HIV Breakthrough: Protein That Fights Immunodeficiency Identified
A Canada-U.S. research team has solved a major genetic mystery: How a protein in some people’s DNA guards them against killer immune diseases such as HIV. In an advance online edition of Nature Medicine, the scientists explain how the protein, FOX03a, shields against viral attacks and how the discovery will help in the development of a HIV vaccine.
“HIV infection is characterised by the slow demise of T-cells, in particular central memory cells, which can mediate lifelong protection against viruses,” said lead researcher Rafick-Pierre Sékaly, a Université de Montréal professor and a researcher at the Centre Hospitalier de l’Université de Montréal and the French Institut national de la santé et de la recherche médicale (Inserm).
“Our group has found how the key protein, FOX03a, is vital to the survival of central memory cells that are defective in HIV-infected individuals even if they are treated,” added Dr. Sékaly, who produced his study with CHUM and Inserm colleagues including Elias El Haddad and Julien van Grevenynghe. Collaborators also included Jean-Pierre Routy, a McGill University Health Centre researcher and professor at McGill University and Robert S. Balderas, Vice-President of Research and Development at BD Biosciences of San Diego, CA.
Public support for the research came through Genome Canada and Génome Québec, among others, while private contributions came via a segment of BD (Becton, Dickinson and Company). “Public-private collaborations such as this play an important role in advancing medical research,” Robert S. Balderas. “BD Biosciences was pleased to provide powerful research instruments, reagents and technical expertise to support this breakthrough research.”
The breakthrough emerged by studying three groups of men: One HIV-negative sample, a second HIV-positive group whose infection was successfully controlled through tritherapy and a third group whose HIV did not show any symptoms. Called elite controllers, this third group fended off infection without treatment because their immune system, which would normally be attacked by HIV, maintained its resilient immune memory through the regulation of the FOX03a protein.
“Given their perfect resistance to HIV infection, elite controllers represent the ideal study group to examine how proteins are responsible for the maintenance of an immune system with good anti-viral memory,” said Dr. Haddad. “This is the first study to examine, in people rather than animals, what shields the body’s immune system from infection and to pinpoint the fundamental role of FOX03a in defending the body.”
Beyond HIV treatment, Dr. Sékaly said his team’s discovery offers promise for other immune diseases. “The discovery of FOX03a will enable scientists to develop appropriate therapies for other viral diseases that weaken the immune system,” he said, citing cancer, rheumatoid arthritis, hepatitis C, as well as organ or bone marrow transplant rejection.
Paul L’Archevêque, president and CEO of Génome Québec, lauded Dr. Sékaly’s team for their breakthrough and the people who volunteered for the study. “This discovery, the first such study in humans, is a major step forward in the understanding of how our immune system responds to life-threatening infections such as HIV. This advance stems directly from research co-financed by Génome Québec, which demonstrates the impact that genomic research can have in improving healthcare.”
This research was made possible by public and private institutions across Canada, the United States and France: the Université de Montréal, CHUM, Inserm, MUHC, Genome Canada, Génome Québec, Fonds de la recherche en santé du Québec, Canadian Institutes of Health Research, National Institutes of Health and BD Biosciences.
Nature Medicine Published online: 2 March 2008 | doi:10.1038/nm1728
Transcription factor FOXO3a controls the persistence of memory CD4+ T cells during HIV infection
Julien van Grevenynghe, Francesco A Procopio, Zhong He, Nicolas Chomont, Catherine Riou, Yuwei Zhang, Sylvain Gimmig, Genevieve Boucher, Peter Wilkinson, Yu Shi, Bader Yassine-Diab, Elias A Said, Lydie Trautmann, Mohamed El Far, Robert S Balderas, Mohamed-Rachid Boulassel, Jean-Pierre Routy, Elias K Haddad & Rafick-Pierre Sekaly
The persistence of central memory CD4+ T cells (TCM cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of TCM cell decline predicts HIV disease progression. In this study, we show that TCM cells and effector memory CD4+ T cells (TEM cells) from HIV+ elite controller (EC) subjects are less susceptible to Fas-mediated apoptosis and persist longer after multiple rounds of T cell receptor triggering when compared to TCM and TEM cells from aviremic successfully treated (ST) subjects or from HIV– donors. We show that persistence of TCM cells from EC subjects is a direct consequence of inactivation of the FOXO3a pathway. Silencing the transcriptionally active form of FOXO3a by small interfering RNA or by introducing a FOXO3a dominant-negative form (FOXO3a Nt) extended the long-term survival of TCM cells from ST subjects to a length of time similar to that of TCM cells from EC subjects. The crucial role of FOXO3a in the survival of memory cells will help shed light on the underlying immunological mechanisms that control viral replication in EC subjects.