Background
We explored the potential of combining the cIAP inhibitor AZD5582 with the BCL-2 inhibitor Venetoclax (VTX) to reverse latency and clear reactivated infected CD4+ T cells in a nonhuman primate model of HIV.
Methods
Thirty SIVmac239M-infected rhesus macaques (RMs), 18 males and 12 female, began antiretroviral therapy (ART) at 4 weeks post-infection (wpi). At 68 wpi, they were divided equally into three groups: A) ART-only, B) ART + VTX, and C) ART + VTX + AZD5582. VTX was given either intramuscularly (15 mg/kg) or orally (300 mg) in 3 cycles of 4 daily doses to Groups B and C. Group C also received weekly intravenous AZD5582 (0.1 mg/kg) for 10 weeks, followed by an analytical treatment interruption (ATI) 4 weeks after the final AZD5582 infusion. Additionally, plasma concentrations for AZD5582 and VTX were measured by HPLC MS/MS in a subset of RMs in groups B and C (N=5 RMs per group).
Results
AZD5582 effectively reversed latency, with on-ART viremia exceeding 60 copies/ml in 6/10 RMs in the ART + VTX + AZD5582 group. The level of intact SIV proviruses in mononuclear cells isolated from peripheral blood and bone marrow was significantly lower after intervention with ART + VTX + AZD5582 (p<0.0001 for both sites), while levels remained stable in ART-only controls. Despite this impact on the intact reservoir, RMs from all groups experienced viral rebound after ATI within a similar timeframe. Area under the curve of on-ART viremia in the ART + VTX + AZD5582 group was not associated with post-intervention reservoir size, suggesting that the decline in intact proviral DNA was due more to VTX than to AZD5582. Indeed, AUC of VTX concentrations was positively correlated with the fold decline in intact reservoir size in PBMCs (Spearman r=0.9, p=0.08). A weak negative association between VTX AUC and post-ATI rebound viremia AUC (Spearman r= -0.60, p=0.350) was also observed.
Conclusions
The combination of AZD5582 and VTX reduced the intact SIV reservoir in peripheral blood and bone marrow but did not delay viral rebound after ATI. These findings highlight the intricate relationship between latency reversal, reservoir size, and viral rebound.
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