Innate protection against intrarectal SIV acquisition by a live Simian-Human immunodeficiency virus vaccine

Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical against SIV/HIV acquisition. Here, we evaluated the efficacy of a SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded as there was no cross-reactivity between SIV and SHIV Envelope antibodies. After eight low-dose rectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated 83% efficacy, compared to six naïve controls, suggesting protection could be achieved in the absence of anti-Envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for the preventing viral acquisition, as none of the CD8-depleted macaques were infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation, and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 (PF4) on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity and may provide new opportunities for novel HIV vaccines or therapeutic strategy development. To define the biomarkers on the CD41+CD14+ monocyte-platelet aggregates (MPAs), single-cell RNAseq analysis was performed on two PBMC samples (one vaccinated V56 and one naïve N2).