Preferential engagement of the anti-inflammatory ATP/adenosine axis by HIV vaccine candidate with V1-deleted envelope in male rhesus macaques

We evaluate the efficacy and immunogenicity of HIV clade A/E A244 envelope (Env) immunogens with the 23 amino acids of variable region 1 deleted (ΔV1) or retained (wild-type [WT]) in macaques. Only the ΔV1 regimen significantly reduces the risk of mucosal acquisition of clade C simian/human immunodeficiency virus (SHIV) 1157(QNE)Y173H versus controls, providing 81% efficacy and leaving 10 of 12 immunized animals uninfected. ΔV1 vaccination induces higher systemic antibody-dependent cellular cytotoxicity (ADCC) targeting helical-V2 and anti-inflammatory myeloid cells, which, together with IL-17 + NKp44 + innate lymphoid cells (ILCs) and systemic PD-1 + helper T cells, correlated with reduced infection risk. By contrast, WT immunization induces higher IL-15, CCR2 + pDC, and gp70/V1V2-biased responses, which, along with mucosal IFN-γ + NKG2A − NKp44 − ILCs, were associated with increased susceptibility. Ex vivo , ΔV1 gp120 reduced CCR5 expression on CD4 + T cells relative to WT gp120, consistent with the anti-inflammatory mucosal response by ΔV1-vaccine regimens in vivo . Thus, V1 deletion promotes an anti-inflammatory mucosal landscape less permissive to HIV seeding and dissemination following virus exposure.