Candidate host epigenetic marks predictive for HIV reservoir size, responsiveness to latency reversal, and viral rebound

Objective: This study aimed to identify candidate host epigenetic biomarkers predicting latency reversal agents (LRA) efficacy and HIV-1 rebound kinetics during analytical treatment interruption (ATI). Design: Retrospective longitudinal epigenetic profiling study from 13 people with HIV (PWH) on virologically suppressive antiretroviral therapy (ART) that participated in a LRA (HDAC inhibitor) clinical trial (NCT01680094) and a subsequent optional ATI to monitor for viral recrudescence after ART cessation. Methods: Genome-wide DNA methylation (DNAm) in purified CD4(+) T cells was measured at single-nucleotide resolution using the Infinium MethylationEPIC array. HIV-1 DNA and RNA measures were previously assessed by PCR-based methods and the association of DNAm levels at regulatory sites of the human genome were examined with reservoir size, responsiveness to LRA, and time to viral rebound following ATI. Results: A distinct set of 15 candidate DNAm sites in purified CD4(+) T cells at baseline pre-LRA and pre-ATI significantly correlated with time to viral rebound. Eight of these DNAm sites occurred in genes linked to HIV-1 replication dynamics including (SEPSECS, cg19113954), (MALT1, cg15968021), (CPT1C, cg14318858), (CRTAM, cg10977115), (B4GALNT4, cg04663285), (IL10, cg16284789), (TFPI2, cg19645693), and (LIFR, cg26437306); with the remaining sites at intergenic regions containing regulatory elements. Moreover, baseline DNAm states related to total HIV-1 DNA levels and the fold change in unspliced cell-associated HIV RNA following LRA treatment. Conclusion: Preexisting host epigenetic states may determine HIV-1 rebound kinetics and reservoir maintenance. These findings suggest integrating a suite of DNA methylation markers to improve optimal participant selection and drug regimen in future HIV cure clinical trials.