The leader of Research Project I (assessment of AFE inhibitors in human mucosal explants) will be Robin Shattock, PhD. The project will be located at St George's Hospital Medical School, London, UK, where Dr. Shattock and colleagues have pioneered the culture of mucosal tissue explants (cervical, vaginal, rectal and penile). The human cervical tissue explant model has been successfully used to glean useful new information on the biological processes that may be involved in the sexual transmission of HIV--1. Cells present within cervical and rectal tissue explants, established directly after surgery, represent the immune population first exposed to HIV-1 during sexual transmission in terms of phenotype (e.g., co-receptor expression), state of activation and anatomical location. Thus the model system used by Dr. Shattock most directly reflects what happens during mucosal challenge of humans by an incoming virus. It is a promising tool in any mechanism-based approach to rational microbicide design. Thus we will evaluate AFE inhibitors, provided by the Research Support Core, that target HIV-1 interactions with CD4, CLR or CCR, or that impact on virus uptake and dissemination by migratory dendritic cells. The purpose of these studies is to: evaluate AFE inhibitor combinations for their activity against a diverse set of primary HIV-1 isolates from multiple genetic subtypes, including viruses from countries where the male-to-female spread of HIV-1 is particularly common; define the activity of inhibitors under physiologically relevant conditions (pH 4-8, in the presence of semen or blood); identify potential toxic or inflammatory effects in human tissues and cells; determine whether the formulation of different AFE inhibitors impairs their antiviral activity, or increases their toxicity. The specific questions being considered are: Do AFE inhibitors and combinations influence mucosal HIV-1 infection of cervical and rectal explants? Which AFE inhibitors or combinations are most effective at inhibiting both localized HIV-1 infection and migratory cell dissemination of virus from mucosal tissue? Do AFE inhibitors, combination and formulations show acceptable tissue compatibility in explant models? Which formulation characteristics provide effective drug penetration without enhancement of HIV-1 infection? This kind of study, together with our overall knowledge of the virus-cell entry processes and animal models, will facilitate the rational selection of potential AFE inhibitor combinations for primate studies, then human clinical trials.
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