Short-term oral pre-exposure prophylaxis (PrEP) against HIV-1 modulates the transcriptome of foreskin tissue in young men in Africa

Whilst short-term oral pre-exposure prophylaxis (PrEP) with antiretroviral drugs in men who have sex with men has shown protection against HIV-1 infection, the impact of this regimen on the in vivo foreskin transcriptome is unknown.We collected foreskin tissue after voluntary medical male circumcision from 144 young men (72 from Uganda and 72 from South Africa) randomized to one to two doses of either oral FTC-TAF or FTC-TDF or no drug (untreated controls). This novel approach allowed us to examine the impact of short-term oral PrEP on transcriptome of the male genital tract.A single dose of FTC-TDF did not affect the foreskin transcriptome in relation to control arm, however one dose of FTC-TAF induced upregulation of AKAP8, KIAA0141, HSCB and METTL17. Following two doses of either FTC-TDF or FTC-TAF, there was an increase in 34 differentially expressed genes for FTC-TDF and 15 for FTC-TAF, with nine DEGs in common: KIAA0141, SAFB2, CACTIN, FXR2, AKAP8, HSCB, CLNS1A, DDX27 and DCAF15. Functional analysis of DEGs revealed modulation of biological processes related to cellular stress, anti-inflammatory and anti-viral pathways.These results show that short course oral PrEP in men elicits abnormal expression of several genes involved in mitochondrial function. Oral PrEP in men is not a benign formulation but modulates genes in foreskin which may prevent HIV acquisition.