GENETIC VACCINES AGAINST HIV MUTANTS

Project: Research project

Project Details

Description

DESCRIPTION: Given the wide sequence divergence of HIV across the globe,
and its frightening ability to mutate within a single human being, a vaccine
with a small repertoire of cross-reactive immune responses will have limited
utility. Given the critical necessity for an HIV vaccine, this application
will develop genetic vaccines that generate cross-reacting immune response
by several mechanisms. We will test 1) a multi-gene vaccine; 2)
multi-mutant vaccines; and 3) DNA shuffled vaccines. In the multi-gene
approach, the host is exposed to a cocktail of the different protein from
the pathogen in the hope that conserved epitope(s) will generate protective
responses against other HIV variants. For the multi-mutant approach,
representatives of one antigen from several viral isolates or clades are
used in the vaccine to produce cross-protection. While both multi-gene and
multi-mutant approaches have some capacity to generate cross-protective
immune responses, neither has a proactive mechanism for anticipating
emerging HIV variants. To anticipate these emerging variants better, we
will use DNA shuffling to recombine and mutate current HIV clades into a
population of novel epitopes with an expanded ability to produce
cross-reactive responses. Towards these goals, the following Specific Aims
will be tested in HLA-A*0201 transgenic mice: Specific Aim 1. Multi-gene
vaccine. Characterize the diversity of cytotoxic T lymphocyte (CTL) and
antibody responses generated by the HIV-1 ELI library. Specific Aim 2.
Multi-mutant vaccines. Characterize the level of cross-clade immune
responses generated by gp160 clade representatives. Specific Aim 3. Immune
Competition and Antagonism. Determine the level of possible interference
produced by problematic epitopes in these complex vaccines. Specific Aim 4.
DNA-shuffled vaccines. Characterize the cross-clade immune responses
generated by gp160 clade representatives mutated by DNA shuffling. Since
the vaccines will be tested in HLA-A*0201 transgenic mice, this should allow
direct translation of the information acquired in these project to be
translated into humans. If these Aims are successful, then these three
layers of vaccines can be combined to create a vaccine with an exceptional
capacity to cross protect against existing HIV clades and those that will
emerge in future years. The vaccines may also have therapeutic potential,
in shutting down the avenues of mutational escape for HIV in an infected
individual.
StatusFinished
Effective start/end date3/1/984/30/06

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)