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

Abstract

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 tenofovir (TFV) disoproxil fumarate (FTC-TDF) or tenofovir alafenamide (FTC-TAF) 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 four genes 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 differentially expressed genes revealed modulation of biological processes related to mitochondrial stress (KIAA0141, HSCB and METTL17), anti-viral and anti-inflammatory pathways (CACTIN and AKAP8). Our results show that short-course on-demand oral PrEP in men modulates genes in foreskin tissue which are likely unfavorable to HIV acquisition and replication. We also describe an upregulated expression of genes involved in diverse mitochondria biology which may potentially result in worsened mitochondria-related. These results warrant further studies to assess the role of short-course and prolonged oral PrEP on biological processes of the foreskin mucosa.

Unveiling the Role of Protein Kinase C θ in Porcine Epidemic Diarrhea Virus Replication: Insights from Genome-Wide CRISPR/Cas9 Library Screening

“…SPAG8 has been investigated as a potential host factor for human papillomavirus (HPV) infection [ 46 ]. GNG7 and METTL17 have been identified as potential host factors for the infection of cyprinid herpesvirus 2 (CyHV-2) and HIV-1 [ 47 , 48 ]. We further analyzed the role of these host factors and their underlying mechanisms in PEDV-infected individuals to identify potential therapeutic targets.…”

A randomized clinical trial of on-demand oral pre-exposure prophylaxis does not modulate lymphoid/myeloid HIV target cell density in the foreskin

“…The details of the procedure used for RNA sequencing of foreskin tissue have been previously described [ 18 ]. Transcriptomes were derived from combined inner and outer foreskin from each participant.…”

Bacterial microbiome and host inflammatory gene expression in foreskin tissue

“…Details of the RNASeq protocol have been published previously [ 26 ]. Briefly, foreskin samples were disrupted and homogenized using a Tissuelyzer (Qiagen) and total RNA isolated using the RNeasy Kit (Qiagen) according to manufacturer's instructions.…”

“…The 16S ASVs were filtered and combined as described for the differential abundance analysis and also CLR-transformed. As the previous analysis showed minimal differences between in expression between the control arms from the two clinical sites [ 26 ], we again analyzed specimens from the entire trial as a single data set. We calculated the correlation between the gene counts and bacterial relative abundances, then filtered for r > 0.4 and Benjamani-Hochberg-adjusted p-value <0.05.…”

“…Foreskin tissue was collected and subjected to both 16S rRNA sequencing and RNASeq to characterize the bacterial microbiome and inflammatory gene expression. Additional studies in this cohort have shown differences in mitochondrial gene expression [ 26 ] but no differences in inflammatory gene expression [ 26 ] or lymphoid/myeloid cell density in the foreskin [ 27 ] between treatment arms. We hypothesized that there would be a relationship between the microbiota and inflammatory gene expression, but that short courses of PrEP, as utilized in a dose-finding trial, would not result in significant disruptions of either.…”