IRCM researchers pave the way for a better understanding of HIV infection and<br>AIDS

A scientific breakthrough on how HIV takes control of cell division

MONTREAL, Sept. 3 /CNW Telbec/ - Dr. Éric A. Cohen, Director of the Human Retrovirology research unit at the Institut de recherches cliniques de Montréal (IRCM), and his team published yesterday, in the online open-access journal PLos Pathogens, the results of their most recent research on the role of the Vpr protein in HIV (human immunodeficiency virus) infection and AIDS (acquired autoimmune deficiency syndrome).

"We previously identified that HIV, when infecting target cells, blocks cell division and induces cell death," says Dr. Cohen. "We then discovered that the Vpr protein was involved in this process."

HIV-1 encodes several proteins, including the viral protein R (Vpr), which plays an important role in the development of acquired immunodeficiency syndrome (AIDS). Vpr blocks normal cell division, a process believed to increase viral replication and to trigger immune cell death. The researchers recently showed that Vpr performs this activity by interacting with a cellular protein complex (E3 ligase) involved in ubiquitination. Ubiquitination is characterized by the conjugation of a small protein called ubiquitin to various other proteins to regulate their degradation or activities. They also demonstrated that Vpr engages this protein complex to ubiquitinate a yet to be discovered host factor, whose degradation triggers the arrest of cell division.

"We understand the process, but we still don't know which cellular factor is targeted by Vpr to block cell division and where these events are occurring within the infected cell," explains Dr. Jean-Phillippe Belzile, a postdoctoral fellow in Dr. Cohen's research unit and first author of the article. "If we can identify this unknown host factor and determine its role in the cell cycle, it will undoubtedly have an impact on our understanding of HIV infection and the processes of immune cell death that characterize AIDS. We believe that the identification of this host factor could, in the long run, lead us to new potential therapeutic targets."

In this study, the researchers demonstrated that Vpr forms mobile structures called foci on the DNA of host cells. They also found that formation of these nuclear foci by Vpr is required to block cell division. They further showed that Vpr engages the E3 ligase within these mobile structures, and uses them to find a DNA-bound cellular protein and target it for degradation. This mechanism, in turn, results in the activation of a host cell response leading to a cell division block. 

"Getting such insight into this process is very important, as it gives us and the scientific community a direction to focus our efforts to identify this unknown host factor, thereby contributing to a better understanding of the role of Vpr during HIV infection and AIDS pathogenesis," adds Dr. Cohen.

This research project was supported by the Canadian Institutes of Health Research (CIHR), the Canadian Foundation for Innovation (CFI) and the Canada Research Chairs program. "This is an important step forward in the battle against HIV/AIDS," said Dr. Marc Ouellette, Scientific Director for the CIHR Institute of Infection and Immunity. "Enhancing our knowledge on the molecular mechanism of HIV infection is an excellent example of what fundamental research is all about: finding new approaches and narrowing the focus through discovery that might provide the basis for an effective therapy."

On a global scale, it has been estimated that in 2010, 33 million people lived with HIV, and 2 million deaths were related to AIDS.¹ According to the Public Health Agency of Canada, approximately 65,000 lived with HIV (including AIDS) in Canada in 2008. They also estimate that the number of new HIV infections ranges from 2,300 to 4,300 per year.

About Dr. Éric A. Cohen
Éric A. Cohen is a Doctor of Molecular Biology from the Université de Montréal. He is Director of the Human Retrovirology research unit at the IRCM. He is also Professor of Virology in the Department of Microbiology and Immunology at the Université de Montréal, and Adjunct Professor in the Department of Medicine (Experimental Medicine Division) at McGill University. Dr. Cohen is the recipient of the Canada Research Chair in Human Retrovirology.

In 2007, Dr. Cohen's team identified a cellular protein complex targeted by the HIV-1 Vpr protein to stop the division of infected cells. This year, his laboratory discovered a new mechanism through which HIV-1 Vpr manipulates natural immunity. His research team also identified a mode of action used by the HIV-1 Vpu to antagonize Tetherin, a host factor that blocks HIV-1 production and transmission; this viral counteraction is believed to have contributed to the emergence of HIV-1 in humans. These scientific breakthroughs could open new avenues for therapeutic intervention against HIV and AIDS.

About the Institut de recherches cliniques de Montréal (IRCM)
Founded in 1967, the IRCM (www.ircm.qc.ca) is currently comprised of 37 research units in various fields, namely immunity and viral infections, cardiovascular and metabolic diseases, cancer, neurobiology and development, systems biology and medicinal chemistry, and clinical research and bioethics. It also houses three specialized research clinics, as well as eight core facilities and two research platforms with state-of-the-art equipment. The IRCM employs 450 people and is an independent institution affiliated with the Université de Montréal. The IRCM clinic is associated to the Centre hospitalier de l'Université de Montréal (CHUM). The IRCM also maintains a long-standing association with McGill University.

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¹ Joint United Nations Programme on HIV/AIDS (UNAIDS), 2008 Report on the global AIDS epidemic.

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