Important note: Information in this article was accurate in March 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, March 1, 1999
Daniel J. DeNoon, Senior Editor
If so, it might provide the most complete inactivated whole-virus retroviral vaccine yet created. The major question, of course, is whether such a vaccine could be safe.
"We've basically stuffed as much inactivated virus as we can into macaques. There were no infections," said Jeffrey Lifson of the National Cancer Institute-Frederick Research and Development Center, Frederick, Maryland.
Lifson spoke in a poster discussion session at the 6th Conference on Retroviruses and Opportunistic Infections, held January 31-February 4, 1999, in Chicago, Illinois.
Using the same approach as colleague Larry O. Arthur (see accompanying article), Lifson's team is going in another direction. Instead of creating a DNA vaccine that expresses zinc-finger-mutant HIV particles, they are chemically cross-linking the essential zinc fingers to produce an inactivated whole-virus vaccine.
To cross-link the cells the group is relying on a finding first reported by Lifson colleague J.L. Rossio at the 1997 Keystone Symposium on AIDS pathogenesis. Rossio reported that the disulfide compound aldrithiol-2 (2,2'-dipyridyl disulfide) could inactivate HIV while preserving all of the virus's surface proteins.
Lifson et al. used a similar compound, 2,2'-dithiodipyridine, to inactivate the virus. After exposure to the compound HIV retained conformationally intact surface proteins, was able to bind cells in a CD4-dependent fashion, but could not initiate reverse transcription.
Safety studies showed that a prototype vaccine based on simian immunodeficiency virus (SIV) did not result in infection even when given at huge doses.
Immunogenicity studies, now underway, are testing 100 (micro)g injections without adjuvant. There are two protocols: one using inactivated wild-type SIV, and the other using the nef-deleted mutant SIV successfully used by Harvard researcher Ronald Desrosiers and colleagues as a live attenuated vaccine.
The next step, Lifson said, would be to use SHIV - a hybrid virus combining the HIV envelope with the SIV core.
"I think this is a good proof-of-concept of a whole inactivated vaccine," Lifson said.
Should the immunogenicity studies bear fruit, challenge studies would be next. But should the vaccine be found protective, Lifson warned that human trials would not begin immediately.
"Before we would be looking at anything like this going into people we would need further safety studies - and perhaps further attenuation," Lifson said. "First we want to see if it works [in primates]."
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