Molecular analysis of the mucosal SIVsmm transmission bottleneck

阐明HIV-1和SIV在阴道、宫颈和阴道粘膜表面传播的瓶颈 直肠，包括感染所必需的最早期病毒-宿主相互作用的精确定义， 有助于设计有效的疫苗。我们的实验室已经采取了重大步骤， 通过制定一个实验框架来确定传播/创始人， HIV-1和SIV基因组负责生产性感染（Keele 2008; Keele 2009; Salazar 2009）， 发展原位方法以表征粘膜下的早期病毒-宿主细胞相互作用 传播（Li 2005; Estes 2006; Estes 2007; Estes 2008; Li 2009 a）。目前的项目结合为 使用自然发生的SIVsm传播/创始者病毒进行的首次ivag、ir和iv传播研究 项目目标是确定SIVsmm传播的直肠、阴道和宫颈瓶颈的特征， 鉴定被传播的/创始人SIVsmm有效感染的初始细胞类型，并鉴定早期先天性 抑制或促进生产性病毒感染的免疫反应。通过检查 来自SIVsmm株FTq、D215和 SL92 b，沿着SIVmac 239和含有复杂SIVsmm准种的感染性猴血浆，我们将检验以下假设：在阴道、子宫颈和直肠的粘膜界面处存在对SIVsmm传播的明显屏障。这些屏障在性质上是被动的（筛分）和主动的，后者选择具有传播和生产性感染所必需的特定细胞向性和复制特性的病毒。本项目的具体目标是：（1）定量和描述自然发生的SIVsmm在直肠、宫颈阴道和静脉传播中的瓶颈

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