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

描述(申请人提供)：感染妇女宫颈阴道液中的HIV很可能被抗Env抗体包裹。由于艾滋病毒是通过性传播的，这些抗体并不总能预防接受者的感染，因此可能数量或质量都不足以在体内中和病毒。但是，生殖道分泌物中包裹HI的抗体能促进粘膜传播吗？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。这一假说是基于我们的发现，由于上皮细胞Fc新生儿受体(FcRN)的pH依赖，HIV免疫复合体的跨细胞作用显着增强。此外，传播/创始(T/F)的艾滋病毒毒株往往更好地与抗体结合，更容易中和 比感染后期分离的菌株更容易感染，这增加了抗体选择菌株或成功通过粘膜表面传播的可能性。我们将完成以下具体目标：1)确定恒河猴阴茎暴露于SIV后，pH和低浓度抗体对传播效率的影响。已建立的阴茎暴露模型将被修改，以测试抗Env抗体的效果，其浓度与 在女性生殖道分泌物中发现了与阴茎SIV传播有关的抗体；2)阐明了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和未包被病毒的动物的T/F毒株数量及其环境基因序列。此外，还将构建假病毒，以确定T/F环境假病毒能否在抗体/pH依赖的细胞穿透试验中与非T/F环境假病毒区分开来。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，这将改变目前的范式，并为疫苗开发提供信息。具体地说，如果免疫复合病毒在通过男性生殖器组织的粘膜传播方面的行为与裸露病毒不同，那么目前的动物挑战模型，据我们所知，完全利用裸露病毒，将需要重新评估。此外，疫苗接种产生的抗体反应需要成功地与与病毒结合的供体抗体竞争，并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针对FcRN介导的细胞转运的新的预防策略。

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.