The impact of antibody and pH on female-to-male SIV infection

描述（由申请人提供）：感染妇女的酸性宫颈阴道液中的HIV可能被抗Env抗体包被。由于艾滋病毒是性传播的，这些抗体并不总是能预防受体伴侣的感染，因此可能没有足够的数量或质量来中和体内的病毒。但是，生殖道分泌物中包裹HI的抗体是否有助于粘膜传播？这个问题将通过阴茎SIV暴露的恒河猴模型来解决。我们将检验抗体促进慢病毒通过生殖道粘膜传播的假设。该假设是基于我们的发现，由于上皮细胞Fc新生儿受体（FcRn）的pH依赖性参与，HIV免疫复合物的转胞吞作用显著增强。此外，艾滋病毒的传播/创始（T/F）毒株往往与抗体结合得更好，更容易被中和 而不是在感染后期分离的菌株，这增加了抗体选择菌株或通过粘膜表面成功传播的可能性。我们将完成以下具体目标：1）确定pH和低浓度抗体对恒河猴阴茎暴露于SIV后传播效率的影响。将修改已建立的阴茎暴露模型，以检测抗Env抗体的作用，浓度与 在女性生殖道分泌物中发现，对阴茎SIV传播的影响; 2）描述抗体在阴茎暴露后选择SIV T/F株中的作用。将比较感染抗体包被病毒和未包被病毒的动物的T/F毒株数量及其env序列。此外，将构建假病毒，以确定T/F Env假病毒是否可以在抗体/pH依赖性转胞吞试验中与非T/F Env假病毒进行表型区分。我们相信这项研究将定义一种全新的慢病毒性传播机制，产生关于感染早期事件的关键数据，这将改变目前的模式并为疫苗开发提供信息。具体而言，如果免疫复合病毒在通过雄性生殖器组织的粘膜传播方面与裸病毒表现不同，则目前的动物攻毒模型（据我们所知，仅使用裸病毒）将需要重新评估。此外，疫苗接种产生的抗体应答需要成功地与结合病毒的供体抗体竞争，并且具有足够的数量和质量，以避免促进传播的可能性。最后，这项研究可能会提出新的预防策略，针对FcRn介导的转胞吞作用。

DESCRIPTION (provided by applicant): HIV in the acidic cervicovaginal fluids of infected women is likely coated by anti-Env antibodies. Since HIV is sexually transmitted, these antibodies do not always prevent infection in the recipient partner and therefore may be of insufficient quantity or quality to neutralize virus in vivo. But could the antibodies that coat HI in genital tract secretions facilitate mucosal transmission? This question will be addressed with a rhesus macaque model of penile SIV exposure. We will test the hypothesis that antibody facilitates lentivirus transmission across genital tract mucosa. The hypothesis is based on our finding of marked enhancement of transcytosis of HIV immune complexes due to pH-dependent engagement of epithelial cell Fc neonatal receptors (FcRn). In addition, transmitted/founder (T/F) strains of HIV tend to bind better to antibodies and to be more susceptible to neutralization than are strains isolated late in infection, raising the possibility that antibody selects strains or successful transmission across mucosal surfaces. We will accomplish the following specific aims: 1) Determine the impact of pH and low concentrations of antibody on transmission efficiency following penile exposure of rhesus macaques to SIV. An established penile exposure model will be modified to test the effects of anti-Env antibody, at concentrations similar to those found in female genital tract secretions, on penile SIV transmission; and 2) Delineate the role of antibody in selecting T/F strains of SIV following penile exposure. The number of T/F strains and their env sequences, from animals infected with antibody-coated and with uncoated virus, will be compared. In addition, pseudoviruses will be constructed to determine if T/F Env pseudoviruses can be phenotypically distinguished from non-T/F Env pseudoviruses in antibody/pH-dependent transcytosis assays. We believe this research will define a completely novel mechanism of sexual transmission of lentiviruses, generating critical data on early events in infection that will shift current paradigms and inform vaccine development. Specifically, if immune-complexed virus behaves differently than naked virus with respect to mucosal transmission across male genital tissue, current animal challenge models, which, to our knowledge, exclusively utilize naked virus, would require re-evaluation. Additionally, antibody responses generated by vaccination would need to successfully compete with donor antibody bound to virus and be of sufficient quantity and quality to avoid the potential of facilitating transmission. Finally, this research may suggest novel prevention strategies targeting FcRn-mediated transcytosis.