Scientists find new HIV-host subtleties.
Genetic variability is a well-known feature of the AIDS-causing virus, HIV. But new research described in Montreal this week at the Fifth International Conference on AIDS suggests that many of the variations scientists see among different strains of HIV -- including apparently inconsistent responses to antibodies and changing preferences for various target cells -- are part of the virus' predictable natural history in the human body. The new information both complicates an already daunting biomedical puzzle and presents some unforseen opportunities to halt disease progression, researchers say.
During the course of an AIDS infection, HIV becomes progressively more toxic to cells and gains the ability to infect a broader variety of cells. Strains that infect only one kind of white blood cell called T lymphocytes can change very suddenly -- within as little as one viral generation -- so that they infect only monocytes and macrophages, other types of immune cells. Researchers remain baffled about how this targeting change occurs.
Ten feizi of the MRC Clinical Research Center in Harrow, England, and others looked at macrophage- and T-lymphocyte-infecting versions of HIV. They report finding specific changes in the number and type of molecular side-chains on the protein spikes protruding from the viruses' outer envelopes, which allow viruses to gain access to new cell types. Moreover, Jay A. Levy of the University of California, San Francisco (UCSF) reports indirect evidence that factors in an infected person's blood may mediate such changes. He says individual variations in blood levels of these envelope-modifying factors could explain differences in the disease-causing potential of initially identical HIV strains in different individuals. Levy hopes to block these envelope changes, thus keeping the virus from spreading to different kinds of cells -- such as brain cells -- within the body.
Levy's team also looked at the role of an HIV gene called nef, which appears to suppress HIV replication during periods of latency. In specifically engineered, cultured cells, the researchers compared nef's influence on two strains of HIV. The less virulent came from patients in an early stage of infection; the other came from a later stage of infection. When nef was active, the early-stage HIV strains became almost totally latent, as expected. But late-stage HIV ignored nef's commands. A better understanding of the nef gene, its product and the factors that make some HIVs insensitive to it may lead to an improved ability to force HIV into permanent latency, says Levy.
UCSF's Jacques Homsy and others also examined a phenomenon called antibody-dependent enhancement in individuals who harbor HIV. Unlike a typical immune reaction, in which "neutralizing" antibodies bind to and at least partially inactivate their targets, this poorly understood immune reaction -- present in some AIDS patients--actually boosts HIV activity. Over the course of several years, the team studied 15 HIV-infected people at various disease stages ranging from asymptomatic to full-blown AIDS. They found that virus-enhancing antibodies gradually increased in patients as symptoms worsened. However, several patients' antibodies neutralized some virus strains while enhancing others.
That unpredictability, says Levy, could be very bad news for vaccine makers. Scientists will have to identify and disable at least some of the immune system elements involved in antibody-dependent enhancement before a safe AIDS vaccination program can be initiated, he says.
Homsy this week reported identifying one such molecule on white blood cells that appears critical to antibody-dependent enhancement.
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|Date:||Jun 10, 1989|
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