AUTHOR=Petkov Stefan , Herrera Carolina , Else Laura , Lebina Limakatso , Opoka Daniel , Seiphetlo Thabiso B. , Pillay Azure-Dee AP. , Mugaba Susan , Namubiru Patricia , Odoch Geoffrey , Ssemata Andrew S. , Serwanga Jennifer , Kaleebu Pontiano , Webb Emily L. , Khoo Saye , Martinson Neil , Gray Clive M. , Fox Julie , Chiodi Francesca 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1009978

DOI=10.3389/fimmu.2022.1009978

ISSN=1664-3224

ABSTRACT=<p>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 <italic>in vivo</italic> 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 <italic>AKAP8</italic>, <italic>KIAA0141</italic>, <italic>HSCB</italic> and <italic>METTL17</italic>. 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: <italic>KIAA0141</italic>, <italic>SAFB2</italic>, <italic>CACTIN</italic>, <italic>FXR2</italic>, <italic>AKAP8</italic>, <italic>HSCB</italic>, <italic>CLNS1A</italic>, <italic>DDX27</italic> and <italic>DCAF15</italic>. Functional analysis of differentially expressed genes revealed modulation of biological processes related to mitochondrial stress <italic>(KIAA0141, HSCB and METTL17)</italic>, anti-viral and anti-inflammatory pathways (<italic>CACTIN</italic> and <italic>AKAP8)</italic>. 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.</p>