Preferential engagement of the anti-inflammatory ATP/adenosine axis by HIV vaccine candidate with V1-deleted envelope in male rhesus macaques
Cell Reports Medicine, 2026
Silva de Castro I., Rahman M., Bissa M., Goldfarbmuren K., Schifanella L., Sarkis S., N’guessan K., Ma Z., Gutowska A., Stamos J., Doster M., Woode E., Smith J., Kozlowski P., Williams L., McKinnon K., Tomaras G., Shen X., Montefiori D., Santra S., Paquin-Proulx D., Maldarelli F., Cardozo T., Franchini G.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Infectious Diseases | Pathophysiology | Monkey Plasma |  Olink Target 48 |
Abstract
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.