UAB Study Yields New Findings About Nature’s Defenses Against HIV

Researchers at the University of Alabama at Birmingham (UAB) have discovered a novel mechanism by which HIV escapes the body’s natural defenses. The study, which examined how the virus evades HIV antibodies in humans, may have important implications for vaccine studies. Details of the study, led by Dr. George Shaw, UAB professor of medicine and Howard Hughes Medical Institute investigator, are published in the March 20 issue of Nature.

March 19, 2003

BIRMINGHAM, AL — Researchers at the University of Alabama at Birmingham (UAB) have discovered a novel mechanism by which HIV escapes the body’s natural defenses. The study, which examined how the virus evades HIV antibodies in humans, may have important implications for vaccine studies. Details of the study, led by Dr. George Shaw, UAB professor of medicine and Howard Hughes Medical Institute investigator, are published in the March 20 issue of Nature.

“When a virus invades, the body produces antibodies that target and destroy the virus by attaching to it and preventing it from entering and replicating within cells,” said Shaw. “Viruses generally escape these so-called neutralizing antibodies by changing their surface structure to prevent antibodies from attaching. With most viruses, this change occurs at the specific sites on the virus’s surface where the antibody would normally attach.”

However, with HIV, researchers found the virus avoids antibody recognition in a fundamentally different way. “HIV changes its coat protein at multiple sites distinct from the antibody-combining sites,” Shaw said. “Escape results from steric, or positional, repulsion of antibody binding by a shifting cloud, or shield, of sugar molecules called glycans that coat its surface. We coined the term ‘evolving glycan shield’ to describe this novel mechanism of virus escape.”

The first step in unmasking the interaction between the virus and HIV antibodies was the development of a new blood test to confirm the presence and activity of HIV neutralizing antibodies. The second step was to analyze changes in the genetic composition of HIV in patients’ blood over the course of their illness. “By combining the new laboratory test for viral resistance to antibodies with genetic and biological changes in circulating virus in patients, we confirmed the presence of virus inhibition and escape from neutralizing antibodies,” Shaw said.

The laboratory test developed by the UAB team showed that HIV antibodies are effectively eliminating more sensitive strains of virus. “Unfortunately, as the antibodies are working to rid the body of one strain, new, more resistant strains are emerging,” Shaw said.

The new findings provide researchers with a deeper understanding of strategies and obstacles for HIV vaccines. “In infected individuals, the body’s defense system is continually playing catch up,” Shaw said. “By the time the body launches a counterattack by making neutralizing antibodies, there is already a massive amount of virus in the body. It has been estimated that as many as 10 billion HIV virions are produced daily leading to the infection of many millions of cells long before neutralizing antibodies are first detectable.”

In humans not yet infected, a vaccine designed to induce the production of neutralizing antibodies might turn the table, giving the body’s defense system the upper hand or perhaps preventing infection altogether. “In the presence of pre-existing neutralizing antibodies, the virus might not be able to escape,” Shaw said.

The new test, or ones like it, may prove useful in evaluating HIV antibody-inducing vaccines already being developed and tested. “Meanwhile, scientists can be satisfied in knowing that they have added one more piece to the complex HIV/AIDS puzzle,” said Shaw. “One of the rewards of scientific research is seeing something that hasn’t been seen before, recognizing the finding for what it is, and sharing the discovery with the scientific community, leaving science as a body indelibly changed. When this is done repeatedly, by many scientists, important advances often follow.”

Other researchers who collaborated on the study are Peter D. Kwong, Ph.D., with the National Institutes of Health Vaccine Research Center; UAB researchers Xiping Wei, Ph.D., Julie Decker, Dr. Shuyi Wang, Huxiong Hui, Jesus Salazar-Gonzalez, Ph.D., Maria Salazar, Dr. Michael Saag, Dr. J. Michael Kilby, John Kappes, Ph.D., Dr. Xiaoyun Wu and Dr. Beatrice Hahn; and Princeton University researchers Natalia Komarova, Ph.D., and Martin Nowak, Ph.D.