IL-15 Therapy Combined with TGF-Beta Blockade for Sustained HIV Remission

The overall goal of this proposal is to evaluate the safety and therapeutic potential of a novel strategy towards a cure of HIV infection. The proposed treatment combines soluble IL-15/IL-15Rα with a TGF-β pathway blockade and therapeutic

vaccination to enhance/restore function of anti-viral immunity that will lead to sustained viral remission following anti- retroviral therapy (ART) interruption against HIV, using the SIV/Rhesus macaque (RM) model. Persistence of viral

reservoirs and dysfunctional anti-HIV immunity represent two major obstacles that must be addressed to achieve sustained

viral remission via blocking viral reactivation in the absence of ART. ART is highly effective in controlling virus replication

but does not significantly improve T cell function and fails to eliminate viral reservoirs. Anti-viral CD8 T cells are critical

for the control of HIV/SIV replication, yet these cells are largely excluded from secondary lymphoid organs which host a

significant population of viral reservoirs during ART, primarily in T follicular helper cells (Tfh) that reside in B cell follicles

and germinal centers (GC). Thus, novel therapies that that not only restore/enhance function of both anti-viral CD8 T cells

and NK cells, but also promote follicular homing of these cells while viral reservoirs are being reactivated will significantly

enhance clearance of infected cells within lymphoid tissues, thereby contributing to sustained viral remission following analytical ART interruption (ATI). Our preliminary data demonstrate that treatment with the TGF-β pathway inhibitor galunisertib (GAL) improves anti-retroviral bioavailability in human lymphoid endothelial cells and cytokine (IL-

15/IL15Ra) treatment in vivo markedly enhances the magnitude, proliferation and cytotoxic potential of SIV-specific CD8+ T and NK cells with follicular homing potential, which is critical for the reduction of reemerging viremia post ART

interruption. In addition, in vitro stimulation of chronically infected PBMC with IL-15/IL15R therapy plus GAL treatment

resulted in higher proliferation anti-viral CD8 T cells and NK cells. Importantly, in vivo administration IL-15/IL15Ra plus GAL treatment in ART treated macaques enhanced antiviral CD8 T cell and NK cell function. Given these highly encouraging results, we propose to comprehensively test the effects of IL-15/IL-15Ra therapy plus GAL treatment either

alone or in combination on different T and NK cell subsets during chronic SIV infection under the umbrella of ART (Aim

1), and investigate how these changes affect viral reservoirs under ART and viral control after ART interruption (Aim 2).

Last, we will combine the optimal cytokine therapy with vaccination to further enhance the magnitude and breadth of SIV-

specific CD8 T cell responses that we hope will further improve the therapeutic benefit (Aim 3). These studies will advance our knowledge about how IL-15/IL-15a therapy plus GAL differentially influence the reservoirs and function of different subsets of T and NK cells during chronic SIV infection and ART, and what immune mechanisms are induced by dual

therapy and vaccination, and how these contribute to control of chronic SIV/HIV infection in vivo.