Development of tissue explant models for microbicide evaluation

描述（由申请人提供）：开发艾滋病毒疫苗的尝试不成功，导致对新的预防策略的巨大需求，其中最令人鼓舞的是杀微生物剂。一种有效的杀微生物剂将通过降低性传播率来减轻艾滋病流行的严重程度。已经开发了许多模型系统来提供对雄性到雌性性传播机制的深入了解，包括外植体培养和恒河猴阴道传播模型。这些系统已成功地用于评价和鉴定候选杀微生物剂。在建立评估女性对男性性传播的系统方面，进展要小得多。目前还没有女性对男性性传播的模型系统可以确定潜在的杀微生物剂是否能够预防通过阴茎的感染。为了填补这一空白，本申请寻求开发使用人阴茎组织的外植体培养系统。这将有助于评价候选杀微生物剂预防艾滋病毒通过性途径传播给男性的有效性和安全性。此外，我的实验室最近开发了一种方法，可以检测组织中的单个病毒体。该系统将进一步发展，以确定艾滋病毒如何与人类阴茎组织正常相互作用。在本申请的R21组件中，我们将优化这些系统，以确定HIV与完整组织的正常相互作用以及随后的病毒复制。在申请的R33阶段，我们将评估不同候选杀微生物剂单独和组合的潜力，以改变HIV与组织的相互作用并预防HIV感染和复制。我们还将确定暴露于杀微生物剂是否会导致组织中可能对正常细胞功能产生有害影响的任何变化。 该申请旨在开发新的方法，以确定是否可以使用化学品来预防艾滋病毒的性传播。这些方法将用于确定保护免受艾滋病毒感染的效力，以及在人体测试之前化合物的安全性。人们希望，预防艾滋病毒感染将减少世界上感染艾滋病毒的人数，减缓艾滋病的流行。

DESCRIPTION (provided by applicant): Unsuccessful attempts to develop a vaccine against HIV have led to a great need for new preventative strategies, the most encouraging of which are microbicides. An effective microbicide would decrease the severity of the AIDS epidemic by decreasing the rate of sexual transmission. A number of models systems have been developed to provide insights into the mechanisms of male-to-female sexual transmission including explant cultures and the rhesus macaque vaginal transmission model. These systems have been successfully used to evaluate and identify candidate microbicides. There has been much less progress in the development of systems to evaluate female-to-male sexual transmission. There are currently no model systems of female-to-male sexual transmission that can determine whether potential microbicides are capable of preventing infection via the penis. To fill this gap, this application seeks to develop an explant culture system using human penile tissue. This will enable the efficacy and safety of candidate microbicides that prevent the sexual transmission of HIV to males to be evaluated. Additionally, my laboratory has recently developed methodology that allows the detection of individual virions in tissue. This system will be further developed to determine how HIV normally interacts with human penile tissue. In the R21 component of this application we will optimize these systems to determine the normal interaction of HIV with intact tissue and subsequent viral replication. In the R33 phase of the application we will evaluate the potential of different candidate microbicides, individually and in combination, to alter HIV interaction with the tissue and prevent HIV infection and replication. We will also determine if exposure to the microbicide causes any changes in the tissue that may have deleterious effects on normal cell function. The application seeks to develop new methods that determine whether chemicals can be used to prevent the sexual transmission of HIV. These methods will be used to determine the potency of protection from HIV infection, and the safety of the compounds before they are tested in humans. It is hoped that preventing HIV infection will decrease the number of people in the world infected with HIV and slow the AIDS epidemic.