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Accelerated aging [by 5 years] with
HIV begins at the time of initial HIV infection
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HIV has an "early and substantial" impact on aging in infected people, accelerating biological changes in the body associated with normal aging within just two to three years of infection, according to a study by UCLA researchers and colleagues.
The findings suggest that new HIV infection may rapidly cut nearly five years off an individual's life span relative to an uninfected person.
"Our work demonstrates that even in the early months and years of living with HIV, the virus has already set into motion an accelerated aging process at the DNA level," said lead author Elizabeth Crabb Breen, a professor emerita at UCLA's Cousins Center for Psychoneuroimmunology and of psychiatry and biobehavioral sciences at the David Geffen School of Medicine at UCLA. "This emphasizes the critical importance of early HIV diagnosis and an awareness of aging-related problems, as well as the value of preventing HIV infection in the first place."
Previous research has suggested that HIV and antiretroviral therapies used to keep the infection under control are associated with an earlier onset of age-related conditions typically associated with aging, such as heart and kidney disease, frailty, and cognitive difficulties.
The research team analyzed stored blood samples from 102 men collected six months or less before they became infected with HIV and again two to three years after infection. They compared these with matching samples from 102 non-infected men of the same age taken over the same time period. The authors say this study is the first to match infected and non-infected people in this way. All the men were participants in the Multicenter AIDS Cohort Study, an ongoing nationwide study initiated in 1984.
https://newsroom.ucla.edu/releases/hiv-speeds-up-biologic-changes-associated-with-aging
"Our access to rare, well-characterized samples allowed us to design this study in a way that leaves little doubt about the role of HIV in eliciting biological signatures of early aging," said senior author Beth Jamieson, a professor in the division of hematology and oncology at the Geffen School. "Our long-term goal is to determine whether we can use any of these signatures to predict whether an individual is at increased risk for specific aging-related disease outcomes, thus exposing new targets for intervention therapeutics."
The researchers noted some limitations to the study. It included only men, so results may not be applicable to women. In addition, the number of non-white participants was small, and the sample size was insufficient to take into consideration later effects of highly active antiretroviral treatment or to predict clinical outcomes.
There is still no consensus on what constitutes normal aging or how to define it, the researchers wrote.
The Multicenter AIDS Cohort Study, or MACS, is a large-scale research project that uses demographic factors, habits, disease history and sexual history among men who have sex with men to examine the natural and treated history of HIV infection and AIDS. It is one of the few cohort studies in the world to have biological samples available both before and after documented HIV infection in the same individuals. In 2019, MACS was combined with the Women's Interagency HIV Study to form the MACS/WIHS Combined Cohort Study, or MWCCS.
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Accelerated aging [by 4.8 years] with HIV begins at the time of initial HIV infection ...initial viral load & immune damage linked, viral suppression as quickly as possible & sustained is critical
In the first ever study of this size and design, we have examined epigenetic aging over the course of initial HIV infection in more than one hundred persons, with five epigenetic measures of biological aging within six months or less before HIV infection, and again in the same persons shortly after initial HIV infection.
Participants from the Multicenter AIDS Cohort Study (MACS) who were included in the current substudy of initial HIV infection were predominantly white, non-Hispanic, college-educated men who have sex with men (Table 1), similar to the overall MACS demographics at the initiation of the study in the 1980s (Kaslow et al., 1987). There were slightly more non-white men among the persistently HIV-seronegative (SN) participants (26/102) compared to the participants who became HIV-infected and seroconverted (SC; 13/102, p = 0.02), which is consistent with the larger MACS biomarker study from which the participants for this substudy were drawn (Wada et al., 2015).
"This clearly demonstrates an early and substantial impact of HIV infection on the epigenetic aging process that begins in the first months and years of living with HIV.....EEAA and PEAA consistently showed significant results associated with HIV infection, with a median biological age acceleration of 4.8 years in SC, after adjusting for chronologic age."
