The impact of human immunodeficiency virus-1 viral replicative capacity on infection of human cervical and rectal tissue explants ex vivo

Abstract

Characterization of the targets and kinetics of HIV infection within rectal and genital tissues is central to the assessment of novel prevention agents. The ex vivo models available are helpful for studying the initial stages of HIV‐1 infection, such as defining the primary HIV target cells and the factors that influence viral replication kinetics. Five HIV-1 clade C, 1 clade A and 1 clade A/D HIV-1 TF variants were isolated from IAVI Protocol C; a prospective acute infection cohort, and their infection of PBMCs (n=7), rectal (n=59) and endo- and ecto-cervical (n=49) tissue explants were assessed relative to HIV1BaL over 15 days in culture. There was no statistical difference in the rates of replication of the HIV-1 variants relative to HIV-1BaL in endo- and ectocervical tissues with the exception of HIV-1K4791 which replicated significantly higher in ectocervix than endocervix. Interestingly, HIV-1 variants defined as having “high replicative capacity” (RC) replicated to similar rates as those defined as low RC in cervical tissues in these experiments. We observed high levels of inter-donor variation in all tissues tested, however we detected HIV-1 replication in PBMC, rectal and cervical tissues with varied kinetics. HIV-1 variants infected both CD3+Th17 cells as well as non-T cells within rectal and cervical tissues 2 days after infection. The infected non-T cells were large and irregularly shaped; a phenotype consistent with myeloid dendritic or macrophages, and we aim to confirm the identity of these cells using tailored combinations of antibodies in future using existing stored samples. We have successfully transferred and established an explant culture system at KAVI-ICR for studying early events of HIV‐1 transmission in cervical and rectal tissues ex vivo. They are valuable tools to test the efficacy of microbicides in the prevention of HIV‐1 transmission study HIV-1, as well to evaluate HIV-1 vaccine candidates