AIDSWEEKLY Plus; Monday, April 27, 1998
Daniel J. DeNoon, Senior Editor
The protection was the first demonstration that local administration of an artificial peptide-based vaccine elicited long- lasting, HIV specific local mucosal and systemic cytotoxic T- lymphocyte (CTL) responses.
"We can't be sure that the protection was due to lytic activity," said Jay Berzofsky of the National Cancer Institute, Bethesda, Maryland. "But there is clear evidence that one can get protection against mucosal challenge by stimulating CD8(+) cells locally."
Berzofsky spoke in 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.
The vaccine used in the mouse experiments was PCLUS3-P18IIIB, a multideterminant cluster of peptides. The cluster contains the peptide P18IIIB, which is an HIV neutralization epitope located at the tip of the viral gp120 V3 loop. The cluster also contains discrete overlapping T-helper T-cell epitopes common to mice and humans of multiple major histocompatibility complex (MHC) types.
After four intrarectal vaccinations (50 (micro)g per mouse) with or without cholera toxin adjuvant, the mice were challenged (35 days after the first immunization) with recombinant vaccinia virus expressing HIV surface antigens. Far lower level infection was seen in the immunized mice.
Studies with anti-CD8 monoclonal antibodies demonstrated that the protective immune responses were mediated by CD8(+) T cells.
Further analysis demonstrated that the protective responses were dependent on two cytokines, interleukin 12 (IL-12) and interferon gamma (IFN-g).
Berzofsky and colleagues have gradually been tailoring their peptide cluster so that it elicits the types of immune responses considered essential to a successful HIV vaccine. To accomplish this they have used a stepwise approach, focussing on improving immune response to the vaccine in seven distinct areas: strength, breadth, type of response, affinity of antibody, balance (avoidance of harmful immune responses), speed, and location of response.
"By this stepwise approach we hope we will be able to build up the kind of immune responses we need for an HIV vaccine," Berzofsky said.
The NCI research team has recently published some of these findings in the Proceedings of the National Academy of Sciences: a report on the mucosal immunization of mice (PNAS, 1998;95:1709-14) and a report on the enhanced immunogenicity of the PCLUS construct (PNAS, 1997;94:10856-61).
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