Interaction of HIV with Macaque Genital Tract

说明(由申请人提供)：这项提案的长期目标是增进对男性向女性性传播机制的了解，这可用于促进旨在治疗艾滋病毒感染早期事件的杀微生物剂和疗法的开发。尽管粘膜T细胞和朗格汉斯细胞已被确定为女性生殖道潜在的早期感染目标，但病毒如何穿过上皮屏障进入这些目标细胞仍然是一个谜。为了深入了解这一过程，有人提议利用一种新技术来识别组织中的单个艾滋病毒病毒粒子。霍普实验室此前已经使用宫颈外和宫颈内组织外植体以及生物工程上皮培养系统验证了这一系统。然而，这些类型的系统只是试图模仿体内发生的事情。现在是时候将这些研究扩展到女性到男性性传播的动物模型上了。这些系统中最具特点的是恒河猴模型，该模型使用SIV修改为使用HIV包膜蛋白(SIV)。该提案旨在为实验提供资金，以表征艾滋病毒与恒河猴雌性生殖道的相互作用，并为艾滋病毒如何获得阴道粘膜中的目标细胞以及首先感染的细胞提供见解。这些研究将确定女性生殖道中作为艾滋病毒进入底层组织屏障的效率较低的部分。他们还将确定HIV与阴道粘膜中的靶细胞的潜在相互作用，并可能深入了解哪些细胞是主要感染的。他们还可能确定艾滋病毒与细胞隔间的相互作用，这将为艾滋病毒如何进入组织并在组织内移动的机制提供见解。与人类健康的相关性：因此，这些拟议的研究与申请高度相关，因为更好地了解男性到女性的性传播机制可以帮助开发用于治疗艾滋病毒感染的早期事件(传播周围事件)的杀微生物剂和疗法。

DESCRIPTION (provided by applicant): An increase in the understanding of the mechanisms of male-to-female sexual transmission is the long-term goal of this proposal which can be used to facilitate the development of microbicides and therapies designed to treat the early events of HIV infection. Although mucosal T cells and Langerhans cells have been identified as potential early targets of infection in the female genital tract how the virus gains access to these target cells after traversing the epithelial barriers remains a mystery. To gain insights into this process it is being proposed to utilize a new technology that allows the identification of individual virions of HIV in tissue. The Hope Lab has previously validated this system using ectocervical and endocervical tissue explants and bioengineered epithelial culture systems. However, these types of systems only attempt to mimic what takes place in vivo. It is now time to extend these studies to an animal model for female-to-male sexual transmission. The most characterized of these systems is the rhesus macaque model using SIV modified to use the HIV envelope protein (SHIV). The proposal seeks to fund experimentation to characterize the interaction of HIV with the rhesus macaque female genital tract and provide insights into how HIV gains access to target cells in the vaginal mucosa and those cells first infected. These studies will identify portions of the female genital tract that are less efficient as barriers to HIV entering the underlying tissue. They will also identify the potential interaction of HIV with target cells in the vaginal mucosa and possibly give insight into what cells are infected primarily. They may also identify the interaction of HIV with cellular compartments that will provide insights into the mechanisms of how HIV can enter and move within the tissue. HUMAN HEALTH RELEVANCE: Therefore, these proposed studies are highly relevant to the request for applications because a better understanding of the mechanisms of male-to-female sexual transmission can be used facilitate the development of microbicides and therapies designed to treat the early events of HIV infection (peritransmission events).