AIDSWEEKLY Plus; Monday, April 27, 1998
Daniel J. DeNoon, Senior Editor
Combined with mounting safety data from preliminary human clinical trials, the new findings propel DNA vaccines to the forefront of AIDS vaccine research.
"The glass ceiling is no longer there," said David Weiner of the University of Pennsylvania. "Protection from SHIV can be achieved with DNA."
Weiner spoke during a presentation to the 1998 Palm Springs Symposium on HIV/AIDS, "Towards an HIV Vaccine: Immunopathogenesis of HIV Infection," held March 5-8, 1998, in Palm Springs, California.
He discussed his team's development of a multicomponent HIV DNA vaccine, which is licensed to Apollon Inc., Malvern, Pennsylvania.
"The idea is to deliver as much of the virus as possible," Weiner said.
The strategy is based on the ability of live, attenuated simian immunodeficiency virus (SIV) vaccines to induce potent protection. Safety concerns make the use of a live HIV vaccine problematic, but functionally attenuated HIV DNA might closely approximate a live vaccine.
Weiner and colleagues are developing constructs for three classes of HIV genes: structural/enzymatic (gag/pol/rev) gene constructs, accessory (vpr/vpu/vif/nef) gene constructs, and envelope (env) subtype (A, B, C, D, and E) gene constructs.
In human clinical trials, DNA encoding env (subtype B) and rev have safely been administered; ongoing trials (so far with no evidence of safety concerns) are testing combined env/rev and gag/pol vaccines. "There has been very good safety so far and evidence of immune responses," Weiner said. "We will have to wait a while to see what this all means."
Current theory holds that DNA vaccines are able to transfect professional antigen-presenting cells (APCs), which quickly migrate to the peripheral lymph nodes and sensitize T cells to the encoded antigens.
"This model also supports that we can build the type of costimulatory molecules into the vaccine that APCs normally include," Weiner said. "You can use cytokine [genes] to drive immune responses toward Th1 [cellular] or Th2 [antibody] responses."
Indeed, mouse studies show that DNA vaccines incorporating the Th1 cytokine interleukin 12 (IL-12) suppress antibody responses but greatly increased cytotoxic T-lymphocyte (CTL) responses.
Building on these findings, Weiner and colleagues inoculated macaque monkeys with plasmids incorporating SHIV IIIB env and gag/pol genes. Some of the animals also received plasmids incorporating the Th1 cytokines IL-2 or interferon gamma (IFN-g) or the Th2 cytokine IL- 4.
Two monkeys received the SHIV DNA alone or with one of the cytokine DNAs. They were then challenged with SHIV. One animal in each group - with the notable exception of the IL-4 group - was protected.
Two of the three protected animals had high-level HIV specific cellular immune responses, but one animal that did develop such responses was not protected.
"Neutralizing antibodies were not correlated with protection," Weiner said. "The role of cellular responses is under investigation."
An IL-12 vector is also being developed; Weiner said that chimpanzees inoculated with this vector develop very high proliferative responses.
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