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Biomarker Tracks Accelerated HIV-Associated Aging

Infection Adds Five Years on Average to Biological Age

By measuring a molecular signature of aging, researchers have found that HIV infection accelerates aging, adding an average of five years to someone’s biological age. The more rapid aging is occurring in people receiving antiretroviral treatment, so that even though treatment enables them to live for many decades, they remain at higher risk of aging-related chronic disease.

Studies of people with HIV infection have noted a higher risk of diseases associated with aging, such as liver and kidney failure, cancer, and heart disease. While the observations have suggested that HIV infection causes accelerated aging, there hasn’t been a biologically based marker of aging with which scientists could clarify and quantify the impact of HIV on aging.

In search of such a marker, scientists at the University of Nebraska Medical Center, led by Howard Fox, M.D., Ph.D., in collaboration with scientists at the University of California, San Diego School of Medicine, led by Trey Ideker, Ph.D., turned to epigenetics, a term for changes to DNA that affect its function without altering the sequence of bases that make up DNA. Through epigenetic processes, experience can alter the genome, silencing or activating genes.

Previous research by Ideker’s group had found that aging is associated with an epigenetic change called methylation, the addition of a chemical (methyl) group to specific sites on the DNA chain. In this new work, analysis of the “methylomes” in the blood cells of 137 HIV-positive individuals found marked differences in methylation in comparison with 44 matched but HIV-negative individuals. The investigators controlled for factors besides HIV infection that might alter methylation, such as other health conditions and differences in the methylation levels of different types of cells, given that HIV can alter cell populations. Building on information from previous research on methylation and aging, the team found that methylation tracked well with chronological age in those without HIV. In HIV-positive individuals, however, the changes in methylation were accelerated, adding an average of five years to “epigenetic” age. This fast forward occurred even in those who had had HIV for short duration, less than five years. Previous models found that aging-related changes in methylation parallel increases in mortality; the changes found here in HIV positive patients suggest a 19 percent increase in mortality.

“The medical issues in treating people with HIV have changed,” says Fox. “We’re no longer as worried about infections that come from being immunocompromised. Now we worry about diseases related to aging, like cardiovascular disease, neurocognitive impairment, and liver problems.”

The team also found that one region of the genome was particularly rich in HIV-associated changes in methylation: this region, the human leukocyte antigen locus, encompasses genes that encode molecules that are central to immune responses. The authors suggest that epigenetic processes may contribute to the changes in regulation of this region of the genome and thus the progression, or control, of HIV.

The work provides an objective method of assessing the impact in individuals of HIV on biological age. It provides insight into the mechanisms behind the accelerated aging, and may offer a means of identifying individuals vulnerable to aging-related chronic disease, and who may benefit from more careful attention to monitoring and preventive treatments. Given epigenetic changes observed in the HLA region, it may provide clues to future approaches to controlling infection.

“Among the areas that NIH has identified as high priority for HIV research in the next three to five years are studies on the impact of HIV-associated comorbidities such as premature aging associated with long-term HIV disease and antiretroviral therapy,” said NIMH’s Division of AIDS Research Director Dianne M. Rausch, Ph.D. “This work is important for the insight it provides into the mechanism of HIV-associated accelerated aging and the potential it offers in terms of a biomarker for identifying individuals with HIV infection who are at greatest risk of aging-related disease as well as the development of targeted interventions.”

The study is online April 21 in the journal Molecular Cell.

Reference

Gross AM et al. Methylome-wide analysis of chronic HIV infection reveals five-year increase in biological age and epigenetic targeting of HLA Exit Disclaimer. Molecular Cell (2016). 2016 Apr 21;62(2):157-168.  DOI: http://dx.doi.org/10.1016/j.molcel.2016.03.019.

NIH Grants

MH07390
MH062261
CA184427
Contract funding for CHARTER (CNS HIV Antiretroviral Therapy Effects Research) by NIMH, the National Institute of Neurological Disorders and Stroke, and the National Institutes of Health