Multitargeted Microbicide Combinations to Block HIV

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Topical microbicides, designed
for genital or rectal administration, are needed to prevent HIV infection.
Further rational development of microbicides should build on prior clinical
experiences demonstrating a clear benefit of systemic combination
antiretroviral therapy and the unexpected toxicity of topical agents. This
Program will systematically study local virologic and immunologic effects of
PRO 2000, with the establishment of assays and models that might better
predict outcome. The sound principle of combination therapy will be applied to
the analysis of topicals with in vitro studies aimed at identifying the most
promising combinations. PRO 2000, a naphthalene sulfonic acid, is active
against a wide range of HIV isolates in vitro and inhibits a major HIV cofactor,
the herpes simplex virus (HSV). The drug acts by binding viral
envelope glycoproteins and preventing entry. Vaginal gel formulations
containing up to 4 percent PRO 2000 have been shown to be safe and well
tolerated in two Phase I clinical trials. A combination of PRO 2000 with a
second microbicide that targets a different step in the HIV life cycle should
have distinct advantages over either drug alone, including enhanced efficacy,
reduced mucosal inflammation and an expanded spectrum of activity against
other sexually transmitted pathogens. An iterative approach toward identifying
the best combination of PRO 2000 with a second microbicide is proposed. PRO
2000 combined with PMPA (tenovofir), a nucleotide analogue, and UC781, a non-nucleoside
reverse transcriptase inhibitor (RTI) will be tested. These
compounds are being expeditiously advanced as independent candidates for
microbicide development. PMPA and UC781 inhibit HIV reverse transcription, a
step after viral entry. A multitargeted combination is likely to be more
effective because PRO 2000 blocks cell entry and the RTIs inhibit virus that
successfully evades PRO 2000. Novel candidate virucidal agents in preclinical
development, including bile salts and amphiphilic polymers, will also be
evaluated. In three interrelated projects, the antiviral activity and
inflammatory effects will be examined advancing combinations from cell and
explant culture systems to animal models and pilot clinical studies. Project 1
will focus on identifying compounds that act additively or synergistically
against clinical isolates of HIV using primary cells and explant cultures.
Project 2 will evaluate the impact of microbicide combinations on a dual
infection model of HSV and HIV using human explant cultures. In murine genital
and rectal models, inflammatory effects will be assessed as well as the
activity against HSV-2. In Project 3, three pilot human clinical trials will
be conducted to examine the effects of PRO 2000 on genital tract HIV and on
mucosal immunity in both HIV-infected and uninfected individuals. The proposed
comprehensive preclinical evaluation of combinations and clinical evaluation
of PRO 2000 will lay the groundwork for future clinical trials with optimal
combinations.
StatusFinished
Effective start/end date9/26/026/30/03

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $1,357,925.00

ASJC

  • Drug Discovery
  • Microbiology (medical)
  • Infectious Diseases
  • Virology
  • Pharmacology
  • Pharmaceutical Science
  • Immunology
  • Reproductive Medicine

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.