United Press International - Thursday, 21 September 2000

In their research using rhesus macaque monkeys, the investigators for the first time observed how the virus avoids the body's hefty attack by the powerful "killer" T cells of the immune system, an approach largely overlooked in the frustrating war on AIDS.

Reporting in the British journal Nature, the researchers said the experimental results indicate one way to stave off the death-bearing organism could be through vaccines designed to trigger an early response by the body's disease-fighting immune system against a small HIV protein called Tat.

"We have discovered a potentially promising new approach to attack the AIDS virus," summarized lead study author David Watkins, professor of pathology and laboratory medicine at the University of Wisconsin, Madison. "These results show that infected individuals make immune responses that the virus cannot tolerate. The challenge will be to mimic these responses in an HIV vaccine."

In the study of 18 monkeys, the researchers discovered that when aimed at Tat early in the game, the potent killer T cells can reign in the simian immunodeficiency virus, or SIV, the monkey version of HIV.

These warriors wiped out their original target within four weeks of the monkeys' exposure to the virus, the scientists found. The SIV traces that remained differed slightly genetically from the original strain. These small differences, traced to Tat, apparently were large enough to avoid detection by the attacking immune system, they said.

"This is the first time someone has investigated the entire cellular immune response during the acute phase of infection," said Peggy Johnston, assistant director for AIDS vaccines and associate director of the Vaccine and Prevention Research Program in NIAID'S AIDS division.

"These animal studies open the window on immune events in early HIV infection and provide a rationale for exploring a new approach to designing HIV vaccines," said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., which funded the research. "The results suggest that using vaccines that stimulate immune responses against virus proteins produced within a few hours after infection, such as Tat, may help control HIV."

In fact, scientists speculate such an early approach may be nearly as effective as the use of AZT and other antiretroviral drugs to control HIV.

"This study is very important because it really shows the importance of the early regulatory proteins in the very early phases of interaction between the virus and the body," Alex Sette, chief scientific officer at Epimmune Inc., a San Diego pharmaceutical company conducting preclinical HIV vaccine testing, said in an interview.

"A response against this protein is going to be a very useful component of a vaccine to prevent HIV infection," Sette told United Press International. "The study that just came out documents the importance of this protein early in infection."

Such data have not been available in human research because most subjects are already infected by the time the study begins, he said.

"So there is no access to those crucial early points of infection and nearly always it is not known what was the exact sequence of the virus that infected that particular individual," Sette said.

The Wisconsin group, however, saw how "the virus entirely escaped from the Tat-specific immune response within the first few weeks of infection," Watkins said.

After shifting form, the chameleon-like organism was no longer recognizable to the body's defense system, a finding that holds key implications for novel vaccine approaches, said Watson, Todd Allen and David O'Connor, who conducted the study at the Wisconsin Regional Primate Research Center in Madison.

The multi-pronged battles against AIDS have not taken advantage of the early killer T cell immune responses because by the time the virus is detected in humans, this fleeting first line of defense is not longer in operation, researchers said. Yet an initial squelching before serious trouble begins might prove more effective than subsequent efforts at curtailing the damage, they said.

"If vaccines can induce these killer T cell responses before infection occurs, the opportunity for the virus to subsequently escape from these immune responses would be greatly reduced," Watkins said.

If scientists find that vaccinating monkeys calls the killer T cells to arms in time to prevent infection or significantly reduce the viral amount, they will have a strong incentive to pursue research on HIV vaccines that incorporate similar targets, she said.

In the natural course of viral attack, levels of HIV and SIV peak early -- before being crushed by the killer T cells. But the defeat is not complete, and the few surviving invaders bide their time, regrouping and reshaping themselves beyond recognition until they're ready for another charge-one usually with a different outcome, researchers said.

The trick, scientists said, is to come up with vaccine designs that will shift the final balance of power to the side of the immune system.

That hope has been enlivened by recent advances in genetically typed monkeys, cloned viruses and technological innovations, which made the current study possible, said Patricia D'Souza, a microbiologist in NIAID's AIDS division.

In the next phase, the researchers are inoculating monkeys with regions of the Tat protein recognizable to the killer T cells, in an effort to stimulate an attack at the onset of infection.

"However, this virus has evaded nearly every vaccine-induced immune response to date," Watkins cautioned. "We would be surprised and delighted if the virus did not find a way around this Tat-specific immune response."

In addition to NIAID, the National Center for Research Resources and the Elizabeth Glaser Pediatrics AIDS Foundation funded the research.

The Nature article appears at: http://www.nature.com.
000921
UP000907

Always watch for outdated information. This article first appeared in 2000. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2000. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .