BACKGROUND: Pre-Exposure Prophylaxis (PrEP) for HIV prevention is a novel biomedical prevention method. We have previously modeled PrEP during rectal SHIV exposures in macaques and identified that SHIV-specific T cell responses were induced in the presence of antiretroviral drugs, an observation previously termed T cell chemo-vaccination. This report expands those initial findings by examining a larger group of macaques that were given oral or topical PrEP during repeated vaginal virus exposure. METHODS: Thirty-six female pigtail macaques received up to 20 repeat low-dose vaginal inoculations with wild type (WT) SHIVSF162P3 (n=24) or a clonal derivative with the tenofovir K65R drug resistant mutation (n=12). PrEP consisted of oral Truvada (n=6, WT), tenofovir vaginal gel (n=6, K65R), or tenofovir intra-vaginal ring (n=6, WT). The remaining animals were PrEP-inexperienced controls (n=12, WT; n=6, K65R). SHIV-specific T cells were identified and characterized using IFNgamma ELISPOT and multi-parameter flow cytometry. RESULTS: Of nine animals that were on PrEP and remained uninfected during WT SHIV vaginal challenges, eight (88.9%) developed virus-specific T cell responses. T cells were in CD4 and CD8 compartments, reached up to 4,900 IFNgamma producing cells per million PBMCs, and primarily pol directed. In contrast, the replication impaired K65R virus did not induce detectable T cell responses, likely reflecting the need for adequate replication. CONCLUSION: Virus-specific T cell responses occur frequently in oral or topical PrEP-protected pigtail macaques after vaginal exposure to WT SHIV virus. The contribution of such immune responses to protection from infection during and following PrEP warrants further investigation.

Maraviroc (MVC) is a potent CCR5 co-receptor antagonist that is in clinical testing for daily oral pre-exposure prophylaxis (PrEP) for HIV prevention. We used a macaque model consisting of weekly SHIV162p3 exposures to evaluate the efficacy of oral MVC in preventing rectal SHIV transmission. MVC dosing was informed by the pharmacokinetic profile seen in blood and rectal tissues, and consisted of a human-equivalent dose given 24h before virus exposure followed by a booster post-exposure dose. In rectal secretions, MVC peaked at 24h (10,242 ng/ml) with concentrations at 48h that were about 40 times those required to block SHIV infection of PBMCs in vitro. Median MVC concentrations in rectal tissues at 24h (1,404 ng/g) were 30 and 10 times those achieved in vaginal or lymphoid tissues, respectively. MVC significantly reduced MIP-1beta-induced CCR5 internalization in rectal mononuclear cells, an indication of efficient binding to CCR5 in rectal lymphocytes. The half-life of CCR5-bound MVC in PBMCs was 2.6 days. Despite this favorable profile, 5/6 treated macaques were infected during 5 rectal SHIV exposures as were 3/4 controls. MVC treatment was associated with a significant increase in the percentage of CD3+/CCR5+ cells in blood. We show that high and durable MVC concentrations in rectal tissues are not sufficient to prevent SHIV infection in macaques. The increases in CD3+/CCR5+ cells seen during MVC treatment point to unique immunological effects of CCR5 inhibition by MVC. The implications of these immunological effects on PrEP with MVC require further evaluation.