Background:  Effective pre-exposure prophylaxis (PrEP) can induce T cell chemo-vaccination, i.e., adaptive anti-viral immune responses, as we previously documented in 2 macaques protected from rectal SHIV transmission by oral PrEP. We analyzed T cell immunity in a larger group of macaques, and address whether chemo-vaccination occurs after vaginal exposure to wild type SHIV or a SHIV mutant with diminished replicative capacity, and concurrent with oral or topical PrEP.

Methods:  We gave 36 female pigtail macaques as many as 20 low-dose vaginal inoculations with wild type SHIV_SF162P3 (n = 24) or a K65R-SHIV_SF162P3 clone (n = 12) containing a reverse transcriptase mutation. PrEP consisted of oral Truvada (n = 6, wild type) or vaginally delivered tenofovir (n = 6, wild type; n = 6, K65R); the remaining animals were untreated controls (n = 12, wild type; n = 6, K65R). We determined SHIV-specific T cell induction and duration by IFNγ-ELISPOT from a mean of 10 blood samples per animal before, during, and following virus exposures, over 5 to 8 months.

Results:  Of 12 macaques treated with oral or topical PrEP and exposed to wild type SHIV, 9 remained uninfected. Of the 9, 8 developed substantial SHIV-specific T cell responses (as many as 4930 spot-forming units [SFU]/10⁶ peripheral blood mononuclear cells [PMBC]). Untreated, wild type SHIV-exposed controls also demonstrated SHIV-specific T cells before infection, as did 1 of 2 uninfected controls, but responses only reached 1385 SFU/10⁶ PBMC. T cell responses in PrEP-treated animals were detected more frequently than in controls before infection and in uninfected controls (30 and 7 times, respectively; and in 8 of 9 PrEP-protected compared to 4 of 12 controls, p = 0.02 Fisher’s exact test, 2-sided). Responses also lasted longer (as long as 16 and 5 weeks after last virus exposure, respectively). No responses were detected in 7 K65R-virus exposed, uninfected macaques irrespective of PrEP, indicating that this replication-impaired mutant was not effective in inducing T cell responses.

Conclusions:  T cell chemo-vaccination occurred in a majority of macaques after vaginal exposure to wild type virus, and during topical and oral PrEP. This suggests that chemo-vaccination results in robust, systemic cellular immune responses after vaginal virus exposure, complementing our previous findings of chemo-vaccination after rectal virus exposure. The contribution of such immune responses to protection from infection during and following PrEP warrants further investigation.