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

描述(申请人提供)：HIV最常见的感染途径是在性交期间通过粘膜途径感染。因此，阻断这一传播途径将迅速降低全世界的艾滋病毒发病率。在粘膜暴露后的头几天，艾滋病毒必须克服许多障碍，为在艾滋病毒确定感染之前采取行动提供机会之窗。不幸的是，人们对病毒暴露后发生的关键事件知之甚少。 我们认为HSV-2通过调节粘膜微环境来影响这些早期事件，为了探索如何使用我们最近建立的HSV-2感染猕猴模型和SHV阴道传播模型。这一组合构成了一种新的强有力的工具，可以用来以受控的方式研究SHV感染的早期阶段，探索HSV-2的作用，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高CD4+T细胞的百分比。在早期的WORS中，我们描述了HIV/SIV包膜与7之间的一种特殊的相互作用。高水平表达这种受体的粘膜CD4+T细胞是HIV感染的首选靶点。最近的数据进一步表明，早期传播的病毒对4和7的反应性增强(与慢性分离株和它们对CD4的反应性相比)，这表明 这种分子在感染的最初阶段特别重要。此外，我们发现，体外感染HSV-2的树突状细胞(DC)在共培养中扩大了CD4+T细胞的高亚群，并增加了在这些混合物中的HIV感染。因此，我们假设HSV-2影响宫颈阴道组织内的DC功能，进而增加粘膜中高CD4+T细胞的存在。 我们打算使用HSV-2作为一种工具来剖析高CD4+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中的T细胞和DC生物学(细胞迁移、激活、表型)，以确定这如何影响对反复低剂量SHIVSF162P3阴道攻击的敏感性。此外，使用一种特定地抑制HIV-包膜与4？7结合的药物与增加对4？7亲和力的突变病毒相比，我们将进一步证明4？7-HIV相互作用在SHV感染开始中的重要性。这些研究将提供关键的洞察力，了解艾滋病毒在宫颈-阴道粘膜感染的最早时刻所起的作用，以及HSV-2感染如何影响这一作用，从而开辟应对艾滋病毒传播的新方法。

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.