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Research News.
March 20, 2003— Howard Hughes Medical Institute researchers and their colleagues have discovered one way in which the human immunodeficiency virus (HIV) wins its cat-and-mouse game with the body's immune system. The study, published in the March 20, 2003, issue of the journal Nature, shows that HIV-1, a common strain of the virus that causes AIDS, uses a strategy not seen before in other viruses to escape attack by antibodies, one of the immune system's prime weapons against invading viruses and bacteria. Viruses typically vary the protein sequence, or epitope, of the viral envelope that acts as a docking station for antibodies. This variation alters the docking region on the virus and prevents antibodies from grabbing hold and targeting the virus for destruction. HIV-1, in contrast, continuously changes the arrangement of large sugar molecules studded across its gp120/41 protein coat so that those docking regions for antibodies are obstructed. The research team, led by Howard Hughes Medical Institute investigator George M. Shaw at the University of Alabama at Birmingham (UAB), dubbed the mechanism an evolving "glycan shield," and said the discovery was a surprise. Shaw and his colleagues were just as surprised at the rapidity and extent to which the replicating virus population in infected patients escaped antibody recognition. "Before these findings, the role of antibodies in combating the virus that causes AIDS was not altogether clear. The new data suggest a more active role for HIV-1-neutralizing antibodies in virus containment and an unexpected mechanism of virus escape,” he said. "We found that the neutralizing epitopes on the virus did not change, but instead other parts of the viral envelope mutated, generally in a way that altered specific amino acids to which carbohydrates normally attach," Shaw said. "These changes in glycan molecules prevent the binding of neutralizing antibodies to the virus surface through steric inhibition, thereby enabling the virus to avoid antibody-mediated elimination." The findings show that the immune system does try to fight HIV, and they offer a reason why the virus often wins the battle, he said. "The glycan shield mutates at a faster rate than the immune system can change in order to keep up." Despite the resourcefulness of the virus, Shaw said there is hope for the development of an effective vaccine to protect those people who are currently uninfected but at risk of becoming infected. "While neutralizing antibodies are obviously unable to completely eliminate HIV-1 from infected patients, the fact that they are sufficiently potent as to result in the sequential elimination of one virus population after another suggested that if uninfected patients were vaccinated against HIV-1 with an appropriate immunogen, then neutralizing antibodies in this setting could conceivably have a far greater impact," he said. Better yet, Shaw said, may be the idea of combining an immunogen that elicits neutralizing antibodies with other components of the human immune system, including cytotoxic T-lymphocytes. In the course of their work, Shaw and his colleagues developed a new strategy for detecting HIV-1 antibodies that prevent entry of the virus into human cells. The investigators reasoned that since variants of HIV-1 that are resistant to antiretroviral drugs can be detected in the bloodstream of AIDS patients, if neutralizing antibodies were present and did affect virus replication in vivo, then by testing patients for strains of the virus that had become resistant to antibodies, they could infer their presence and their biological activity. Using a modification of a laboratory assay that they had developed previously to test for viral drug resistance, the investigators demonstrated that not only were HIV-1-neutralizing antibodies present, but they were potent enough to completely eliminate sensitive strains of the virus from the bloodstream of patients in a matter of weeks. The bad news is that these “weaker” strains were replaced by successive strains of the virus that were resistant to each new battery of neutralizing antibodies. The researchers next examined the genetic changes in HIV-1 that resulted in the neutralization-resistant phenotype and discovered mutations in the viral envelope that caused changes in the attachment of the glycan molecules. The discovery extends a picture of a virus that contains a "silent face" composed of masses of large glycan molecules that obscure its true nature to the immune system. However, in order for HIV-1 to engage CD4 cells, part of its attack machinery, including its receptor-binding surface and projecting variable loops, must remain accessible to cellular receptors for the virus. The evolving glycan shield, together with other mechanisms of antibody avoidance, contributes to this process, Shaw said. When the virus initially infects a person without immunity to HIV, it is able to grow unrestricted until the first set of antibodies develops that recognizes proteins within or protruding from holes in the shield. But by then, the virus has randomly mutated its glycan shield, as well as other regions of the envelope, to uncover different working areas, conferring a strong survival advantage to viral particles that cannot now be "seen" by antibodies, which also change their structure in pursuit of the virus. But the cat (the immune system) cannot keep up with the wily mouse (the virus), Shaw said. The virus "changes its silent face around in such a way that these large sugar molecules occlude new antibodies that develop in the patient. In this way, the virus maintains the ability to prevent each successive round of evolving antibodies from attaching," he said. Shaw emphasized that the evolving glycan-shield mechanism of antibody escape, although new, is but one of several mechanisms available to HIV-1 that allow for viral persistence in the face of an evolving antibody repertoire. “The trick,” he suggested, “will be to understand these multiple mechanisms more fully and to find the Achilles' heel. We are not there yet.” Other researchers working with Shaw included Peter Kwong at the National Institutes of Health Vaccine Research Center; Princeton University investigators Natalia Komarova and Martin Nowak; and UAB investigators Xiping Wei, Julie Decker, Shuyi Wang, Huixong Hui, Jesus Salazar-Gonzalez, Maria Salazar, Michael Saag, J. Michael Kilby, John Kappes, Xiaoyun Wu, and Beatrice Hahn.
