Abrupt and altered cell-type specific DNA methylation profiles in blood during acute HIV infection persists despite prompt initiation of ART

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.

Effect of HIV infection and antiretroviral therapy initiation on genome-wide DNA methylation patterns

“…study, that found, in a population of 22 individuals with acute HIV infection, that initiating ART restored less than 1% of the HIV-induced DNA methylation changes in monocytes and had no effect upon DNA methylation alterations in CD4 + T lymphocytes. 39 However, this discordancy in the impact of ART on DNA methylation dynamics might be consequence of the difference in the duration of ART between both studies (approximately 8 months against 96 weeks in the present study), and in differences in the two populations (primary infection versus chronic infection in the present study). Thus, this could indicate that the trend towards normalizing DNA methylation changes induced by HIV does not occur following the immediate initiation of ART, although more longitudinal data are needed to confirm this hypothesis.…”

Butyrate administration is not sufficient to improve immune reconstitution in antiretroviral-treated SIV-infected macaques

“…Although lentiviral infections have been shown to specifically alter these parameters 54 – 57 , disruptions to butyrate-responsive pathways may not be the primary roadblock to complete immune restoration. Lentiviral infections induce widespread epigenetic changes 58 , 59 , many of which persist or rise anew after the initiation of ARV therapy 60 – 63 . Although HDAC inhibitors have been successfully used to reactivate viral reservoirs in latency reversal studies 64 – 66 , sodium butyrate treatment was not associated with increased viremia in our study (Fig.…”

Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome

“…This is in line with a recent study that demonstrated certain epigenetic changes induced upon acute HIV-1 infection not to revert upon ART. 39 …”