MUCOSAL DNA VACCINES FOR T CELL PRIMING AGAINST HIV

Project Details

Description

DESCRIPTION (Adapted from applicant's abstract): The overall objective of
this proposal is to develop a novel strategy to prime for broad T cell
immunity against HIV-1 using eukaryotic expression plasmids (DNA vaccines)
delivered to mucosal surfaces by a highly attenuated Shigella flexneri (or
alternative attenuated) bacterial delivery vehicle. The induction of
HIV-1-specific CD8+ CTL responses, in addition to neutralizing antibody,
will be an important feature of an effective HIV-1 vaccine. In order to
protect against sexual HIV-1 transmission in humans (where infected mucosal
cells may not be readily accessible to parenterally primed memory T cells),
it may be necessary to induce T cell immunity both systemically and at
mucosal sites. The investigators will use a murine model of respiratory
Shigella infection to determine which of several attenuated Shigella strains
(impaired in replication or in cell-to-cell spread), carrying DNA vaccine
plasmids that encode HIV-1 or SIV subunits, engenders the strongest in vitro
CD8+ CTL activity. Responses will be measured against MHC class I-matched
recombinant vaccinia-HIV-1- or SIV-subunit infected targets, following
intranasal (i.n.) inoculation. The investigators will study whether immune
priming with an attenuated Shigella (DNA HIV-1 subunit vaccine) construct at
the nasal site engenders CD8+ CTLs that recognize and lyse human cells
infected with a divergent strain of HIV-1. This will be done by examining
the ability of CD8+ CTL splenocytes recovered from immunized transgenic
human HLA-A2.1 mice to recognize human cells that express A2.1 and that are
infected with HIV-1 strains represented by the immunogen as well as
divergent HIV-1 isolates. Next the investigators will optimize T cell
priming for HIV-1 or SIV-specific CD8+ responses at distant mucosal sites
relevant to protection against mucosal HIV-1 infection in humans, by
immunizing mice i.n., orally, or intravaginally with attenuated bacteria
carrying DNA vaccines with or without direct intramuscular injection of the
corresponding purified DNA HIV-I subunit vaccine plasmid and recover
lymphocytes from genital lymph nodes at various intervals to determine which
schedule optimizes anti-HIV-1 CD8+ CTL responses. Finally, if this strategy
looks promising, the investigators will determine which route of Shigella
(pDVP::SIVgag, env, or pol) inoculation, either p.o. or i.n., primes rhesus
monkeys for optimal systemic and/or mucosal CD8+ CTL responses that may
protect against an intravaginal challenge with virulent SIV.
StatusFinished
Effective start/end date9/30/989/29/02

Funding

  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases

ASJC

  • Immunology

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