Temporal and spatial characterization of HIV/SIV infection at anorectal mucosa using rhesus macaque rectal challenge model

Abstract

The study described herein is a continuation of our work in which we developed a methodology to identify small foci of transduced cells following rectal challenge of rhesus macaques with a non-replicative luciferase reporter virus. In the current study, the wild-type virus was added to the inoculation mix and twelve rhesus macaques were necropsied 2-4 days after the rectal challenge to study the changes in infected cell phenotype as the infection progressed. Relying on luciferase reporter we noted that both anus and rectum tissues are susceptible to the virus as early as 48h after the challenge. Small regions of the tissue containing luciferase-positive foci were further analyzed microscopically and were found to also contain cells infected by wild-type virus. Phenotypic analysis of the Env and Gag positive cells in these tissues revealed the virus can infect diverse cell populations, including but not limited to Th17 T cells, non Th17 T cells, immature dendritic cells, and myeloid-like cells. The proportions of the infected cell types, however, did not vary much during the first four days of infection when anus and rectum tissues were examined together. Nonetheless, when the same data was analyzed on a tissue-specific basis, we found significant changes in infected cell phenotypes over the course of infection. For anal tissue, a statistically significant increase in infection was observed for Th17 T cells and myeloid-like cells, while in the rectum, the non-Th17 T cells showed the biggest temporal increase, also of statistical significance. IMPORTANCEMen who have sex with men are at the highest risk of acquiring HIV via receptive anal intercourse. Understanding what sites are permissive to the virus, and what the early cellular targets are is critical for development of effective prevention strategies to control HIV acquisition amid receptive anal intercourse. Our work sheds light on the early HIV/SIV transmission events at the rectal mucosa by identifying the infected cells and highlights the distinct roles that different tissues play in virus acquisition and control.