Newsday - September 21, 2000
Laurie Garrett, Staff Writer

Although the researchers cautioned that their work is only in monkeys-and they went so far as to say that further studies could undermine this discovery-they nevertheless are excited by the finding, which is reported in today's issue of the British journal Nature.

"It's very, very encouraging, I think," lead researcher Dr. David Watkins of the University of Wisconsin in Madison said in an interview. "And the really exciting thing for all of us is that it's a completely different vaccine design."

The British-born Watkins began this latest approach by wondering why previous HIV vaccine research had looked at the typical target of vaccines: an element of the virus termed a "highly conserved, nonmutable" area.

So far there's been no reported success using that standard approach.

Watkins said he reasoned, "We've got to look at it exactly the other way around. We asked, 'What can the virus not tolerate?'

"It can't tolerate antiretroviral drugs. When those drugs are in the system, the virus must mutate and escape. So, we asked, 'What immune responses can this virus not tolerate?'"

He knew that when rhesus macaque monkeys are initially infected with SIV (the monkey form of HIV) they produce very strong immune responses. The same is true for humans initially infected with HIV. Watkins sought to answer why that response ultimately fails to obliterate the virus. He started by searching for the most highly mutation-prone site in SIV.

In collaboration with Dr. Ronald Desrossiers of the New England Primate Center outside Boston, Watkins' group sequenced the genes of entire SIVs found in rhesus macaques during their first days of infection. A region called "tat" stood out as extremely mutation- prone during early stages of infection.

Every 14 days for eight weeks, Watkins' group measured the anti- SIV immune responses in the 10 monkeys and resequenced the genes of the SIVs in the monkeys' bloodstreams.

They discovered that every monkey produced powerful anti-SIV cellular immune responses against tat. The immune responses were carried out by a class of lymphocytes called CD8-not by the CD4 class most AIDS researchers monitor. All of the monkeys' SIV strains dramatically mutated their tat regions in order to escape the forceful CD8 lymphocytes.

He said he was stunned by the scales of both the immune response and rapidity of viral mutation.

"We saw it first in February, in the four weeks post-vaccination period. Every single wild-type virus was gone, replaced by mutants."

Watkins sent "blinded" SIV samples to Dr. Steven Wolinsky of Northwestern University Medical School in Chicago. The samples were not identified according to which came from the vaccine-treated monkeys and which did not. Wolinsky said he was also stunned by both the power of the CD8 cellular attack upon SIV, and the rapid mutation in the tat genes.

In every case the viruses responded by mutating most or all of the parts of the tat gene that were under immune system attack.

Wolinsky said he thinks those tat gene sites "that escaped the early immune response" could be ideal targets for human immune therapy, which "could have a beneficial role in limiting or preventing disease."

"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," Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), said yesterday in a press release. "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."

Watkins has developed a multi-tat vaccine, formed from large clusters of tat DNA and proteins, that he has administered to another 20 monkeys. In November Watkins' vaccinated animals will receive high doses of wild-type SIV viruses (which are generally more virulent than laboratory strains), and he will learn whether his theory-that the monkeys' immune systems will obliterate the virus in the first moments of infection, before escape mutants can surface-will work in practice. He has already set up collaborative arrangements in South Africa for a human tat vaccine trial, to start rapidly if the monkey data pans out.

"It might be a blind alley," Watkins says, "but we don't know. It's the most exciting thing we've discovered in my 20 years of science, by two logs," meaning a hundredfold.

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