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失败尝试导致了对新的预防战略的极大需要，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降低艾滋病流行的严重性。已经开发了许多模型系统来深入了解男性到女性的性传播机制，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估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取得的进展要少得多。目前还没有女性到男性性行为传播的模型系统，可以确定潜在的杀微生物剂是否能够防止通过阴茎感染。为了填补这一空白，本申请寻求开发一种使用人阴茎组织的外植体培养系统。这将使防止艾滋病毒通过性传播给男性的候选杀微生物剂的有效性和安全性得到评估。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粒子。将进一步开发这一系统，以确定艾滋病毒通常如何与人类阴茎组织相互作用。在这项应用的R21部分中，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。在应用的R33阶段，我们将评估不同候选杀菌剂单独和联合使用的潜力，以改变艾滋病毒与组织的相互作用，防止艾滋病毒感染和复制。我们还将确定接触杀菌剂是否会导致组织发生任何变化，这可能会对正常细胞功能产生有害影响。 该申请寻求开发新的方法，以确定是否可以使用化学物质来防止艾滋病毒的性传播。在对化合物进行人体试验之前，这些方法将用于确定预防艾滋病毒感染的效力和化合物的安全性。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.