Scientists discover new genetic markers that identify which people with HIV are likely to progress faster to Aids-related illnesses

A study published in the prestigious journal Science sheds new light on how specific human genes can lead to the faster progression of Aids-related illness in people living with HIV who are not on treatment. South African scientists led the international research team that discovered that a specific-type Human Leucocyte Antigen (HLA) gene complex helps HIV infected cells to escape the body's first line of defence, an immune cell known as natural killer (NK) cells.

The study of 9 763 people with HIV in South Africa and the USA showed that individuals with the specific HLA type progress from asymptomatic HIV infection to becoming ill with Aids faster. In these individuals, their viral load (number of viruses in their blood) was higher and their CD4 immune cells were destroyed more rapidly, before they started antiretroviral treatment. It is estimated that about 2 million of the approximately 7 million people living with HIV in South Africa have this specific HLA type.

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 US 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, 'Ecole Polytechnique F'ed'erale de Lausanne, MIT, Walter Reed Army Institute of Research, University of California - San Francisco, San Francisco Department of Health, and Microsoft.

Most of the laboratory research for this study, led by Dr Veron Ramsuran and Dr Vivek Naranbhai, was conducted in three laboratories: at the Frederick National Laboratory for Cancer Research (FNLCR) of the National Institute of Health (NIH); the Ragon Institute of the Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT); and Harvard University in the USA and at 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 Dr Ramsuran, with Dr Mary Carrington at FNCLR. Dr Ramsuran is a South African scientist currently at KRISP in the College of Health Sciences, UKZN and is a Research Associate at CAPRISA. Dr 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 almost 10 000 people, the team conducted additional laboratory experiments with cells in test-tubes, including those assessing HIV infectivity. These experiments confirmed 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.

"I was pleasantly surprised by the findings, as I expected the opposite results since the HLA genes were thought to protect against viruses," said Dr Veron Ramsuran, co-leader of the study who is a scientist at KRISP and CAPRISA at the University of KwaZulu-Natal. "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."

"This study demonstrates how, by doing locally responsive investigation as a team at the highest level can lead to new insights. This is the largest genetic study in HIV thus far. Moreover, these findings are exciting because drugs to target the HLA interaction with immune cells are being developed for cancer but may be repurposed for HIV treatment and cure strategies," said Dr Vivek Naranbhai, a co-leader of the study based at Harvard University.

"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 Dr Mary Carrington, Director of the Basic Science Program at FNLCR. "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."

"These results open a new door to understanding why some people become sick with Aids so soon after acquiring HIV infection," says Professor Salim S Abdool Karim, Director of CAPRISA and Pro Vice-Chancellor (Research) at the University of KwaZulu-Natal. "The study's findings highlight the importance of regular HIV testing, so that people with HIV can get to know their status and start antiretroviral treatment early, well before they become ill with Aids."

Smita Maharaj at: [email protected]: 031 260 4609Cell: 082 806 9931