CHARACTERIZATION OF AFE INHIBITORS IN HUMAN CERVICAL/REC

研究项目I（评估AFE抑制剂在人类粘膜外植体中的作用）的负责人将是Robin Shattock博士。该项目将在英国伦敦圣乔治医院医学院进行，Shattock博士和他的同事们在这里开创了粘膜组织移植培养（宫颈、阴道、直肠和阴茎）的先河。人类宫颈组织外植体模型已经成功地用于收集可能涉及HIV性传播的生物学过程的有用新信息-1。在手术后直接建立的宫颈和直肠组织外植体中存在的细胞代表了在性传播过程中首次暴露于HIV-1的免疫群体，其表型（例如共受体表达），免疫状态

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.