Impact of AZD5582 and hetIL-15 on HIV Latency Prevention During Early ART in SIV-Infected Rhesus macaques

HIV infection persists despite suppressive antiretroviral therapy (ART) due to a latent reservoir of memory CD4+ T cells harboring replication-competent virus. One of the many strategies explored for HIV/SIV eradication is based on the “shock & kill” paradigm, which postulates that the reservoir can be reduced or even eliminated by interventions that combine the reactivation of virus production in latently-infected cells (i.e., “shock”, as induced by latency-reversing agents, LRA) with the immune-mediated killing of these cells (i.e., “kill”, as mediated by cytotoxic T lymphocytes, NK cells, antibody-dependent cellular cytotoxicity and other mechanisms). In this study, we evaluated the SMAC mimetic AZD5582, which induces viral reactivation (shock), in combination with heterodimeric interleukin-15 (hetIL-15), which activates and expands cytotoxic T and NK cells (kill), as a strategy to prevent reservoir establishment during early SIV infection and ART. Thirty-five rhesus macaques were infected with barcoded SIVmac239M and initiated on ART two weeks post-infection. Animals received hetIL-15 alone, AZD5582 alone, the combination of both, or ART only, and were monitored longitudinally for 45 weeks. Plasma viral loads were measured for the duration of the study. Reservoir size was assessed in PBMCs and lymph nodes (LNs) by intact proviral DNA assay, and immune cell phenotypes were characterized by flow cytometry. Treatment with AZD5582, alone or in combination with hetIL-15, resulted in slower decline of plasma viremia after ART initiation. Levels of peripheral and LNs CD4+ T cell intact proviral SIV DNA declined in all the groups over the treatment course. The frequency of CD4+ T cells harboring proviral DNA tended to be lower in the animals receiving the SMAC mimetic, alone or in combination with hetIL-15. These results suggest that AZD5582, alone or with hetIL-15, transiently perturbs viral reservoir formation when administered at ART initiation during acute SIV infection, thus suggesting a disruptive effect on the reservoir establishment and providing a rationale for further evaluation as a component of HIV cure strategies.