Abstract Body

Broadly neutralizing antibodies (bNAb) against HIV-1 may target and eliminate virally infected cells expressing envelope (Env) protein, potentially reducing HIV-1 reservoir in people with HIV (PWH). Increased HIV-specific T cell responses have been observed in PWH receiving bNAb therapy during antiretroviral therapy (ART) interuption. We evaluated viral reservoirs and HIV-specific T cell responses in ART-suppressed participants receiving the bNAb elipovimab (EVM), an engineered variant of PGT121 with enhanced Fc-gamma receptor binding.

This phase 1b single and multiple ascending dose study enrolled 32 virologically suppressed PWH on ART and randomized them 3:1 to receive intravenous EVM or placebo with follow-up through day 169 (Cohorts 1 and 2) or 225 (Cohorts 3 and 4). Cohorts 1 (150mg) and 2 (500mg) received a single dose of EVM; Cohorts 3 (150mg) and 4 (500mg) received 5 doses administered biweekly. Plasma and PBMCs were collected longitudinally. HIV-specific T cell responses were evaluated with IFN-? ELISpot assay ex vivo using PBMCs stimulated with Clade B HIV-1 consensus peptides (Gag, Env, Nef and Pol). Total HIV DNA and intact HIV proviral DNA (IPDA) were assessed at baseline and after dosing. EVM sensitivity at baseline was defined using published Env signature. Proviral genotypes were determined using GenoSure HIV Envelope RNA Assay.

Modest increase in HIV-specific T cell responses were observed 12 weeks after the last dose of EVM in the participants of cohort 4, which returned to baseline 24 weeks later. The highest fold increase (FI) was Pol-specific T cells [median FI=2.4; interquartile range (IQR) 1.7 to 3.6] followed by Env-specific T cells (median FI=1.9, IQR 0.9 to 5.8). No significant change in HIV-specific T cells were observed in the other 3 cohorts. Overall, 7/31 (23%) participants were sensitive to EVM by genotyping; 3/6 who received multiple doses of EVM 500mg in cohort 4 were sensitive by genotyping, including 2 participants with the highest FI in HIV-specific T cells. No significant difference in total HIV DNA or IPDA were detected following treatment in any cohort (Wilcoxon matched-pair rank test).

EVM may engage the immune system and augment HIV-specific T cell response in PWH harboring bNAb sensitive viruses. Whether bNAbs can facilitate clearance of the replication competant latent HIV reservoir remains an area of interest and would likely require combinations of bNAbs to increase the breadth of coverage of diverse viruses.