Optimization of Microbicide Combinations Against HIV-1

Project: Research project

Project Details

Description

Description (provided by applicant): Worldwide, the vast majority of 16.4
million new infections with HIV are acquired through sexual transmission.
Compounds that are developed as topical microbicides to prevent HIV
transmission offer a promising alternative while awaiting the development of
an effective vaccine. Project 1 will be focused on the optimization of
combination topical microbicides targeting different points in the HIV life
cycle with the goal of developing a maximally effective and safe formulation
for blocking the sexual transmission of HIV-1. The combinations will all
include formulated naphthalene sulfate (PRO 2000) presently undergoing Phase
II-III evaluation as a single compound as well as a second compound with a
unique antiviral mechanism. PRO 2000 predominantly inhibits viral entry by
interfering with gp120 interaction(s) with the cell surface. Since this
compound is not a virucidal and only works at entry, combining it with
compounds that are virucidal and/or work on a separate phase of the virus life
cycle should have an additive if not synergistic benefit. Additive and/or
synergistic anti-HIV effects of PRO2000 with inhibitors of reverse
transcriptase including the non-nucleoside, UC781 and the nucleotide analogue,
(R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA or tenofovir), and topical
virucidal agents bile salts and amphiphilic polymers will be determined in a
single-cycle infection assay. Lead combinations will then be evaluated in
primary culture and cervical/vaginal as well as rectal tissue explant cultures
in the presence of cervical lavage and seminal fluid. Additional in vitro
studies will focus on the generation of viral variants relatively resistant to
PRO 2000 which will not only provide critical insights into the potential
generation of resistance in vivo but also provide information regarding
potential cross resistance with other compounds. Lastly, this project will
provide virologic support in the clinical evaluation of women exposed to PRO
2000 as proposed in Project 3. These studies will both identify leading
effective combination topical microbicides as well as promising virologic
assays to assess their effectiveness.
StatusFinished
Effective start/end date1/1/016/30/07

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $1,572,025.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development

ASJC

  • Infectious Diseases
  • Virology
  • Immunology
  • Medicine(all)

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