Biological aging and comorbidities are linked to HIV 1 reservoir size despite suppressive antiretroviral therapy

Background The HIV reservoir persists in long-living immune cells after antiretroviral therapy initiation. Proviral DNA integrates at preferential host DNA sites, while HIV transcription continues under treatment, with potential biological consequences. Treated people with HIV remain at increased risk for premature aging and non-AIDS comorbidities compared to people without HIV. Whether HIV reservoir size and activity impact health outcomes during treatment remains unclear. Methods We analyzed 1895 people with HIV using antiretroviral therapy from the 2000HIV cohort to study associations between the reservoir and historic and prospective virologic and immunological response markers, comorbidity outcomes and biological aging scores. The reservoir was assessed by quantifying total and intact proviral HIV DNA in circulating CD4+ T cells, along with measures of HIV transcriptional activity, including cell-associated HIV RNA. Results HIV reservoir markers were highly correlating and associated with older aging scores and adverse virologic outcomes, including quantifiable and residual viremia at study entry and during follow-up. Total HIV DNA, unlike the minor fraction of intact HIV DNA, correlated with prevalent cardiovascular disease, subclinical atherosclerotic disease, liver fibrosis and incident malignancies independent of circulating inflammatory markers and lowest CD4 nadir. Total HIV RNA associated with prevalent cardiovascular disease and liver fibrosis. Conclusion The HIV reservoir associated with older aging scores and long-term health outcomes in people with HIV using antiretroviral therapy, independent of inflammation and immune suppression history. Whether reservoir-reducing interventions lower the risk of non-AIDS comorbidities should be studied in people with high reservoir markers. Funding and trial registration ViiV Healthcare; 2000HIV ClinicalTrials.gov number: NTC03994835