The ‘shock-and-kill’ HIV cure strategy involves latency reversal and immune-mediated clearance of infected cells. Our prior work showed systemic SIV latency reversal using the SMACm / cIAP antagonist AZD5582. Here, we investigated AZD5582 in combination with a cocktail of 4 rhesus-derived SIV Env-specific monoclonal antibodies (mAbs) to reduce viral reservoirs in ART-suppressed rhesus macaques (RMs).
21 RMs were infected with SIVmac239. ART was initiated 8 wks after infection. After 90 wks of ART, 9 RMs received anti-SIV Env mAbs at 20 mg/kg each s.c. followed by AZD5582 at 0.1 mg/kg i.v. wkly for 5 wks; this cycle was repeated once. 6 RMs received the mAb cocktail only. ART was continued in all RMs until study end. Concentrations of SIV mAbs (ITS09.01-LS, ITS102.01-LS, ITS103.01-LS, ITS113.01-LS specific for V2, CD4bs, CD4bs proximal, and MPER, respectively) were evaluated by ELISA. Latency reversal was monitored by plasma SIV RNA and reservoir size was estimated by qPCR for SIVgag DNA in CD4+ T cells and quantitative virus outgrowth assay.
Peak viremia of 107-108 copies/ml occurred 2 wks after SIV infection and ART was successful in suppressing viremia. MAbs peaked in all 15 RMs 24h after infusion with half-lives of 8.6, 6.0, 5.4, and 7.0 days for ITS-09.01-LS, -102.01-LS, -103.01-LS, and -113.01-LS, respectively. AZD5582 led to latency reversal in 7/9 (78%) SIV-infected RMs, with 94/206 (46%) ultrasensitive viral load measurements above baseline. A positive correlation was observed between pre-ART viral load and on-ART viremia during AZD5582 treatment (r=0.89, p=0.002). Levels of peripheral and lymph node CD4+ T cell-associated SIV-DNA declined over the treatment course. Cross-sectional analysis revealed modestly lower spleen CD4+ T cell-associated SIV-DNA in the AZD5582 + SIV mAbs group compared to controls (p=0.03). At study end, virus outgrowth from lymph node CD4+ T cells was significantly lower in the group that received AZD5582 + SIV mAbs compared to controls (p=0.04), trended lower in splenic CD4+ T cells, but did not differ in the periphery.
Our findings provide insight into a novel HIV cure strategy in a relevant preclinical model and confirm the efficacy of AZD5582 in inducing SIV reactivation. Importantly, these data suggest that elimination of infected cells in tissues using a cIAP antagonist and Env-targeting mAb cocktail is possible. Optimization of this approach may lead to enhanced reservoir clearance.