Signal Transduction

Y.X. Huang, W.A. Paxton, S.M. Wolinsky, A.U. Neumann, L.Q. Zhang, T. He, S. Kang, D. Ceradini, Z.Q. Jin, K. Yazdanbakhsh, K. Kuntsman, D. Erickson, E. Dragon, N.R. Landau, J. Phair, D.D. Ho, R.A. Koup, "The role of a mutant CCR5 allele in HIV-1 transmission and disease progression," Nature Medicine, 2:1240-3, November 1996. (Cited in more than 150 papers since publication) Comments by David D. Ho, director of the Aaron Diamond AIDS Research Center at Rockefeller University, New York "We need inhibitors that will work against viruses that become resistant to the currently available drugs." It was an amazing anecdote. Researchers at the Aaron Diamond AIDS Research Center at Rockefeller University had identified subjects who repeatedly engaged in high-risk behavior that exposed them to HIV, but the subjects did not develop AIDS. "A couple of them had blood cells that were not infectable by HIV in a test tube," recalls David D. Ho, director of the center. Actually, further experiments showed that the blood wasn't completely immune to some strains of HIV. "We were puzzled by that," Ho recollects. Then a completed work appeared on ßchemokines (F. Cochi et al., Science, 270:1811-5, 1995). "That suggested that the ß chemokine would block a certain type of HIV, but not another type of HIV." Soon afterward, one group identified the coreceptor CXCR4 that, along with CD4, let the later-stage, T-tropic version of the virus into the cell (Y. Feng et al., Science, 381:667-73, 1996). Next, five groups almost simultaneously published findings that the coreceptor CCR5, paired with CD4, formed the key that allowed the earlier-stage, M-tropic strain of the virus entry (The Scientist, 12[16]:11, Aug. 17, 1998). Those studies provided insight into their subjects' biology, explains Ho: "Once the chemokine receptor story broke, it became very logical to see if these individuals had problems with their chemokine receptors." They had. Cloning out and sequencing the gene that codes for CCR5 in both individuals revealed a 32-nucleotide deletion (R. Liu et al., Cell, 86:367-77, 1996). "It's a pretty small deletion, but it truncates [the coreceptor] and frame-shifts it so it doesn't make any more [protein]." David D. Ho Ho and colleagues naturally wondered if the mutation was more than an anecdote. "Is it a rare explanation? What clinical evidence is there for this?" they asked themselves. They ran PCR-based assays on the DNA of 1,252 homosexual men enrolled in the Chicago component of the Multicenter AIDS Cohort, with two questions in mind: Does the mutation protect against infection, and does the deletion slow disease progression? The answer to each question was yes. All homozygotes for the mutant allele were uninfected. Infected heterozygotes seemed to demonstrate slower disease progression, as was illustrated through higher T-cell counts and lower viral loads. These two findings cement the study's importance to the basic science behind HIV. "It's the first firm example of how host genetics have an effect on the course of HIV," Ho remarks of the highly cited paper. Another study published similar findings using the same sampling population (M. Dean et al., Science, 273:1856-62, 1996). The finding has triggered a hunt for other mutations that affect HIV infection and disease progression. "Now people are looking into other genetic determinants that might play a role," Ho explains. Since the 1996 paper, other articles detailing mutations in CCR2 and the CCR5 promoter gene have been published. Ho expects to see more. "Defects in other coreceptors and their promoters probably play an important role," he adds. "People are going through the polymorphic regions of each one." The mutations also drew the attention of several pharmaceutical companies, because the paper bolstered the notion that the CCR5 coreceptor might be a good place to intervene (P. Smaglik, The Scientist, 12[5]:9, March 2, 1998). "This seems to be a dispensable gene. It's a good target to go after, because these people, in whom it's defective, are doing just fine." Ho anticipates that many companies will begin clinical trials of small-molecule inhibitors in a year or so. In addition, Ho thinks that gp120, the envelope protein that attaches to the coreceptors, can also be attacked with drugs--especially now that recent X-ray crystallography provides a detailed map of its structure (R. Lewis, The Scientist, 12[14]:1, July 6, 1998). Ho agrees that the approach, in theory, looks promising because, unlike protease inhibitors, small-molecule inhibitors could deny the virus entry, rather than attacking it once inside. "It's more elegant if you can prevent the whole thing from getting into the cell," Ho comments. "But at this stage, we look for anything that would break the replication cycle of the virus. If you have a circular situation, you can break it within any point." Ho notes that greater understanding of the virus and its mechanisms has helped to fight the disease, but that its ability to mutate has not yet been thwarted. Drugs that target coreceptors may or may not do that successfully. "We need inhibitors that will work against viruses that become resistant to the currently available drugs," Ho concludes.

Signal Transduction

The Scientist Staff

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