Longitudinal study of surrogate aging measures during human immunodeficiency virus seroconversion
Longitudinal study of surrogate aging measures during human immunodeficiency virus seroconversion
Abstract
Persons living with human immunodeficiency virus (HIV) harbor an increased risk of age-related conditions. We measured changes in telomere length and DNA methylation in the peripheral blood of 31 intravenous drug users, who were followed longitudinally with blood samples pre-HIV (T1), immediately post-HIV (T2; 1.9±1 year from T1), and at a later follow-up time (T3; 2.2±1 year from T2). Absolute telomere length measurements were performed using polymerase chain reaction methods. Methylation profiles were obtained using the Illumina Human Methylation450 platform. Methylation aging was assessed using the Horvath method. Telomere length significantly decreased between T1 and T2 (227±46 at T1 vs. 201±48 kbp/genome at T2, p=0.045), while no differences were observed between T2 and T3 (201±48 at T2 vs. 186±27 kbp/genome at T3, p=0.244). Methylation aging as measured by the age acceleration residual increased over the time course of HIV infection (p=0.035). CpG sites corresponding to PCBP2 and CSRNP1 were differentially methylated between T1 and T2 at a q-value <0.05. Telomere shortening and methylation changes can therefore be observed in the short-term period immediately following HIV seroconversion. Further studies to confirm these results in larger sample sizes and to compare these results to non-HIV and non-injection drug users are warranted.
Introduction
With the benefit of combination antiretroviral therapy (cART), persons living with human immunodeficiency virus (PLWH) have survived to older ages [1,2] with fewer opportunistic infections and AIDS-defining cancers [3,4]. Despite these gains, the rise in the number of age-related conditions such as coronary artery disease [5], chronic obstructive pulmonary disease [6,7], and non-AIDS-defining cancers [8] has sparked interest in how PLWH age. The precise nature of this heightened aging process, whether in fact accelerated or merely accentuated [9], is still unknown. PLWH appear to have shorter peripheral blood telomere lengths compared with uninfected individuals [10–12], yet whether this represents a gradual attrition over the course of HIV infection or an abrupt shortening during periods of acute illness and profound immunosuppression has not been established. Recently, it has been shown in a cohort of cART-treated, virally suppressed PLWH that while telomere length, a surrogate marker of cellular aging, is shorter in PLWH compared with HIV-uninfected individuals, the slope of telomere length vs. age is no different between the two groups [11]. This might suggest that abrupt shortening does indeed occur early on in the course of disease, possibly at the period of intense immunosuppression related to acute HIV infection and prior to the institution of cART.
Identifying the timing of an aging trigger along the course of HIV infection has important scientific and clinical ramifications. At the very least, this allows further investigation into the biology of HIV aging to be situated in the appropriate time frame. Cellular changes observed within this time period provide important clues into the susceptibility of PLWH to age-related conditions. Shortening or preventing the onset of this time period may be one strategy that can improve outcomes in an aging HIV-infected population. Such investigations, however, require longitudinal sampling from subjects before and after HIV seroconversion. In this study, we examined surrogate peripheral blood aging markers in a cohort of injection drug users (IDU) followed longitudinally before and after acquiring HIV, aiming to 1) identify when age acceleration might occur in HIV and 2) describe potential key biologic pathways perturbed during the HIV seroconversion period. Useful biomarkers of aging, according to criteria adopted by the American Federation of Aging Research, are required to fulfill the following objectives: 1) predict the rate of aging; 2) reflect a biologic process associated with aging; 3) be able to be tested repeatedly in an individual without harm; and 4) translate from animals to humans [13]. Our choices of surrogate aging measures, both of which meet these criteria, focus on two distinct mechanisms, the first relating to replicative senescence by measuring peripheral blood telomere length and the second relating to age-associated methylation changes via a DNA methylation clock [14,15]. Shortened telomere length has been shown in some studies to predict mortality [16], age-related diseases [17], and has been widely used as a biomarker of aging. A recent study also demonstrated that the DNA methylation clock is a useful biomarker for detecting accelerated aging effects due to HIV infection [18], but the behavior over time of this biomarker is not yet known. Here we demonstrate for the first time that changes in surrogate aging biomarkers may be observed shortly after HIV infection.
Results
Study cohort
Demographics for the 31 patients enrolled in the study are provided in Table 1. The cohort had a mean age of 35.8 years and 48% were male. Nearly all patients (90%) had concurrent hepatitis C infection. The samples were collected between 1999 and 2004; by T3, only seven (22%) were on cART. The mean time intervals (± standard deviation [SD]) were 1.9 ± 1 years between T1 and T2 and 2.2 ± 1 years between T2 and T3. https://www.aging-us.com/article/101184/text
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