A variety of antiretroviral drugs used to treat HIV infection. Credit: NIAID
Published:
1/26/2018

A study published in the journal Science sheds new light on how a set of human genes can accelerate progression of AIDS-related illness in people living with HIV who are not on treatment.

South African scientists led the international research team, which included Frederick National Laboratory scientists, that involved 9,763 people with HIV in the United States and South Africa.

The research group discovered that a specific-type of gene complex (Human Leucocyte Antigen (HLA)) helps HIV infected cells evade the body’s first line of defense to an HIV infection. This first line of defense is comprised of immune cells known as natural killer (NK) cells.

The study revealed that individuals with the specific HLA type progress faster from asymptomatic HIV infection to becoming ill with AIDS. So, before they could begin antiretroviral treatment, their virus count was higher and their CD4 immune cells were destroyed more rapidly. An estimated 2 million of the approximately 7 million people living with HIV in South Africa have this specific HLA type.

Most of the laboratory research for this study, led by Veron Ramsuran, Ph.D. and Vivek Naranbhai, Ph.D., was conducted in three laboratories: the Frederick National Laboratory for Cancer Research; the Ragon Institute of the Massachusetts General Hospital (MGH); Massachusetts Institute of Technology (MIT); and Harvard University in the United States and the KRISP laboratories at Nelson R Mandela School of Medicine at the University of KwaZulu-Natal in Durban, South Africa.

This work is a culmination of five years of research, which included post-doctoral studies by Ramsuran with Mary Carrington, Ph.D. at the Frederick National Lab, where Carrington directs the Basic Science Program. Ramsuran is a South African scientist currently at KRISP in the College of Health Sciences, UKZN and is a research associate at CAPRISA. Naranbhai is a South African physician and scientist currently at Harvard University and is affiliated with Oxford University, the Ragon Institute and CAPRISA.

Besides studying HLA in the cohort of 9,763 people, the team conducted additional laboratory experiments with cells in culture, including those assessing HIV infectivity. These experiments confirmed that the specific HLA-A expression had a direct effect on NK cells and that blocking the interaction between HLA and NK cells with certain drugs reverses this effect.

“The HLA genes are highly variable across humans and the impact of this variation on how well a given individual infected with HIV can control the virus is very significant, but complex” said Carrington. “Our results show that expression levels of these genes contribute to the overall effect of HLA variation on HIV control through the innate, as well as the adaptive immune response. Now we must carefully consider how to use this information for the benefit of patients with HIV.”

“I was surprised by the findings as I expected the opposite results since the HLA genes were thought to protect against viruses”, said Ramsuran. “The human genome contains genes that help to guard the body against bacteria or viruses. We have now shown a potential detrimental effect of specific HLA types in people living with HIV who are not on treatment. Further, we now understand that this is due to the interaction between HLA-A expression and NK cells.”

The scientists explained that the research findings highlight the importance of regular HIV testing and early antiretroviral treatment, well before people with HIV become sick with AIDS. The study also gives a window into how drugs being developed for cancer to target the HLA interaction with immune cells could also be repurposed for HIV treatment and cure strategies.   

The research team comprised scientists from the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), the Centre for the AIDS Programme of Research in South Africa (CAPRISA) and the Human Pathogenesis Programme (HPP) – all based at the University of KwaZulu-Natal (UKZN) - together with researchers from the U.S. National Institutes of Health, the Ragon Institute, as well as researchers from Harvard, Oxford, Vanderbilt, Northwestern and Stanford Universities, Icahn School of Medicine at Mount Sinai, École Polytechnique Fédérale de Lausanne, MIT, Walter Reed Army Institute of Research, University of California – San Francisco, San Francisco Department of Health, and Microsoft. 

Image: A variety of antiretroviral drugs used to treat HIV infection. Credit: NIAID. 

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