173 – Repeated IL-10/PD-1 Blockades Potently Control SIV Rebound and Limit Reservoir in the Absence of ART

Background

HIV/SIV infection upregulates immunoregulatory factors, including PD-1 and IL-10, which impair antiviral responses and promote viral persistence. Blocking these pathways represents a promising approach to enhance viral control after ART treatment interruption (ATI). Dual IL-10/PD-1 blockade has been shown to limit viral replication post-ATI in SIVmac239-infected rhesus macaques (RMs). Still, it failed to reduce the reservoir, and the numerous doses of anti-IL-10 caused adverse events. Here, we assessed whether two cycles of IL-10/PD-1 blockade across two rounds of ATI, with fewer aIL-10 doses, improve viral control and reduce the SIV reservoir, while limiting treatment burden.

Methods

17 RMs infected with barcoded SIVmac239m initiated ART on Day 42 post-infection and remained on ART for 55 weeks before starting two cycles of aIL-10+aPD-1 (10mg/kg; n=8), or vehicle (n=9), each leading to an ATI (Fig.1). RMs were monitored up to Day 203 after the 2^nd ATI. Blood and lymph node (LN) biopsies were collected to evaluate viral load (VL), intact SIV reservoir, and viral barcode distribution.

Results

RMs treated with aIL-10+aPD-1 showed a stronger viral control during the 1^st ATI, with 52% of the VL measurements <10³ copies/mL, compared to 16% for the vehicle group. This control resulted in a 1.82 log lower VL at ART reinitiation in the treated RMs compared to vehicles. At the 2^nd ATI, the aIL-10+aPD-1 RMs showed an even stronger viral control, with a peak VL 0.82 log lower than that of the vehicles, and 83% of the VL measurements <10³ copies/mL, compared to 34% for the vehicles. This viral control persisted for >175 days post-ATI. Remarkably, the aIL-10+aPD-1 therapy also reduced the intact SIV reservoir in CD4 T cells from the blood and LN in 100% of treated RMs, with a median decline of 0.83 log in blood CD4 T cells between baseline (1^st phase) and necropsy/D203 post-ATI (2^nd phase) and of 0.79 log between Day -2 post-ATI (1^st phase) and Day 98 post-ATI (2^nd phase) in the LN. In the vehicle RMs, an increase of 0.90 and 0.32 log is observed in the blood and the LN for these same time points, resulting in the dual-treated RMs having 1.85 and 0.80 log lower reservoirs in blood and LN, respectively, than vehicle RMs at the latest time point.

Conclusions

Two cycles of IL-10/PD-1 blockade promote a durable SIV control without ART for >175 days and potently reduce the intact reservoir in blood and LN. This represents the 1^st immune-based strategy to reduce SIV persistence in RMs substantially.

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