Toll-like receptor (TLR)-7 agonist and PGT121 administration have previously delayed viral rebound and induced SHIV remission after antiretroviral therapy (ART) interruption in macaques that started ART 7 days post SHIV-SF162P3 infection. We evaluated the impact of TLR-7 agonist and dual broadly neutralizing antibodies (bnAb) on viral rebound in SHIV-infected macaques.
Male rhesus macaques (n=16), pre-screened to exclude protective MHC alleles, were inoculated at wk0 with SHIV-1157ipd3N4 intrarectally. ART (tenofovir, emtricitabine and dolutegravir) was initiated on Day14. Active arm (n=8) animals received oral GS-986, every 2 weeks from wk14-32 and intravenous N6-LS and PGT121 every 2 weeks from wk24-32 unless anti-drug antibodies (ADA) developed. ART was ceased when plasma levels of N6-LS and PGT121 were <0.25mg/mL. Control animals (n=8) received intravenous saline. Plasma SHIV RNA was assessed by qPCR (limit of detection 10 copies/mL) and soluble markers of immune activation by multiplex assay using Luminex.
All animals were SHIV-infected with median SHIV RNA of 5.7 (range 4.1-6.8) log10copies/mL on day14. After ART initiation on day14, SHIV RNA became undetectable in all animals by wk8 and remained undetectable until ART interruption. Due to varying ADA, animals received 7-10 doses of GS-986, 2-5 doses of PGT121 and 2-5 doses of N6-LS. At 24hrs post GS-986 dosing, plasma levels of IFNα, IL-1RA, IL-2, IL-6, IL-10, IL-15, MCP-1, MIP-1b, TNF, GM-CSF, IL-13 and MIP-1a increased significantly and viral blips were not detected. In the active arm, %Ki-67+ NK cells also increased at wk24 when compared to wk14 (p=0.031). Total HIV DNA levels in PBMC prior to ART interruption were not significantly different between arms. Median time to viral rebound was 6 weeks in active arm and 3 weeks in control arm (p=0.024, Figure 1). There was no significant difference in post rebound peak or set-point viremia between groups.
Administration of GS-986 and dual bNAbs was associated with a modest delay in viral rebound. The effect of timing of ART initiation on seeding of the viral reservoir likely influenced the ability to achieve remission. Evaluating this strategy in humans is warranted.