For those who have reliable access to combination antiretroviral therapy (c-ART), HIV has become a chronic and manageable condition.

But as the 1.2 million Americans currently living with HIV have become older, scientists have noticed a particular trend in these patients — a greater prevalence of age-related conditions like heart disease and bone fractures than in the general population, and at a younger age than normally seen. Now, a new study published Thursday in Molecular Cell appears to have confirmed the prevailing theory for the increase: HIV infection prematurely ages its sufferers, possibly by an average of five years.

A Portrait Of Biological Age

The researchers used an emerging method of DNA analysis on the blood samples of 137 patients living with HIV from an earlier long-running study and compared them to 44 control subjects. The method relies on tracking changes in how certain genes switched off or on; a field of study known as epigenetics. Specifically, it looked at DNA methylation, a routine process of gene-editing that either adds or removes a group of one carbon atom and three hydrogen atoms (a methyl group) to a DNA molecule. By measuring methylation changes associated with getting older, the team was able to sketch out a portrait of biological age.

"What we've seen in previous studies is that as we age, methylation across the entire genome changes," said study author Dr. Trey Ideker, a professor of genetics in the Department of Medicine at the University of California, San Diego, in a statement. "Some people call it entropy or genetic drift. Although we're not sure of the exact mechanism by which these epigenetic changes lead to symptoms of aging, it's a trend that we can measure inside people's cells."

They found that, on average, HIV-positive patients had a biological age five years older than their chronological age. This uptick in turn corresponded with a 19 percent increased risk of early mortality compared to their healthier counterparts. Interestingly, the aging effect appeared stable regardless of whether the person had lived with HIV for less than five years or more than 12, indicating the changes occur early on in infection or drug treament and aren’t significantly worsened by lengthy bouts of c-ART.

"We set out to look at the effects of HIV infection on methylation, and I was surprised that we found such a strong aging effect," said Ideker.

Given the technique's newness, Ideker and his colleagues took pains to ensure their findings were valid. They chose blood samples from HIV-positive subjects who had no other chronic health problems like hepatitis C or drug use, ran their results through several different computer models, and repeated the technique on a different group of 48 subjects who tested positive and negative for HIV. It was a worthwhile effort, according to Dr. Peng Jin, a professor of human genetics at the Emory University School of Medicine who was unaffiliated with the study.

“Their data are quite robust and they have a pretty good sample size for the analyses,” Dr. Jin told Medical Daily. “HIV exposure could potentially accelerate the aging process by changing the epigenetic status in the genome.”

While many of the epigenetic changes seemingly brought on by HIV coincided with those seen in aging, there were several unique to the viral disease. In particular, they found reduced methylation in a group of genes known as the human leukocyte antigen locus (HLA). The expression of these genes is important for regulating our immune system, and the researchers found that reduced HLA methylation predicted a lower ratio of CD4 to CD8 T-cells, a measure that predicts the strength of our immune system. In the best case scenario, that could someday mean the development of drugs that directly combat these changes in order to restore immune function and better control the infection, the authors speculated.

Jin however noted that their current findings only point to an association between the two factors, not a direct cause-and-effect relationship. More likely, for the time being at least, is that the epigenetic changes could be used to track how fast the disease is progressing and allow doctors to plan ahead accordingly.

“Patients deemed more likely to suffer from HIV-mediated aging effects might be placed on alternative schedules for preventive care, including early screening and further testing if warranted,” the authors wrote.

Source: Gross A, Jaeger P, Kreisberg J, et al. Methylome-Wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA. Molecular Cell. 2016.