Building on amfAR-Funded Discoveries to Define Drug Targets
By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.
September 18, 2007—Because of the almost endless ways HIV can mutate and thereby evade containment by current drug therapies, new means of suppressing the growth of HIV are urgently needed. This can be approached either by directly acting on the virus or through manipulating obligate human host cell proteins. Three amfAR-funded scientists, writing in two scientific journals published this August, are in the vanguard of this research.
The foundations of this recent work were provided by previous discoveries made by amfAR-funded scientists in the 1990s that led to development of two new classes of anti-HIV medication: Fuzeon (enfuvirtide), the HIV cell fusion inhibitor initially characterized by Dr. Carl Wild, and Selzentry (maraviroc), the CCR5 HIV co-receptor blocker, whose development was guided by research from Dr. Nathaniel Landau’s group.
As reported in the August issue of the Journal of Virology, amfAR-funded scientists Dr. Jacqueline Reeves, then working at the University of Pennsylvania and now at Monogram Biosciences, and Dr. Oliver Hartley of the University of Geneva studied a very basic question: How does HIV change from its initial form, using the CCR5 co-receptor to attach to a host cell, into a mutated form requiring a different co-receptor, CXCR4?
In order to infect a cell, HIV has two necessary portals—the receptor CD4 to which the virus first attaches, and the co-receptor to which the virus binds after it has made contact with CD4. There are two varieties of co-receptor, CCR5 and CXCR4. CCR5 is the means by which virtually all initial infections take place, but given time, particularly in the absence of effective anti-HIV treatment, the virus often evolves into a form that can use CXCR4. And the CXCR4-using version of HIV usually signals a much more virulent disease.
This process of switching co-receptors is also important because an anti-CCR5 drug such as Selzentry is not effective against a mutated CXCR4 virus. Drs. Reeves, Hartley, and colleagues identified the intermediate steps the virus progresses through in the switch from using CCR5 to CXCR4 , and linked these changes to the virus’s susceptibility to destruction by anti-virus antibodies and to its ability to bind tightly to the main HIV receptor, CD4. Interestingly, viruses in the intermediate stage, which do not bind tightly to either CCR5 or CXCR4, appear to increase the strength of their binding to CD4, perhaps to compensate for the relatively weak binding to the co-receptor.
Writing in the August 10 issue of the Journal of Biological Chemistry, amfAR grantee Dr. Pantelis Poumbourios of the Burnet Institute in Victoria, Australia, worked on further understanding the process of HIV-cell fusion, a process that is the target of one of the newest anti-HIV drugs, Fuzeon. After a virus has bound to CD4 and a co-receptor, the next step it needs to undergo in order to enter and infect a cell is fusion with the outer coat of the cell. Spikes that extrude from the surface of the virus, known as gp41, are responsible for mediating the fusion process. Dr. Poumbourios and his research group characterized the cooperation between the two ends of those gp41 spikes in pulling together the virus and the cell so that they can fuse. This new knowledge may facilitate discovery of additional drugs to block this process, and thus the formation of infectious virus.
Dr. Laurence is amfAR’s senior scientific consultant and Dr. Johnston is amfAR’s vice president for research.