HIV infection of male genital tissue

男性生殖组织的艾滋病毒感染

• 批准号: 6841415
• 负责人: ROBIN J SHATTOCK
• 金额: $ 13.3万
• 依托单位: U OF L ST. GEORGE'S HOSPITAL MEDICAL SCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841415
• 关键词: HIV infections; antiinfective agents; cell migration; clinical research; communicable disease transmission; disease /disorder proneness /risk; drug screening /evaluation; flow cytometry; growth media; human subject; immunocytochemistry; inhibitor /antagonist; male reproductive system disorder; mixed tissue /cell culture; monoclonal antibody; mucosal immunity; penis; polymerase chain reaction; receptor expression; reproductive system infection; urethra

DESCRIPTION (provided by applicant): Sexual transmission of HIV-1, the major mode of HIV-1 infection world-wide, occurs across mucosal surfaces. In the face of an expanding epidemic there is an urgent need for effective strategies to block mucosal spread of this infection. However, success of any preventative strategy may be critically dependent upon detailed knowledge of the mechanisms of transmission. While much has been learnt about vaginal and/or rectal transmission, relatively little is known about the mechanisms of HIV transmission to male genital tissue. Indeed, factors governing such transmission and the events between exposure of male genital mucosal surfaces and establishment of clinical infection are still poorly understood. The number and frequency of target cells, the relative susceptibility of different tissue sites (foreskin, glans and urethra) and the mechanisms of trans-epithelial transmission have not been investigated in a systematic fashion. This project aims to test the hypothesis that tissue specific determinants govern relative susceptibility to HIV-1 infection and replication in male genital tissue. In particular, the relative frequency of potential target cells, and receptor expression, will be correlated to ex vivo susceptibility of male genital tissue explants (foreskin, glans and urethra) to HIV-1 infection (cell free and cell associated, using a range of isolates). Male genital tissue will be obtained, with consent, from gender reassignment and other surgical procedures, and optimal culture conditions will be determined using techniques developed for other mucosal explant models (cervical/rectal) already established in the applicant's laboratory. To determine potential mechanisms for any differential susceptibility to HIV infection, the principal target cells for infection, and/or uptake of virus by migratory cells within the different tissue sites will be defined. The use of specific receptor/co-receptors in such mechanisms will be confirmed using a range of available antagonists and blocking Mabs. These studies may provide a major contribution to our understanding of the determinants of HIV-1 infection of male genital tissue, which in turn could be key to successful targeting of strategies and topical microbicides designed to block the sexual spread of HIV infection. The proposed "R21 grant" builds on the applicant's proven track record in investigation of HIV replication in cervical and rectal tissue models, and will bring added value to a number of NIH funded microbicide related programme project grants already underway in the applicant's laboratory.

描述（由申请人提供）：HIV-1的性传播是全球HIV-1感染的主要模式，发生在粘膜表面。面对不断扩大的流行病，迫切需要有效的策略来阻断这种感染的粘膜传播。然而，任何预防策略的成功都可能严重依赖于对传播机制的详细了解。虽然人们对阴道和/或直肠传播了解很多，但对艾滋病毒传播到男性生殖器组织的机制知之甚少。事实上，控制这种传播的因素以及暴露于男性生殖器粘膜表面和建立临床感染之间的事件仍然知之甚少。靶细胞的数量和频率、不同组织部位（包皮、龟头和尿道）的相对易感性以及跨上皮传播的机制尚未以系统的方式研究。该项目旨在检验组织特异性决定因素决定男性生殖器组织对HIV-1感染和复制的相对易感性的假设。特别地，潜在靶细胞的相对频率和受体表达将与男性生殖器组织外植体（包皮、龟头和尿道）对HIV-1感染（无细胞和细胞相关，使用一系列分离物）的离体易感性相关。在征得同意的情况下，将从性别重置和其他外科手术中获得男性生殖器组织，并将使用为申请人实验室已建立的其他粘膜外植体模型（宫颈/直肠）开发的技术确定最佳培养条件。为了确定对HIV感染的任何差异易感性的潜在机制，将定义感染的主要靶细胞和/或不同组织部位内迁移细胞对病毒的摄取。将使用一系列可用的拮抗剂和阻断单克隆抗体来确认特异性受体/共受体在此类机制中的使用。这些研究可能为我们理解HIV-1感染男性生殖器组织的决定因素做出重大贡献，这反过来可能是成功针对旨在阻断HIV感染性传播的战略和局部杀微生物剂的关键。拟议的“R21赠款”建立在申请人在宫颈和直肠组织模型中调查艾滋病毒复制的良好记录的基础上，并将为申请人实验室已经进行的一些NIH资助的杀微生物剂相关计划项目赠款带来附加值。