Virology

Edited by: Stephen P. Hoffert B.J. Doranz, J. Rucker, Y. Yi, R.J. Smyth, M. Samson, S.C. Peiper, M. Parmentier, R.G. Collman, R.W. Doms, "A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors," Cell, 85:1149-58, 1996. (Cited in more than 230 publications through November 1997) Comments by Benjamin J. Doranz, Department of Pathology and Laboratory Medicine, University of Pennsylvania While the cell surface protein receptor CD4 has been identified as the primary receptor for HIV, additional molecules, called coreceptors, are required for the virus to enter and infect a cell. Studies over the past decade have demonstrated that these coreceptors also determine the types of viral strains responsible for person-to-person transmission and the rate of onset of AIDS. For example, cells with the receptor CD4 typically are the target of T-tropic but not M-tropic HIV. T-tropic viruses emerge gradually in HIV-positive patients, have higher replicative ability, and correlate with the onset of AIDS. In contrast, M-tropic HIV, which is actually the virus that is transmitted from person to person, fails to infect cells with only CD4 surface receptors. KEYS TO HIV INFECTION: Benjamin Doranz found that dual-tropic HIV could use any of a number of cofactors to infect a cell. Benjamin J. Doranz and Robert W. Doms, professors of pathology and laboratory medicine at the University of Pennsylvania, were able to show that the chemokine receptor CCR5 (once called CKR-5) functions as a coreceptor with CD4 and thus allows entry of M-tropic HIV into cells. They also found that dual-tropic virus strains, which represent a transitional stage of HIV between the M- and T-tropic stages, were able to infect cells using the coreceptors CCR5, CXCR4 (also known as fusin), CCR2B, or CCR3. "The discovery of the functions of these coreceptors contributes a lot to our understanding of HIV," Doranz explains. "That HIV can utilize so many coreceptors suggests that the virus might evolve over time to utilize other coreceptors present on the surface of a cell." The coreceptor CCR5 grabbed headlines just months after the discovery of its function, when scientists reported that a mutated gene for the coreceptor offered nearly complete protection from HIV infection. In collaboration with an international team of investigators, Doms and Doranz found that nearly 1 percent of people of Caucasian descent had this genetic mutation, which could prevent M-tropic HIV from infecting cells (M. Samson et al., Nature, 382:722-5, 1996). The team, led by researcher Marc Parmentier at the University of Brussels in Belgium, found no individuals homozygous for the mutated gene within a cohort of HIV-infected Caucasians. Experiments showing that HIV cannot utilize the mutated coreceptor offer a molecular explanation for the protection of some individuals, according to Doranz. The discovery by Doranz and Doms that coreceptors are critical for HIV infection continues to receive attention as researchers now focus on ways to exploit coreceptors in developing therapies for HIV. Doranz recently collaborated in a study that showed that the small-molecule inhibitor ALX40-4C prevents HIV from utilizing the coreceptor CXCR4 for entry (B.J. Doranz et al., Journal of Experimental Medicine, 186[8]:1395-1400, 1997). The study, which appeared in October, found that the inhibitor worked against T-tropic HIV strains as well as ligands and antibodies that naturally bind to the coreceptor CXCR4. However, the inability of ALX40-4C to block M-tropic or dual-tropic strains from replicating in cells that express both CXCR4 and CCR5 suggests that HIV can often adapt to use CCR5 if CXCR4 is not available, Doranz explains. Research on coreceptors for HIV continues, as scientists are hopeful that it could provide a molecular basis for new drug therapies aimed at blocking receptor sites and thereby preventing the progression of HIV infection to AIDS. But some barriers must be overcome for the development of such treatments. "HIV mutates rapidly, and you never know which chemokine receptor the virus will target, " Doranz says. "You could run the chance of actually hastening the onset of AIDS by blocking CCR5 receptors and encouraging the use of CXCR4. Our discoveries show that we need to know more about how coreceptors interact and complement each other before a drug therapy can be considered safe."

Virology

The Scientist Staff

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