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  11th International Workshop
on HIV and Aging
30 September - 2 October 2020
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Getting HIV Infection Speeds Up Epigenetic Clock (and Biologic Aging) Right Away
  11th International Workshop on HIV & Aging Virtual Meeting, September 30 to October 2, 2020
By Mark Mascolini for NATAP and Virology Education
US men who became infected with HIV saw their epigenetic clocks speed up within the first months or years of infection [1], a change suggesting accelerated biological aging reflected by DNA methylation patterns [2]. An age-matched group of men at risk for HIV infection who did not get infected had no change in their epigenetic clocks over the same brief period.
In the past decade Steve Horvath of the University of California, Los Angeles (UCLA) showed that DNA methylation can be used to measure the age of human tissues and cells, providing a so-called epigenetic clock [2] that "tells time"—biological time, not chronological time—by tracking DNA methylation. Work by Horvath [3] and others linked both treated and untreated HIV infection to accelerated DNA methylation aging patterns. But these studies were limited by their cross-sectional design.
In a new study a UCLA group including Beth Jamieson and Horvath determined DNA methylation patterns in peripheral blood mononuclear cells (PBMCs) collected before and after US men in the Multicenter AIDS Cohort Study (MACS) acquired HIV infection. They used both the original Horvath DNA methylation age estimate as well as newer tools that can predict lifespan and healthspan or can estimate changes in telomere length.
The UCLA team focused on 102 MACS men with a documented time of HIV seroconversion while in the MACS and matched them by chronological age (within 2 years) and HCV status to 101 MACS men who did not acquire HIV infection. Frozen PBMCs were available for an average 3.5 months before the estimated date of HIV infection and for an average 2.2 years after infection. Men without HIV made MACS study visits around the time of their matched HIV-positive partner.
Besides using Horvath's Age Acceleration Residual (AAR) method, the researchers calculated epigenetic age acceleration with four other calculators: Extrinsic epigenetic age acceleration (EEAA), Phenotypic epigenetic age acceleration (PEAA), and Grim epigenetic age acceleration (GEAA) clocks, and a DNA methylation-based estimator of Telomere Length (DNAmTL). The investigators used a linear mixed-effects model to identify variables that affected epigenetic clock changes: HIV status, hepatitis B status, smoking, body mass index, and race. The EEAA, PEAA, and GEAA clocks predict time to death and all-cause or cause-specific mortality. The EEAA chronometer has an added advantage in studies of people with HIV: it considers lymphocyte subsets.
Median age at HIV seroconversion (or at an equivalent visit in the HIV-negative group) was 37 years, and median time between pre-HIV and post-HIV samples (or equivalent) was 2.7 years (or 3.0 years). No epigenetic measure changed significantly between the pre- and post- visits in HIV-negative men.
In contrast, in men who acquired HIV, three epigenetic clocks sped up after the men got infected: From the pre-HIV visit to the post-HIV visit, AAR recorded a 1.4-year age acceleration residual (P = 0.002), EEAA a 4.7-year epigenetic age acceleration (P < 0.001), and PEAA a 4.7-year epigenetic age acceleration (P < 0.001). DNAmTL, which reflects older biological age by telomere shortening, showed significantly shorter telomeres from the pre-HIV visit to the post-HIV visit (-0.26 units, P < 0.001). The GEAA clock did not change significantly in men who got HIV infection.
The linear mixed-effects model determined that accelerated epigenetic time in EEAA, PEAA, and DNAmTL reflected only HIV status (P < 0.0001). None of the other variables affected epigenetic time.
The UCLA team concluded that acute HIV infection explains "significant acceleration of epigenetic aging in multiple clocks over a relatively short timeframe"--just over 2 years on average. And HIV infection itself emerged as the only predictor of this speed-up. They proposed that quicker PEAA and EEAA clocks and telomere shortening suggest that people risk more morbidities and a shorter lifespan soon after they pick up HIV infection. The EEAA clock and the DNAmTL gauge hint that rapid immune system changes explain these heightened risks. The investigators said longer follow-up of newly HIV-infected people may help determine whether big epigenetic changes right after HIV seroconversion alter with time or antiretroviral therapy.
1. Jamieson B, Breen E, Shih R, et al. Acceleration of multiple measures of aging-related epigenetics during HIV seroconversion. 11th International Workshop on HIV & Aging Virtual Meeting, September 30 to October 2, 2020. Abstract 6.
2. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. doi: 10.1186/gb-2013-14-10-r115.
3. Horvath S, Levine AJ. HIV-1 infection accelerates age according to the epigenetic clock. J Infect Dis. 2015;212:1563-1573. doi: 10.1093/infdis/jiv277.