Thanks to combination antiretroviral therapy, many people with HIV can be expected to live decades after being infected. Yet doctors have observed that these patients often show signs of premature aging.
Now a study published in the April 21 issue of Molecular Cell has applied a highly accurate biomarker to measure just how much HIV infection ages people at the biological level - an average of almost five years.
"The medical issues in treating people with HIV have changed," said Howard Fox, M.D., Ph.D., a professor in the University of Nebraska Medical Center Department of Pharmacology and Experimental Neuroscience and one of the corresponding authors of the new study. "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 tool used in the new study looks at epigenetic changes in people’s cells. Epigenetic changes affect the DNA, but not the DNA sequence. Once they occur, they are passed down from one generation of cells to the next, influencing how genes are expressed.
The particular epigenetic change used as a biomarker in this research was methylation, the process by which small chemical groups are attached to DNA. Methylation of DNA can impact how genes get translated into proteins.
"What we’ve seen in previous studies is that as we age, methylation across the entire genome changes," said Trey Ideker, Ph.D., a professor of genetics in the University of California, San Diego Department of Medicine and the study’s other corresponding author. "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."
The 137 patients included in the analysis were enrolled in CHARTER (the CNS Antiretroviral Therapy Effects Research study), a long-term study aimed at monitoring HIV-infected individuals who are being treated with combination antiretroviral therapy.
Subjects were chosen for having minimal confounding conditions. A total of 44 HIV-negative control subjects also were included in the initial analysis. An independent group of 48 subjects, both HIV positive and negative, were used to confirm and expand the findings.
Dr. Fox praised the work of Sue Swindells, M.B.B.S., professor and medical director of the UNMC HIV Clinic and a co-author on the paper, and the clinic staff for their efforts in enrolling subjects for the study.
"They were wonderful," Dr. Fox said.
In addition to the discovery that HIV infection led to an average advance in biological aging of 4.9 years, the researchers note that such a change correlates with an increased risk of mortality of 19 percent.
"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," Dr. Ideker said.
"Another thing that was surprising was that there was no difference between the methylation patterns in those people who were recently infected [less than five years] and those with chronic infection [more than 12 years]," said Dr. Fox, who is senior associate dean for research and development in the UNMC College of Medicine.
This work may offer a means of identifying those at increased risk for aging-related disease and who many benefit from more monitoring and preventive efforts, Dr. Fox said.
The investigators said it’s possible drugs could eventually be developed to target the kinds of epigenetic changes observed in the study.
But the more immediate implications are much simpler. They note that people infected with HIV should be aware that they’re at greater risk for age-related diseases (such as neuro-cognitive issues, cardiology problems, and increased bone loss), and they should work to diminish those risks by making healthy lifestyle choices regarding exercise and diet as well as drug, alcohol, and tobacco use.
This study was supported by the National Institute of Mental Health, the National Cancer Institute, and the California Institute for Regenerative Medicine.
Molecular Cell, Gross et al: "Methylome-wide analysis of chronic HIV infection reveals five-year increase in biological age and epigenetic targeting of HLA."
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