AIDSWEEKLY Plus, Monday, 19 May 1997
Daniel J. DeNoon, Senior Editor

Nobel Laureate David Baltimore has a plan for AIDS vaccine development: back to the basics.

Baltimore heads the National Institutes of Health AIDS Vaccine Research Committee, established in January 1997 to coordinate the agency's efforts to develop an HIV vaccine. He spoke in a plenary address to the 9th Annual Meeting of the National Cooperative Vaccine Development Groups for AIDS (NCVDG), held May 4-7, 1997, in Bethesda, Maryland.

Baltimore has his own ideas about the best approach to an AIDS vaccine. But he is committed to pursuing all approaches, even those that now appear doomed.

"From the committee point of view it's 'let a thousand flowers bloom,'" he said. "I think this is the only reasonable approach."

Instead of dumping disappointing approaches, Baltimore urged researchers to go back to the drawing board and seek to improve them.

For example, he said that there is "still a lot of opportunity" for peptide-based HIV vaccines. He urged that developers of such vaccines try to maximize antigen presentation and to minimize their specificity.

While noting that live attenuated vaccines are the "most exciting today," he suggested that a killed-virus approach may be more acceptable.

"A killed-virus vaccine is much easier to think about," Baltimore said. "I think we need to revivify this approach."

Baltimore provided a laundry list of questions for basic research to address:

* The structure/function of the HIV Env protein.

* Antibody, mucosal, and cellular immune responses to HIV.

"Lots of us are convinced that cytotoxic lymphocyte [CTL] are very important, if not most important," he said.

* Improved animal models. "Maximize the primate model, develop new models," Baltimore advised.

* Human immunology. Of special interest are dendritic cells and other antigen-presentation systems.

In the second part of his lecture, titled "Fighting with HIV while It Fights Back," Baltimore talked about his own view of HIV disease.

"It has become quite obvious to me that while the antibody response to the virus is very florid, it is unclear how important it is," he said.

The crucial event in HIV disease appears to be the immune system's initial battle with the virus, characterized by initial control of viremia and establishment of a set point at which virus titers are maintained until they finally increase prior to disease onset.

But why, exactly, does this occur?

"When I think of the role of antibodies in all this, I draw a blank," Baltimore said. "So, is it CTL? We don't have an answer. My guess is it's probably true."

In his own laboratory, the Massachusetts Institute of Technology researcher has focused on stimulating anti-HIV CTL responses. He began by attempting to determine whether cells infected by HIV are somehow protected from elimination by CTL, perhaps by a virus-induced factor.

In studies using primary T cells, Baltimore found that HIV infected cells "dramatically" down-regulated MHC class I receptors. Cells harboring the virus had 10 to 20 times fewer of these receptors than uninfected cells.

"Virus infected cells actually lose, during infection, the molecule that they present to CTL," Baltimore said.

But if the cells were infected by HIV mutants lacking the nef gene - similar to the live attenuated vaccines that have protected monkeys against AIDS - no MHC class I down- regulation occurred.

"The clinical implications are unclear," Baltimore said. "However, there may be a population of infected cells that are resistant to CTL lysis and which contribute to the development of AIDS."

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