Similar to acceleration in the EEAA and PEAA epigenetic clocks, aaDNAm TL showed accelerated telomere shortening over the course of initial HIV infection in SC participants, but essentially no change in SN participants over the approximately three years evaluated in this study. Because age acceleration in the EEAA clock correlates with increases in the number of senescent T cells, which are terminally-differentiated aged cells no longer able to divide, and TL is similarly linked to cell division, the strong association of both of these measures of accelerated biological aging with initial HIV infection may be due, at least in part, to rapid changes in the cells of the immune system itself......HIV infects CD4 T cells and monocytes/macrophages of the immune system, and its impact on the number of T cells of various subtypes is part of the hallmark of initial HIV infection and, ultimately, its accompanying immunodeficiency( Killian et al., 2004). Therefore, it is possible that HIV-induced changes in T cell numbers or frequencies may be inextricably linked to observed changes in epigenetic measures over the course of initial HIV infection.
"......demonstrating a role for initial HIV infection even after controlling for T cell changes, and supports the concept that the amount of HIV present as a result of the viral set-point may contribute to the magnitude of the early acceleration of biological aging according to these three epigenetic measures. It is important to acknowledge, however, that the viral set-point is the cumulative result of the interplay of virologic, immunologic, and genetic factors over the course of the initial period of HIV infection, and not the virus itself acting in isolation. Nonetheless, the possibility of HIV VL early after infection contributing to accelerated biological aging, with predicted risks of earlier mortality and immune system senescence by EEAA and PEAA, and dramatic estimates of shortened telomeres, adds yet another reason to strive to achieve clinical suppression of HIV in as many persons with HIV as possible, as soon as possible after infection."
A recent report by our group of a preliminary study of 15 pairs of HIV-infected and uninfected MACS participants demonstrated that initiation of HAART may slightly improve epigenetic measures of accelerated aging, but does not return any of them to levels comparable to HIV-uninfected persons of the same chronologic age (Sehl et al., 2020).
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Accelerated aging with HIV begins at the time of initial HIV infection
June 30, 2022
Over a relatively short time frame (less than three years on average), during which age-matched HIV-uninfected men showed no significant changes or acceleration in any epigenetic measure of aging, men who became infected with HIV showed highly significant age acceleration in three out of four of the epigenetic clocks as well as accelerated estimated telomere shortening (Figure 2). In mixed models, taking demographic and clinical co-variates or absolute cell counts or percentages of five T cell subsets into account (Tables 2 and 4 and S10), age acceleration in two epigenetic clocks, EEAA and PEAA, and shortening in the DNAm-based estimate of TL [telomerase] remained significantly associated with initial HIV infection. This clearly demonstrates an early and substantial impact of HIV infection on the epigenetic aging process that begins in the first months and years of living with HIV. This result in multiple epigenetic measures is not simply due to the correlations observed between the measures, as each was developed separately. Rather, because all were constructed for the purpose of examining epigenetic or biological aging, it is not surprising that they are correlated to each other and that more than one of the epigenetic measures point to a role of initial HIV infection in age acceleration. EEAA and PEAA consistently showed significant results associated with HIV infection, with a median biological age acceleration of 4.8 years in SC (sero-converted), after adjusting for chronologic age.
By design, the mean time intervals between peripheral blood mononuclear cell (PBMC) samples at Visits A and B were very similar in SC (2.9 years, range 1.3-3.7), and SN (2.7 years, range 0.9-4.0). Mean absolute CD4 T cell counts were stable in SN from Visit A to B at approximately 1000 cells/mm3, and similar to the mean CD4 counts seen in SC at the pre-HIV infection visit (Visit A, 1087 cells/mm3, p = 0.2). As expected, after initial HIV infection, the SC showed dramatically lower mean CD4 T cells at Visit B (mean = 616 cells/mm3, p < 0.001), but also had a wide range (73-1210 cells/mm3).