March 27, 2003— As health agencies around the world race to pinpoint the cause of severe acute respiratory syndrome (SARS), researchers are reporting success in developing a new theoretical model that shows how the pressure exerted by the immune response of an infected population can drive evolution of influenza virus. The model does not aim to predict the emergence of new strains of influenza, but it does suggest that a short-lived general immunity to the virus might affect the virus's evolution. If immunologists can understand the basis of such a response by influenza virus, then vaccine designers might use that understanding to develop a vaccine that offers more general immunity to the virus, said the scientists. The researchers — led by Howard Hughes Medical Institute international research scholar Neil M. Ferguson at Imperial College London — published an article outlining their model in the March 27, 2003, issue of the journal Nature. Co-authors are Alison Galvani from the University of California,at Berkeley, and Robin Bush from the University of California, Irvine. “The principal question we were trying to address with this model is what biological factors determine the particular patterns we see in influenza evolution,” said Ferguson. “We wanted to understand the role of immunity in determining the competition between different flu strains.” Strains of flu virus differ from one another largely in the genes that code for surface molecules called glycoproteins, which are the primary targets of the body's immune system in defending against flu viruses, said Ferguson. Evolutionary changes in immune response against such “antigen” molecules are the reason that new vaccines must be developed against emerging strains of virus. A central mystery, said Ferguson, was why only a few new flu strains emerge over time, replacing other strains that go extinct. Limitations on genetic variance distinguish influenza from other RNA viruses such as HIV and dengue fever, which exist in a wide range of variants, he said. “Given basic evolutionary theory, one might expect naïvely that new influenza strains wouldn't necessarily drive the others extinct, and the virus population would get more and more diverse,” he said. “Understanding what stops that happening was the key question posed in this study.” To explore evolutionary dynamics, Ferguson and his colleagues developed a computer-intensive mathematical model that simulated mutation in individual genetic units, or codons, of the viral coat and the effect of those changes on the transmission of the virus in human populations. They included mutations that affected immune-related properties of the virus, as well as those that did not. The researchers hypothesized that modeling could yield information on the genetic diversity of the virus population that would result from changes induced by mutation. The researchers ran their model with various assumptions about mechanisms that might determine viral genetic diversity, and compared the resulting simulated viral populations with real-world genetic sequence data on populations of influenza strains. “If you naively build a model which captures current understanding in the flu research community of how the virus works, then the model predicts increasing diversity through time - exactly what is not seen,” said Ferguson. “We therefore inferred that there must be some other form of interaction between strains happening in the population,” he said. “The best fit to genetic data was obtained when a secondary, non-specific immune response was included in the model, on top of the normal adaptive immune response which recognizes individual virus strains. This secondary response gives a person complete protection against nearly all variants of the influenza virus, but only for a short period of time.” This kind of protection, said Ferguson, would last only for perhaps weeks after infection, after which it would fade, rendering a person vulnerable to reinfection with a different viral strain. Virologists had previously postulated that temporary, non-specific immunity might exist “but it hasn't been thought of up until now as being a very significant driver, either of influenza evolution or of epidemiology. However, this work indicates that non-specific responses probably have a critical effect on both influenza transmission and evolution,” said Ferguson. Since the mechanism of this kind of immunity remains unknown, Ferguson adds that it remains to be seen whether it might provide the basis of a more general influenza vaccine. “If innate immunity is responsible, then exploiting this for vaccine development might be difficult due to the negative clinical consequences for the individual associated with inflammatory responses,” said Ferguson. “However, if it's due to an adaptive immune response recognizing other non-changing viral antigens, then vaccines that target those antigens might have a longer-term effect than the annual protection afforded by current vaccines,” he said. More generally, said Ferguson, this type of modeling offers basic insights into the factors that drive influenza evolution that might improve understanding of which dominant variants that are likely to arise. “If we can understand in much more detail the biological relationship between the genome of the virus and its antigenic phenotype, then we'll be able to get to much more predictive mathematical models of the evolution of the virus,” he said. He emphasized that improved understanding will depend upon improved data from more detailed global surveillance of all influenza variants, not just the newly emerging pathogenic variants. Ferguson said that the general approach to modeling that he and his colleagues employ is also being adapted to understand the evolution of other RNA viruses including HIV.
EDITED BY: Khizar Tauseef Ahemd Ashraf |
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