By Dean A. Haycock
Special To BioWorld Today
He is identified in the impersonal scientific literature by the code WEAU. Not long after being infected with the AIDS virus, WEAU developed a high fever. Unlike most newly infected individuals, his initial symptoms were severe and he went to a hospital emergency room. There he became part of a unique study that may help resolve a long lasting question in the AIDS field: Just how important are the immune system's cytotoxic T lymphocytes (CTL) in the body's defense against AIDS?
WEAU's early battle with HIV is significant because his immune response was studied soon after he was infected. Most HIV cases are detected using antibody tests but it takes months for the body to produce antibodies.
"Very few studies have been done on the acute phase of the infection because it is very hard to find patients at that time," Persephone Borrow, an assistant member of the Scripps Research Institute, in La Jolla, Calif., said.
Borrow is the first author of "Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTL) during primary infection demonstrated by rapid selection of CTL escape virus," which appears in the February issue of Nature Medicine. WEAU was identified by Borrow's coauthor, George Shaw of the department of medicine at the University of Alabama, in Birmingham. The subject of their paper is the battle between WEAU's immune system, specifically his CTLs, and the particular strain of HIV-1 that invaded his body.
Most researchers agree that CTLs play an important role in controlling the virus but they have not been able to agree on the extent of that role. The paper by Borrow et al., and a second in the same issue of Nature Medicine, by Philip Goulder, of the University of Oxford, and his colleagues titled "Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS," help answer the question of how important CTLs are in the immune response to AIDS. Together, they show that CTLs control the virus quite well but only until the virus manages to evade them by producing new versions of itself.
CTL Response Critical In Control Of HIV
These adapted viruses are called escape virus variants. After they appear, the CTLs can not longer recognize them. The escape variants replicate unchecked and HIV infection progresses to AIDS. By studying WEAU's CTL response to the virus from early in his infection until his death three years later, Borrow and her coworkers have provided definitive evidence that the CTL response is critical in the initial control of the virus.
"CTL response is actually mediating an enormously strong pressure on the virus population. It is basically a very strong controlling force on virus replication," Borrow told BioWorld Today.
WEAU's CTLs initially kept the virus in check. They also, ironically, produced selective pressure on the virus to escape from CTL control. "Very rapidly over time in this patient, that initial virus population was completely replaced by a virus variant which was bearing amino acid mutations within this epitope," Borrow said, "And those mutations actually conferred escape from recognition by the CTL directed epitope. "The virus escaped by changing one amino acid in the epitope of its gp160 protein which is what the CTLs used to recognize it.
Borrow and her group demonstrated the biological significance of the CTL response in vivo by measuring the timing, magnitude and genetic pathway of the "escape." They found these factors to be comparable to those associated with the escape pressure produced by antiretroviral therapy.
"If you look at the kinetics with which the CTL escape virus was selected it is very similar to the kinetics with which drug resistant mutants come up when you have patients in the chronic stages of the infection and you start giving them antiretroviral therapy with a single antiretroviral agent," Borrow said.
According to the authors, WEAUs CTL response early in his infection was doing as good a job of suppressing the virus as an antiretroviral agent could do.
"Because we were able to see this happening in this individual, we were actually able to prove that this CTL response is having a very important controlling force on virus replication," Borrow said.
A similar conclusion can be drawn from the work described by Goulder et al. They studied six patients whose CTLs mounted a strong attack on HIV. Two of the subjects in the Goulder study developed AIDS. In both individuals, the viruses escaped by undergoing identical mutations. Unlike WEAU, however, these mutations did not appear until nine to 12 years after infection. Again, the results suggest that the CTL response plays a very important role in the body's defense against HIV.
"One thing that the data very clearly state in terms of vaccines is that you want your ideal vaccine to induce a CTL response to HIV. I am not saying it should only do that to the exclusion of any other kind of immune response. We haven't looked at all in this paper at antibodies or any of the other immune factors but I think that is one that this data very clearly shows," Borrow said.
Furthermore, Borrow added, the vaccine should be directed against several epitopes so you would not create selective pressure for escape mutations as occurred so readily in the case of WEAU.
In the future, Borrow and her colleagues would like to examine other individuals soon after exposure.
"Perhaps we will recognize people bearing a broader number of epitopes very early in the infection," Borrow said. She would then like to correlate the overall number of epitopes with the rate of disease progression. *