forward by exploring the safety and mechanisms of action of a combined fingolimod and hetIL-15 treatment administered with ART in acute SIV infection. We hypothesize that these agents will synergize to enhance SIV-specific defenses in LN, at a time when these defenses are robust; decrease SIV reservoir size; and promote viral remission after ART interruption. Using the highly relevant model of SIV-infected, ART-treated RMs, we will first determine the safety, mechanisms of action, and immunological impact of the single and combined FTY720 and hetIL-15 interventions (Aim 1). If our hypothesis is correct, the proposed studies will provide in vivo evidence of the synergy of FTY720 and hetIL-15 in decreasing virus reservoirs, both in circulation and in lymphoid tissues during ART (Aim 2), and promoting delayed viral rebound and/or durable control of SIV replication after analytical treatment interruption (Aim 3). The proposed studies will be conducted in the most relevant preclinical model of HIV infection; using two molecules that are either approved by the FDA (fingolimod, for multiple sclerosis) or being tested in clinical trials (hetIL-15). Our studies are necessary to provide insights into the safety and mechanisms of the combination to ascertain if such a strategy is safe and plausible for testing in people living with HIV. We believe that the proposed studies are innovative and higly significant to the HIV cure agenda.
The overarching goal of this project is to explore the safety, mechanisms of action, and therapeutic potential of a novel, combined fingolimod and het-IL-15 intervention administered with ART to RMs during acute SIV infection. Specifically, we propose that the combined administration of fingolimod and het-IL-15 will synergize mobilizing and enhancing robust antiviral defenses at lymphoid sites of HIV persistence, decreasing SIV reservoir size, and promoting durable control of virus after ART interruption. !
