Developing inhibitors of SEVI-enhanced transmission of HIV
Jerry Yang
University of California, San Diego
Basic Biomedical Sciences
2010
Worldwide, some 7,000 new HIV infections occur each day. These new infections could be prevented by the availability of an effective microbicide. A recent clinical trial showed that a vaginal gel formulation of the experimental microbicide Tenofovir could reduce the rate of HIV-1 transmission by 39% overall, and by 54% in women with high gel adherence. This success underscores the value of microbicides and also highlights the urgent need to develop new and improved approaches.
Another recent, yet controversial, study reported that a substance found in semen (called Semen-derived Enhancer of Virus Infection, or SEVI) facilitates the viral attachment of HIV-1 to immune cells and can enhance sexual transmission of HIV-1 by up to 400,000-fold. To follow up on this report, we have shown that a proprietary drug candidate from our lab, that was designed to form bio-resistive molecular coatings on amyloidogenic substances such as SEVI, can efficiently block semen-mediated enhancement of HIV-1 infection in in vitro assays. The concept of a bio-resistive coating is based on the hypothesis that synthetic molecules that bind to amyloids with high density and uniformity can exhibit collective functional properties, such as the capability to inhibit the interaction of the amyloids with other cellular components (in analogy to “Scotch-guarding” or “Teflon-coating” the amyloids). Our group was the first to introduce a bio-resistive coatings strategy to neutralize the toxicity of aggregated amyloid-beta peptides in Alzheimer’s disease. Our very promising initial studies with the formation of bio-resistive coatings on SEVI peptides strongly supports that (i) SEVI contributes to semen-mediated enhancement of HIV infection, and (ii) SEVI represents a novel target for microbicide development.
In this research, we will explore a new design platform for amyloid-targeting molecules that we expect will be more effective for inhibiting SEVI-mediated enhancement of HIV infection compared to our currently available molecules. Briefly, we will synthesize oligomeric and polymeric versions of amyloid targeting agents and will determine whether this strategy improves 1) binding of the molecules to aggregated SEVI peptides, and 2) efficacy for reducing SEVI-enhanced attachment and infection of HIV in cells compared to monomeric amyloid targeting agents. We expect that these studies will validate the hypothesis that multimeric amyloid-targeting molecules could be potentially useful as potent supplements to current HIV microbicide candidates for combating the sexually transmitted spread of HIV. The data resulting from completion of the proposed research will provide a foundation to advance this project beyond the pilot stage and to test this novel approach to attenuating SEVI-enhanced infection of HIV in animal models. The ultimate goal of this project will be to identify a set of lead candidates that can be advanced towards clinical evaluation as soon as possible.
