Role of integrins in HIV/SIV transmission across cervico-vaginal mucosa

描述（由申请人提供）：艾滋病毒最常见的是通过性交粘膜途径获得。因此，阻断这种传播途径将迅速降低全球艾滋病毒发病率。在粘膜暴露后的最初几天，HIV必须克服许多障碍，在HIV建立感染之前提供采取行动的机会。不幸的是，病毒暴露后发生的关键事件知之甚少。 我们建议HSV-2通过调节粘膜微环境来影响这些早期事件，为了探索如何影响，我们将使用我们最近建立的HSV-2感染猕猴模型与SHIV阴道传播模型相结合。这种组合构成了一种新的强大工具，以受控的方式研究SHIV感染的最早阶段，探索HSV-2的影响，并确定影响传播的事件。有趣的是，我们发现直肠HSV-2感染增加了感染部位（直肠组织）、血液和引流淋巴结中<$4 <$7高CD 4 + T细胞的百分比。在早期的研究中，我们描述了HIV/SIV包膜和<$4 <$7之间的特定相互作用。表达高水平该受体的粘液CD 4 + T细胞（<$4 <$7 high）构成HIV感染的优先靶点。最近的数据进一步表明，早期传播的病毒表现出对<$4 <$7的反应性增加（与慢性分离株及其对CD 4的反应性相比），表明 这种分子在感染的初始阶段尤其重要。此外，我们发现，树突状细胞（DC）感染HSV-2在体外扩增的<$4 <$7高亚群的CD 4 + T细胞在共培养，并增加这些混合物中的HIV感染。因此，我们假设HSV-2影响宫颈阴道组织中DC的功能，这反过来又增加了粘膜中<$4 <$7高CD 4 + T细胞的存在。 我们打算使用HSV-2作为一种工具来剖析<$4 <$7 highCD 4 + T细胞在HIV通过宫颈阴道粘膜传播的早期事件中的作用。我们将研究HSV-2如何调节宫颈阴道组织内的T细胞和DC生物学（细胞迁移、活化、表型），以确定这如何影响对重复低剂量SHIVSF 162 P3阴道激发的易感性。此外，使用一种特异性抑制HIV包膜与<$4 <$7结合的药物，与一种对<$4 <$7亲和力增加的突变病毒相比，我们将进一步证明<$4 <$7-HIV相互作用在SHIV感染发病中的重要性。这些研究将提供关键的洞察力，以了解<$4 <$7在宫颈阴道粘膜HIV感染的最早时刻的作用，以及HSV-2感染如何影响这一点，为解决HIV传播开辟新的方法。

DESCRIPTION (provided by applicant): HIV is most commonly acquired by mucosal route during sexual intercourse. Therefore, blocking this means of transmission will rapidly decrease HIV incidence worldwide. In the first days following mucosal exposure HIV must overcome numerous barriers offering a window of opportunity to act before HIV establishes infection. Unfortunately, the critical events that take place after viral exposure are poorly understood. We propose that HSV-2 influences these early events by modulating the mucosal microenvironment and, to explore how, we will use our recently established macaque model of HSV-2 infection in combination with a model of SHIV vaginal transmission. This combination constitutes a new powerful tool to study the earliest stages of SHIV infection in a controlled manner, explore the effect of HSV-2 and identify the events that influence transmission. Interestingly, we found that rectal HSV-2 infection increases the percentage of ¿4¿7highCD4+ T cells in the site of infection (rectal tissue), blood, and draining lymph nodes. And in earlier wors we described a specific interaction between the HIV/SIV envelope and ¿4¿7. Mucosal CD4+ T cells expressing high levels of this receptor (¿4¿7high) constitute a preferential target for HIV infection. Recent data has further indicated that early-transmitted viruses exhibit increased reactivity for ¿4¿7 (compared to chronic isolates and to their reactivity for CD4), suggesting that this molecule is especially important during the initial stages of infection. Additionally, we foun that dendritic cells (DCs) infected with HSV-2 in-vitro expand the ¿4¿7high subset of CD4+ T cells in co-culture and increase HIV infection in these mixtures. Thus, we hypothesize that HSV-2 influences DC function within the cervico-vaginal tissue and that this, in turn, increases the presence of ¿4¿7highCD4+ T cells in the mucosa. We intend to use HSV-2 as a tool to dissect the role of ¿4¿7highCD4+ T cells during early events of HIV transmission across the cervico-vaginal mucosa. We will study how HSV-2 modulates T cell and DC biology within the cervico-vaginal tissues (cell migration, activation, phenotype) to determine how this influences susceptibility to repeated low-dose SHIVSF162P3 vaginal challenge. Moreover, using a drug that specifically inhibits HIV-envelope binding to ¿4¿7 versus a mutant virus that has increased affinity for ¿4¿7 we will further demonstrate the importance of the ¿4¿7-HIV interaction in the onset of SHIV infection. These studies will provide critical insight into the role of ¿4¿7 in the earliest moments of HIV infection across the cervico-vaginal mucosa and how this is influenced by HSV-2 infection, opening up novel approaches to tackle HIV spread.