Viruses are evolutionary wiseguys; they have devised elaborate weapons that allow them to sneak past immune system defenses. But a team at King's College, London, has shown that in the case of HIV-1 infection, some human T cells are not completely vulnerable to an HIV-1 viral attack. Michael Malim and colleagues have found a human gene, CEM15, whose product actually inhibits HIV-1 infection and may eventually provide a potential new target for drug therapy.1 Yet, the wiseguy mien has not completely disappeared: While the protein encoded by the newly discovered gene normally protects certain T cells against HIV-1 infection, its antithesis, Vif (viral infectivity factor), overcomes CEM15 and establishes the disease.
"This is the first intracellular gene product that I know of," says John Moore, professor of microbiology and immunology at Cornell University. "That there was such a factor to find has been suspected for two or three years. ... It's a very elegant piece of work."
Vif proteins are produced by HIV-1 and other primate immunodeficiency viruses, although how they precisely work is still a mystery. But scientists do know that without Vif, viruses like HIV-1 are crippled and cannot replicate sufficiently to establish infection. Some believe that Vif operates during the late stages of HIV virus replication, somehow overcoming some cells' seemingly innate resistance to the virus--this innate resistance stems from the newly discovered CEM15 gene.
It was the study of Vif's role in HIV-1 infection that put Malim, a professor of infectious diseases, and colleagues onto CEM15's trail. The London team and one from the University of Pennsylvania suspected that such a gene existed after they discovered a previously unknown phenotype that resists HIV-infection and other retroviruses.2
Malim's group and another at Oregon Health Sciences University simultaneously published the existence of an unidentified cellular factor that could inhibit HIV-1 infection, but could be overcome by the presence of Vif protein.2,3 Now, Malim and colleagues have identified that cellular factor.1 They studied HIV-1 infection in T cells where the Vif protein was either fully functional or deleted. In cells classified as permissive, HIV-1 could replicate and set up infection whether or not Vif was present. Conversely, nonpermissive cells are those in which HIV-1 cannot replicate without Vif, indicating an innate defense system in those particular cells.
To locate this anti-HIV cellular factor, researchers looked for genes that are expressed solely in the nonpermissive cells. After identifying the candidate gene (CEM15), Malim's team transferred it to permissive cells and found that the CEM15 protein could confer resistance to HIV-1 infection as found in nonpermissive cells. Investigators then knew they had the elusive factor. "Human cells contain at least one gene that has natural anti-HIV activity," says Malim, but the virus encodes its own countermeasure, the Vif protein, and infection proceeds. "I think it's possible that other anti-HIV genes exist. There are quite a lot of examples of host genes that act against other viruses."
But how the CEM15 gene product works is unknown, he says. "Cells have all sorts of measures that are not immune-based to overcome viral infection, but this is the first instance of a gene like this. HIV has been in humans for maybe 70 years, but the gene has been around a lot longer and is conserved down to mouse. Maybe it is involved in resistance to other pathogens, but we just don't know."
Mario Stevenson is a professor of molecular medicine, University of Massachusetts, Worcester. "Viruses use multiple strategies to interfere with the ability of the host to recognize them at various levels," he says. Viral mechanisms can hamper the immune system's ability to present viral antigens; viruses can also interfere with the function of cytotoxic T cells. Moore notes that, so far, CEM15's normal function remains a mystery, but it does show some sequence similarity to a cytidine deaminase enzyme involved in mRNA editing.
Researchers hope that the newly discovered interaction between Vif and CEM15 will help them find ways to inhibit Vif, a quest they have been on for awhile. It also could help them learn to enhance CEM15's activity or make it resistant to Vif in some way.
"Once you know how [CEM15 works], it shouldn't be too difficult to figure out how Vif is working," Stevenson says. "Then you can do high-throughput screening to block it. If you can come up with drugs to interfere with VIF, then the cellular factor [CEM15] can go unimpeded. Then you have the situation where, in the presence of drugs, the virus can't replicate."
Nicole Johnston (email@example.com) is a freelance writer in Hamilton, Ontario, Canada.
1. A.M. Sheehy et al., "Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein," Nature, 418:646-50, Aug. 8, 2002.
2. J.H.M. Simon et al., "Evidence for a newly discovered cellular anti-HIV-1 phenotype," Nature Medicine, 4:1397-1400, 1998.
3. N. Madani, D. Kabat, "An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein," Journal of Virology, 72:10251-5, 1998.