HIV Infection as an Independent Factor Accelerating Epigenetic Ageing in Men Treated with Integrase Inhibitors: A Case-Control Study.

HIV infection was strongly associated with global DNA hypomethylation in men successfully treated with INSTI-based cART.

• 48 men living with HIV receiving integrase inhibitor (INSTI)-based combined antiretroviral therapy (cART) were compared to 50 uninfected men in a case-control design.
• Global DNA methylation was measured in all participants.
• The association between HIV infection and global DNA hypomethylation was described as 'strong'.
• Statistical and machine learning methods were used to analyze results.
• All HIV-positive participants were considered successfully treated based on their cART regimen.

HIV infection was significantly associated with higher expression of the DNA methyltransferase gene DNMT1.

• DNMT1 expression was examined in all 98 participants (48 HIV-positive, 50 controls).
• The association between HIV infection and increased DNMT1 expression was described as 'significant'.
• Increased DNMT1 expression is interpreted by the authors as a marker of accelerated epigenetic ageing.
• DNMT1 is a maintenance methyltransferase; its upregulation in the context of global hypomethylation was noted as a key finding.

HIV infection was not associated with DNA methylation levels of site-specific genes CNOT2, DPP6, FOXG1, and NPTX2.

• Site-specific methylation was measured at four loci: CNOT2, DPP6, FOXG1, and NPTX2.
• No statistically significant association was found between HIV infection status and methylation at any of these four gene-specific sites.
• These genes were examined as part of a broader panel of site-specific DNA methylation markers.
• Both global and site-specific methylation analyses were conducted in the same participant cohort.

HIV infection was not associated with expression levels of DNMT3a or DNMT3b methyltransferase genes.

• Expression of DNMT3a and DNMT3b, both de novo methyltransferases, was measured in all participants.
• No significant association was found between HIV infection and expression of either DNMT3a or DNMT3b.
• This contrasts with the significant upregulation observed for DNMT1 in HIV-positive men.
• The differential expression pattern suggests a specific effect of HIV on maintenance methylation rather than de novo methylation machinery.

HIV infection was confirmed as an independent factor accelerating epigenetic ageing after accounting for lifestyle factors.

• All participants completed a questionnaire probing lifestyle factors, which were included in the analysis.
• Basic laboratory blood tests were performed in all participants.
• Both statistical and machine learning methods were used to assess independence of HIV infection as a predictor.
• The conclusion of independence implies that lifestyle confounders did not fully explain the observed epigenetic differences.
• All HIV-positive participants were on INSTI-based cART, allowing the study to isolate HIV infection effects from older antiretroviral drug classes.