Oct. 21, 1997 In May and June of last year, scientists discovered several new receptors on the surface of immune-system cells that are required -- along with the long-known CD4 receptor -- for HIV-1 to enter and infect those cells.
Now, little more than a year later, researchers at the University of Pennsylvania Medical Center and the University of Texas Medical Branch at Galveston have identified a small molecule that blocks one of these so-called coreceptors, preventing infection by a number of the HIV strains that target T cells. These strains of the virus are associated with progression from relatively asymptomatic HIV infection to the disease AIDS.
The discovery suggests that novel combination therapies that inhibit the full set of coreceptors could well prove effective in preventing or treating HIV infection and AIDS. The findings are reported in the October 20 Journal of Experimental Medicine. Two additional papers announcing similar results appear in the same issue.
"The importance of these studies is that they provide proof of principle," says coauthor Robert W. Doms, MD, PhD, an assistant professor of pathology and laboratory medicine at Penn in whose laboratory many of the experiments were conducted. "They show that we can develop small molecules to inhibit these newly identified coreceptors that HIV absolutely needs to get into cells, thus preventing infection."
The inhibitory molecule investigated in the study is a small peptide called ALX40-4C, the anti-HIV activity of which was first noted last year by senior author William A. O'Brien, PhD, at Galveston. Lead author Benjamin J. Doranz, BA, a researcher in Doms' laboratory, performed experiments indicating that ALX40-4C operated by blocking one of the coreceptors, CXCR4, which is used by the strains of HIV that infect T cells in the later stages of disease progression, known as T-tropic viruses. Another coreceptor, CCR5, is used by viral strains that show a predilection for macrophages in the earliest stages of infection, referred to as M-tropic viruses. Over time, in an infected person, viruses evolve from using CCR5 to using CXCR4, from M-tropic to T-tropic.
In one set of experiments, seven of ten strains of HIV isolated from patients by O'Brien used the CXCR4 coreceptor, and three of these relied on CXCR4 sufficiently to be blocked by ALX40-4C.
"One or more small molecules like this might delay or prevent evolution of the virus from using CCR5 to using CXCR4," Doms says, noting that it is the viral strains that use CXCR4 that correlate with dropping T-cell counts and progression to AIDS. "We also hope to develop small-molecule inhibitors of CCR5, the receptor used by viruses that start an infection. To be fully effective in countering HIV, we might need a cocktail that included a small-molecule inhibitor of CCR5 in conjunction with one against CXCR4."
In addition to Doranz and Doms, the third Penn-based coauthor is Matthew P. Sharron, BA. Other coauthors on the paper include Kathie Grovit-Ferbasi, Si-Hua Mao, and Matthew B. Goetz at the West Los Angeles Veterans Affairs Medical Center and the University of California at Los Angeles School of Medicine. Eric S. Daar with the Cedars-Sinai Medical Center and the UCLA School of Medicine is also a coauthor. ALX40-4C is manufactured by Allelix Inc., Mississauga, Ontario, Canada.
Grant funding for this work was provided by the National Institutes of Health. Doranz was supported by a predoctoral fellowship from the Howard Hughes Medical Institute.
The University of Pennsylvania Medical Center's sponsored research ranks fifth in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation -- $149 million in federal fiscal year 1996. In addition, for the second consecutive year, the institution posted the highest growth rate in its research activity -- 9.1 percent -- of the top ten U.S. academic medical centers during the same period.
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