Background:
HIV infection cannot be cured despite suppressive antiretroviral therapy (ART) due to a persistent reservoir of latently-infected memory CD4 T cells harboring replication competent virus. Here, we tested the SMACm/cIAP antagonist AZD5582 in combination with the heterodimeric interleukin-15 (hetIL-15), the native form of the cytokine that activates and expands cytotoxic T and NK cells, as a novel approach to prevent the establishment of the virus reservoir during the early stages of infection and/or ART.
Methods:
31 rhesus macaques (RMs) were infected with genetically barcoded SIVmac239M and started ART at 2-weeks p.i.. 9 RMs received hetIL-15 via sq injections of escalating dose of 10-40 ug/kg (weekly for 10 weeks) starting 3 days before ART initiation; 9 RMs received iv AZD5582 at 0.1 mg/kg weekly for 10 weeks starting at ART initiation; 9 RMs received the combination of hetIL-15 and AZD5582 over the same experimental phase as outlined above. 4 animals served as treatment-naïve, ART-only controls. Plasma viral loads were measured longitudinally for 16 weeks and the reservoir size was estimated in PBMC and lymph nodes (LN) by IPDA. CD8 T cells, CD4 T cells, and NK cells phenotypes were characterized by flow cytometry.
Results:
Treatment with AZD5582, alone or in combination with hetIL-15, resulted in slower decline of plasma viremia after ART initiation, and SIV viral load was significantly higher at day14-15-17-21-25-49 and 70p.i. in AZD5582 treated RMs, indicating that treatment with the SMACm was associated with a longer lifespan of the productively infected cells. Levels of peripheral and LN CD4 T cell intact proviral SIV DNA declined in all the groups over the treatment course. The frequency of IPDA+ CD4 T cells tended to be lower in the animals receiving the SMACm, alone or in combination with hetIL-15, with a statistically significant difference at day25p.i in both PBMC and LN. Interestingly, levels of granzyme B at day25p.i. were higher in LN CD8 T cells of the treated animals compared to the controls.
Conclusions:
Altogether, these findings suggest that treatment with AZD5582, alone or in combination with hetIL-15, may reduce the size of virus reservoir when administered at the time of ART initiation during acute SIV infection, thus suggesting a disruptive effect on the reservoir establishment. These data are consistent with previous work on the latency reversing activity of AZD5582 and provides rationale for further exploring this compound as a curative agent for HIV infection.