Opposite effects of chronic HIV infection and antiretroviral medication on organismal and organ-specific biological aging.

Proteomic age acceleration significantly correlates with DNA methylation age acceleration in people with HIV.

• Six organ-specific and three organism-wide aging clocks were derived from plasma proteomics of healthy individuals.
• Two independent cohorts of people with HIV (PWH) were assessed.
• Proteomic age acceleration correlation with DNA methylation age served as a validation of the proteomic aging clocks.
• This correlation supports the biological validity of the proteomic aging measures used in the study.

Proteomic age acceleration is linked to comorbidities and mortality in people with HIV.

• Both organ-specific and organism-wide proteomic aging clocks were associated with aging-related comorbidities.
• Age acceleration measures were also associated with mortality outcomes.
• The aging clocks were derived from plasma proteomics data.
• These associations were assessed across two independent cohorts of PWH.

HIV infection accelerates systemic biological aging.

• Accelerated biological aging was observed using six organ-specific and three organism-wide aging clocks.
• The acceleration was detected in two independent cohorts of people with HIV on combination antiretroviral therapy.
• Aging acceleration was measured relative to healthy individuals from whom the clocks were derived.
• This finding was consistent across multiple clock modalities.

Mendelian randomization demonstrated causality between organ aging and inflammatory or metabolic complications in PWH.

• Causal relationships were identified between specific organ aging and downstream inflammatory complications.
• Causal relationships were also identified between organ aging and metabolic complications.
• Mendelian randomization was used to move beyond association to causal inference.
• These causal effects link chronic HIV infection, biological aging, and age-associated diseases.

Accelerated biological aging in PWH is related to the total HIV reservoir size.

• A positive association was found between total HIV reservoir size and degree of biological age acceleration.
• This relationship suggests that residual viral burden, even in treated HIV, contributes to aging acceleration.
• The finding implicates viral reservoir as a mechanistic driver of accelerated aging.
• This association was observed in the context of people on combination antiretroviral therapy.

Specific antiretroviral drugs reduce biological age acceleration in PWH.

• Not all antiretroviral drugs had the same effect on biological aging.
• Certain specific antiretroviral drugs were associated with reduced age acceleration.
• This finding suggests opposite effects of HIV infection (accelerating aging) and some antiretroviral medications (reducing aging acceleration).
• These drug-specific effects highlight potential targets for improving health span in PWH.
• The effect was assessed using the plasma proteomic aging clocks across cohorts.

People with HIV on combination antiretroviral therapy have an elevated risk for aging-related non-AIDS comorbidities.

• This elevated risk for non-AIDS comorbidities motivates the investigation of biological aging in PWH.
• The comorbidities are aging-related, suggesting a shared mechanism with accelerated biological aging.
• This context forms the clinical motivation for the study's design.
• The risk exists despite viral suppression achieved through antiretroviral therapy.