Abstract
HIV-1 disrupts the host epigenetic landscape with consequences for disease pathogenesis, viral persistence, and HIV-associated comorbidities. Here, we examined how soon after infection HIV-associated epigenetic changes may occur in blood and whether early initiation of antiretroviral therapy (ART) impacts epigenetic modifications. We profiled longitudinal genome-wide DNA methylation in monocytes and CD4+ T lymphocytes from 22 participants in the RV254/SEARCH010 acute HIV infection (AHI) cohort that diagnoses infection within weeks after estimated exposure and immediately initiates ART. We identified monocytes harbored 22,697 differentially methylated CpGs associated with AHI compared to 294 in CD4+ T lymphocytes. ART minimally restored less than 1% of these changes in monocytes and had no effect upon T cells. Monocyte DNA methylation patterns associated with viral load, CD4 count, CD4/CD8 ratio, and longitudinal clinical phenotypes. Our findings suggest HIV-1 rapidly embeds an epigenetic memory not mitigated by ART and support determining epigenetic signatures in precision HIV medicine.Trial Registration:NCT00782808 and NCT00796146.
Highlights
Human immunodeficiency virus (HIV-1) infection is characterized by a rapid takeover of the host immune system and lasting impact on the immune system
Acute infection was associated with early DNA methylation changes in purified monocytes and CD4+ T cells isolated from blood
We explored whether AHI-associated DNA methylation changes in monocytes and CD4+ T lymphocytes at the earliest stages of acute HIV-1 infection were associated with clinically relevant outcomes following antiretroviral therapy (ART)
Summary
Human immunodeficiency virus (HIV-1) infection is characterized by a rapid takeover of the host immune system and lasting impact on the immune system. Multiple studies provide evidence that HIV-induced cellular reprogramming occurs in host immune cells by altering epigenetic processes, including DNA modifications such as DNA methylation[1], chromatin landscape and accessibility[2,3], three-dimensional chromatin organization[4], and cell typespecific transcriptional programs[5]. Together, these studies suggest that HIV-1 targets the reshaping of the host epigenome to drive transcriptional changes related to dysfunctional innate and adaptive immune defenses, promoting immune evasion, viral replication, and viral persistence.
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