Exposing HIV-Infected Cells to Antibody Attack
Interest in the role of antibodies—traditionally thought of as a vital component of any vaccine designed to prevent HIV infection—has been growing in the context of HIV cure research. This was reflected in a meeting— Development of Monoclonal Antibodies for HIV Treatment and Cure—convened by the National Institutes of Health and the Gates Foundation, June 3–4, in Rockville, MD.
Antibodies are generally thought of for their ability to neutralize virus that has not yet infected cells, whereas the main stumbling block in curing HIV is cells that are already infected. But antibodies have additional functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), that can directly target infected cells. ADCC occurs when a cell of the immune system—an effector cell such as a natural killer (NK) cell—binds to an antibody that in turn binds to the surface of an infected cell. The NK cell can then kill the infected cell.
Writing in the May issue of the Proceedings of the National Academy of Sciences, amfAR fellow Dr. Navid Madani of Harvard Medical School and a large team of researchers described a method of boosting the ability of antibodies to kill HIV-infected cells via ADCC. The ADCC effect hinges on the presence of the Env protein on the surface of infected cells. Env originates on the surface of the virus and binds to CD4 proteins on susceptible cells. After infection, some Env remains on the cell surface.
HIV protects itself from antibody attack by using two of its own proteins, Nef and Vpu, to decrease exposure of Env on the cell surface. To override this mechanism, Madani and colleagues used various forms of infecting virus, as well as variations of the CD4 protein, to enhance the ADCC-mediated killing of infected cells generated in a petri dish, as well as in cells taken from HIV-positive individuals. The authors envision that the combination required for this approach might be delivered by vaccine (for the antibodies) plus an oral formulation of modified CD4 proteins.
Dr. Madani collaborated with researchers from the University of Montreal; University of Pennsylvania; Institut de biologie et de technologie de Saclay, France; University of Maryland; Johns Hopkins University; the Scripps Research Institute; and Duke University.
amfAR recently funded another project that will combine the antibody 3BNC117—optimized for ADCC—with the cancer drug romidepsin, the most promising agent to date in terms of its ability to shock the virus out of latency. For more details, click here.
Dr. Johnston is amfAR’s vice president and director of research.