HIV May Cause Premature Aging in Infected Individuals

The results of a methylome-wide analysis of human immunodeficiency virus (HIV) chronically infected, combination anti-retroviral therapy (cART)-treated individuals recently published in Molecular Cell suggest that HIV+ individuals have an epigenetic age 4.9 years older than healthy controls, resulting in an expected total mortality risk increase of 19%. Additionally, the human leukocyte antigen (HLA) locus was found to be hypomethylated in these individuals, and the HIV methylation aging signature was validated in purified cells as well.

The study was presented by Andrew M. Gross, a PhD candidate in the Bioinformatics and Systems Biology Program of the department of medicine at the University of California in San Diego, California. Due to the increasing number of HIV+ individuals treated with cART, those infected with HIV are living longer, but also showing signs of accelerated aging. The reasons underlying this observation have yet to be fully elucidated, although biological, as opposed to chronological, age advancement has been correlated with several factors including gender, genetic polymorphisms, and diseases including cancer and diabetes.

Previously conducted studies have produced HIV-mediated age advancement estimates ranging from 0—20 years; however, sampling effects, co-morbidities, and relatively low incidence rates of any single age-associated disease have hampered efforts to accurately quantify this number. Because biological age advancement may influence the onset of other age-associated disorders and is thought to be associated with epigenetic changes to the genome in general, Gross et al developed, "... biological aging models that allow us to establish a clear quantitative link between HIV infection and aging as observed in the general population." Independent of aging or other factors, Gross and colleagues also sought to find any specific genomic regions with methylation states particularly associated with HIV infection.

A genome-wide DNA methylation profiling study was conducted using whole-blood DNA samples collected from 137 non-Hispanic white males without other health issues enrolled in the CNS Antiretroviral Therapy Effects Research study (CHARTER), a long-term study to monitor HIV+ individuals who are being treated with cART. Additionally, samples from 44 healthy non-Hispanic white male controls were also included and an independent group of 48 individuals with and without HIV was used to confirm study findings.

This profiling study produced an array of findings implicating epigenetic changes in the premature aging of HIV+ individuals on cART including a strong shared phenotype of HIV and age. After benchmarking and refinement of their epigenetic aging models, important findings included advanced DNA methylation age in HIV+ individuals and age advancement independent of HIV duration or cellular composition. Additionally, HIV and aging were found to have both shared and distinct methylation patterns. For example, HIV was associated with hypomethylation of the HLA locus in an age-independent manner.

In a summation of these findings, Gross and colleagues said they had identified, "... both global and targeted epigenomic effects of HIV, including specific hypomethylation of the HLA locus." This result is of great significance, as the HLA genes encode the major histocompatibility complexes, which are important antigen-presenting molecules involved in regulating the acquired immune response and its impact on innate immunity.

To contextualize the results of their research, Gross et al stated, "Our findings help address a long-standing debate regarding the effects of HIV infection on biological aging in cART-treated individuals, in a manner that can be assessed numerically using an epigenome-based readout. Together, these results shed light on the epigenetic consequences and/or gerontological aspects of chronic HIV infection."

In addition to their findings supporting a tangible gerontological phenotype of chronic HIV infection, Gross and colleagues noted the potential clinical implications of their discoveries by stating "... the methylation aging model allows for patient-by-patient estimates. Patients deemed more likely to suffer from HIV-mediated aging effects might be placed on alternative schedules for preventative care, including early screening and further testing if warranted."

William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.