Molecular analysis of the mucosal SIVsmm transmission bottleneck

HIV-1和SIV在阴道、宫颈和宫颈粘膜表面传播瓶颈的阐明 直肠，包括对感染所必需的最早期病毒-宿主相互作用的准确定义，可能是 在设计有效的疫苗方面起到了重要作用。我们的实验室已经迈出了重要的一步 通过开发一个实验框架来确定传播者/创建者，从而实现这些目标 负责生产性感染的HIV-1和SIV基因组(Keele 2008；Keele 2009；Salazar 2009)和 发展原位方法来表征粘膜下早期病毒与宿主细胞的相互作用 传播(LI 2005；ESTES 2006；ESTES 2007；ESTES 2008；LI 2009a)。当前项目合并为 首次使用自然传播的SIVsm/创始人病毒进行IVAG、IR和IV传播研究 项目目标是描述SIVsmm传播的直肠、阴道和宫颈瓶颈，以 确定传播/创始人SIVsmm最初有效感染的细胞类型，并识别早期先天 抑制或促进生产性病毒感染的免疫反应。通过检查 新城疫病毒FTQ、D215和D215株分子克隆传毒/方正病毒的传播性 SL92b、SIVmac239和含有复杂SIVsmm准种的传染性猴血浆，我们将检验以下假设：SIVsmm传播的明显屏障存在于阴道、宫颈和直肠的粘膜界面。这些屏障在本质上既是被动的(筛选)，也是主动的，后者选择具有特殊细胞取向和复制特性的病毒，这些病毒是传播和生产性感染所必需的。该项目的具体目标是：(1)量化和描述自然发生的SIVsmm对直肠、宫颈阴道和静脉传播的瓶颈。

Elucidation of the bottleneck to HIV-1 and SIV transmission at mucosal surfaces of the vagina, cervix and rectum, including a precise definition ofthe eariiest virus - host interactions necessary for infection, could be instrumental in the design of effective vaccines. Our laboratories have taken significant steps toward addressing these goals by developing an experimental framework with which to identify transmitted/founder HIV-1 and SIV genomes responsible for productive infection (Keele 2008; Keele 2009; Salazar 2009) and by developing in situ methods to characterize early virus - host cell interactions underlying mucosal transmission (Li 2005; Estes 2006; Estes 2007; Estes 2008; Li 2009a). The current project combines forthe first time ivag, ir and iv transmission studies using naturally-occurring SIVsm transmitted/founder viruses Project objectives are to characterize the rectal, vaginal and cervical bottleneck to SIVsmm transmission, to identify the initial cell types productively infected by transmitted/founder SIVsmm, and to identify early innate Immune responses that act to constrain or facilitate productive viral Infection. By examining the transmissibllity of molecularly-cloned transmitted/founder viruses from SIVsmm strains FTq, D215 and SL92b, along with SIVmac239 and infectious monkey plasmas containing complex SIVsmm quasispecies, we will test the following hypothesis: Distinct barriers to SIVsmm transmission exist at mucosal interfaces of the vagina, cervix and rectum. These barriers are both passive (sieving) and active in nature, the latter selecting for viruses with particular cellular tropism and replication properties necessary for transmission and productive infection. Specific Aims of the project are: (1) To quantify and characterize phylogenetically the bottleneck to rectal versus cervicovaginal versus intravenous transmission by naturally-occurring SIVsmm