Research finds hidden genetic clues that may explain HIV resistance and treatment

More than one million people in the U.S. live with human immunodeficiency virus (HIV), less than one percent of whom are known as “elite controllers” who can suppress the virus to levels below detection without medication. New research from The Feinstein Institutes for Medical Research at Northwell Health has found that “human endogenous retroviruses (HERVs),” a subset of transposable elements (TEs) found in genomic dark matter, may play a crucial role in explaining how this group can naturally suppress the HIV virus, potentially leading to new avenues for HIV treatments.

The research, co-supervised by Douglas F. Nixon, MD, PhD, director of the Feinstein Institutes’ Institute of Translational Research, and Cedric Feschotte, PhD, of Cornell University, and led by Cornell University’s Manvendra Singh, PhD, and Sabrina Leddy published this week in Genome Biology, shows that these elite controllers have distinct patterns of HERV activity in their CD4+ T cells, immune cells targeted by HIV. These HERVs, derived from ancient retroviral infections that infected our ancestors hundreds of thousands to millions of years ago, are known as ancient deoxyribonucleic acid (DNA) sequences.

While they are no longer able to replicate and infect new cells, HERVs can impact the activity of human genes, including those involved in immune responses. Heightened HERV activity has been correlated with increased expression of genes that contribute to combating HIV.

“This research is crucial because it offers a fresh perspective on HIV suppression,” said Dr. Nixon, who is co-corresponding author on the study. “By exploring the role of HERVs, we’ve uncovered a potential new pathway for developing future therapies that could mimic the natural resistance seen in elite controllers and provide critical insights into how these individuals, and others, could suppress the virus.”

Dr. Nixon and the team also identified a link between HERV activity and a group of proteins called KZFPs, which normally suppress HERVs. Elite controllers have lower levels of certain KZFPs, potentially explaining the increased HERV activity. Essentially, the “brakes” on these immune-boosting HERVs may be partially released in elite controllers.

“Dr. Nixon’s discoveries reshape our understanding of how the DNA residue deposited by ancient viruses into the human confers some people with natural resistance to HIV,” said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes and Karches Family Distinguished Chair in Medical Research. “These important findings open new research pathways to novel HIV therapies.”

Similar to the work related to HIV and these “elite controllers,” recently published HERV research from Dr. Nixon showed a new gene expression pattern that was linked to common mental health disorders including schizophrenia and depression.