Among SC, the mean time interval between estimated date of HIV infection and the post-HIV infection PBMC sample at Visit B was 2.2 years (range 0.7-3.3 years). The calendar dates of estimated HIV infection ranged from 1985-2006, with 86% of the infection dates before 1995; regardless of calendar time, all SC post-HIV infection samples were before the initiation of highly active antiretroviral therapy (HAART) (Castillo-Mancilla et al., 2016). Mean plasma HIV viral load (VL) in SC at or immediately preceding Visit B was 49,757 copies/mL (median 14,084 copies/mL), ranging from a single individual with <50 copies/mL up to 948,000 copies/mL.
To our knowledge, this is the first truly longitudinal case/control study to analyze the impact of initial HIV infection on epigenetic age, utilizing multiple DNAm-based measures and comparing the results to well-matched controls aging in the absence of HIV. In conjunction with the wealth of other clinical and demographic data available, we tested our hypothesis that initial HIV infection, and specifically the HIV viral load, would be major contributing factors to early accelerated epigenetic aging, as characterized by multiple DNAm patterns which develop in the first years of living with HIV. Likewise, we believe that this is the first longitudinal examination of genome-wide DNAm changes associated with initial HIV infection.
Highlights
• Accelerated epigenetic aging begins within three years after initial HIV infection
• No epigenetic aging was observed in age-matched men over the same time period
• T cell changes after HIV infection did not account for all epigenetic changes
• Initial HIV infection is associated with significant genomic methylation changes
Summary
Living with HIV infection is associated with early onset of aging-related chronic conditions, sometimes described as accelerated aging. Epigenetic DNA methylation patterns can evaluate acceleration of biological age relative to chronological age. The impact of initial HIV infection on five epigenetic measures of aging was examined before and approximately 3 years after HIV infection in the same individuals (n=102). Significant epigenetic age acceleration (median 1.9-4.8 years) and estimated telomere length shortening (all p≤ 0.001) were observed from pre-to post-HIV infection, and remained significant in three epigenetic measures after controlling for T cell changes. No acceleration was seen in age- and time interval-matched HIV-uninfected controls. Changes in genome-wide co-methylation clusters were also significantly associated with initial HIV infection (p≤ 2.0 x 10-4).
These longitudinal observations clearly demonstrate an early and substantial impact of HIV infection on the epigenetic aging process, and suggest a role for HIV itself in the earlier onset of clinical aging.
Results
Demographics
Participants from the Multicenter AIDS Cohort Study (MACS) who were included in the current substudy of initial HIV infection were predominantly white, non-Hispanic, college-educated men who have sex with men (Table 1), similar to the overall MACS demographics at the initiation of the study in the 1980s(Kaslow et al., 1987). There were slightly more non-white men among the persistently HIV-seronegative (SN) participants (26/102) compared to the participants who became HIV-infected and seroconverted (SC; 13/102, p = 0.02), which is consistent with the larger MACS biomarker study from which the participants for this substudy were drawn (Wada et al., 2015). The SN and SC groups did not differ significantly by Hispanic ethnicity or level of education (minimum p values > 0.3). Mean age in SC and SN at Visit B (post-HIV infection or equivalent visit) was 39.0 and 38.5 years, respectively, reflecting the matching criteria (range 22-72 years across all participants). Likewise, because of matching criteria, the percentage of SC and SN with HCV infection were similar and small (2-3%), and both groups had low rates of active Hepatitis B Virus (HBV) infection at both visits (1-3%). As expected, based on reports of ≥90% Cytomegalovirus (CMV) seroprevalence among homosexual men (Drew et al., 1981; Nerurkar et al., 1987), the MACS men in this substudy for whom CMV serostatus data were available showed very high CMV seropositivity (97-100%) at Visit A, when both SC and SN were HIV-uninfected. Consistent with a previous MACS report among HIV-seropositive participants (Akhtar-Khaleel et al., 2016), SC had more cumulative pack-years of smoking than SN (p = 0.03 by Visit B).
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