Background
People living with HIV (PLWH) are disproportionately burdened by neurocognitive impairment (NCI) and physical frailty. Cognitive frailty, the combination of both, results in poorer outcomes than physical frailty or NCI alone. While epigenetic modifications are linked to each of these conditions separately, cognitive frailty remains understudied, and HIV and cocaine use may worsen outcomes. We investigated epigenetic profiles to identify methylation patterns predictive of cognitive frailty in people living with and without HIV and cocaine use.
Methods
We conducted a preliminary epigenome-wide association study (EWAS) with a subset of participants from the Miami Adult Studies on HIV (MASH) cohort. DNA samples from PBMCs of a random sample were stratified by HIV serostatus and cocaine use and analyzed using the Illumina MethylationEPIC_v-2-0 beadchip. HIV serostatus was confirmed with medical records and cocaine use with urine toxicology. Cognitive frailty was defined with the IANA/IAGG criteria, combining physical frailty (Fried criteria), and neurocognitive impairment (Mini Mental State Examination). Linear regression models examined associations between methylation patterns, cognitive frailty, HIV status, and cocaine use, adjusting for confounders. Significant CpG were identified with F test for the overall model (p< 0.01) and t-test for cognitive frailty (p<0.05).
Results
Average age (n=31) was 63.35 ±3.2SD, 100% were male, non-Hispanic Black, and 61.3% had a high school education or less. All were virally suppressed with an average CD4 cell count of 564.44±295.6SD. One CpG site (cg08287344) in EWAS had significant differential methylation patterns among the HIV/COC groups associated with cognitive frailty (p=2.64×10-7 of F test; p=0.05 for cognitive frailty, p=3.52×10-7 for HIV/COC). DNA methylation levels were lower in PLWH using cocaine who had cognitive frailty compared to HIV-negative participants not using cocaine and without cognitive frailty (Fig.1).
Conclusions
PLWH with cocaine use and cognitive frailty show greater epigenetic dysregulation compared to HIV-negative counterparts who do not use cocaine. Lower DNA methylation levels indicate changes in gene expression related to inflammation, neurocognitive decline, or drug-related stress. This suggests cocaine use may exacerbate epigenetic effects of HIV, potentially contributing to worsening health and cognitive outcomes. Further research is needed to explore these mechanisms.
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