Virology

HOT RECEPTION: From left, NIAID investigators Edward Berger, Paul Kennedy, Christopher Broder, and Yu Feng helped to break open the field of HIV coreceptor research with their discovery of fusin. Comments by Edward A. Berger, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases Within three years after the discovery of HIV as the causative agent of AIDS, scientists identified the CD4 molecule as the primary cellular receptor for HIV. They believed the virus entered target cells by an initial binding event between the envelope glycoprotein (Env) molecules on the viral membrane and CD4 molecules on the target cell surface. Yet as early as 1986, it became clear that the Env-CD4 interaction was not sufficient to promote the fusion reaction that results in HIV infection. Research teams searched for a coreceptor for roughly a decade. In 1996, a research team from the National Institute of Allergy and Infectious Diseases (NIAID) led by Edward A. Berger, chief of the molecular structure section, Laboratory of Viral Diseases, discovered the HIV coreceptor they dubbed "fusin" (later CXCR4); this molecule allowed HIV infection in CD4-expressing nonhuman cells through fusion with Env-mediated cells, and it blocked infection and fusion with naturally permissive CD4+ human target cells. This discovery brought about an explosion of research on coreceptors for HIV and has helped scientists better understand the transmission and pathogenesis of the disease. To discover the coreceptor, the NIAID team devised a cDNA screening strategy that deliberately made no assumptions about the molecular nature of the cofactors--the only requirement was that the cDNA allowed fusion of the virus to CD4-expressing cell types. The screening strategy included an assay in which Env-expressing cells fusing with CD4-positive target cells activated a "reporter gene." After several rounds of screening, the NIAID team isolated a single cDNA capable of conferring fusion activity to the CD4-expressing cells. DNA sequencing revealed that it was a previously described orphan receptor within the superfamily of G protein-coupled receptors. The coreceptor functioned selectively for more aggressive T-cell-line-tropic (TCL-tropic) virus strains. When HIV is transmitted between two people, the virus isolated from the blood of the recipient is typically macrophage-tropic (M-tropic). During this early stage of infection, most patients are asymptomatic and the immune system remains healthy. At later stages of infection, TCL-tropic viruses appear in the blood, marking the onset of full-blown AIDS. Other researchers later showed that fusin was a chemokine receptor, and the molecule was renamed CXCR4--the fourth receptor for CXC. Berger says the NIAID study provided scientists with crucial insights on the selectivity of HIV infection and helped to set the groundwork for the identification of other coreceptors. Just a month after the fusin publication, Berger's team and four other research groups independently reported that CCR5 is a major coreceptor for M-tropic strains of the virus (G. Alkhatib et al., Science, 272:1955-8, 1996; H. Choe et al., Cell, 85:1135-48, 1996; H.K. Deng et al., Nature, 381:661-6, 1996; B.J. Doranz et al., Cell, 85:1149-58, 1996; T. Dragic et al., Nature, 381:667-73, 1996). "Once we discovered fusin, it became obvious what type of molecule to look for in the search for other coreceptors," Berger notes. "The coreceptor discoveries have drastically influenced the way we look not only at the immediate problem of HIV entry and tropism, but also the broader questions of HIV transmission, pathogenesis, and therapy." The explosion of research in the coreceptor field has provided scientists with targets for anti-HIV drugs under development. While showing promise, therapies involving coreceptors pose a challenge to investigators. On the positive side, the chemokine receptors are members of the giant receptor superfamily called G protein-coupled receptors, which the pharmaceutical industry has been very successful at designing drugs to target. "The downside is that a CCR5 blocking drug might favor the replication of CXCR4-using viruses, which are thought to be more pathogenic," Berger says. "But the fact that people who are heterozygous for an inactivating CCR5 mutation show slower disease progression suggests that inhibiting CCR5 may be helpful."

Virology

The Scientist Staff

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