Influence of viral and immune interventions on early events following oral SIV infection

大多数艾滋病毒感染发生在粘膜表面，包括直肠、阴道、阴茎或口腔。 粘膜。口腔艾滋病毒传播发生在两个不同的环境中，出生于 感染艾滋病毒的妇女和接受的与感染艾滋病毒的伴侣的精液的口腔接触。针对HIV+母亲 母乳喂养对婴儿健康的好处往往超过艾滋病毒传播的风险，因此， 每年仍有15万婴儿感染艾滋病毒。此外，流行病学研究还提供了 明确的证据表明，艾滋病毒可以通过接受性口交传播。到目前为止，评估 由于不知道确切的时间和时间，粘膜SIV的传播受到了阻碍 传输事件已经发生的地方。例如，在评估口腔SIV传播时，我们 以前在24小时和48小时在全身的淋巴结中发现了SIV DNA和RNA，但 无法确定传输事件是否发生在整个上部的一个或多个位置 消化道。该提案通过使用我们开发的创新技术解决了这一问题 并针对HIV疫苗的交付进行了优化，并评估了术后引流淋巴的变化 上皮内(IEP)疫苗注射到口腔粘膜。在这里，我们使用IEP注射传递SIV病毒 直接进入IEP空间，这是一个与SIV进入和粘膜感染后复制相关的位置。 这种精确的粘膜感染(PMI)模型使我们能够知道黏膜感染的确切位置。在……里面 根据我们的初步数据，我们已经成功地使用PMI启动了口腔和直肠黏膜感染 猕猴。重要的是，通过精确定义感染部位，使我们能够通过 吲哚青绿染料(LTI)以精妙的特异性识别出第一个接触SIV病毒的引流LNS。 我们推测，第一批接触SIV的LNS是抗SIV病毒的启动、广度和大小的关键。 SIV免疫反应，以及旨在刺激先天或获得性免疫反应的早期干预 有可能改善这种最初的淋巴反应。这三个干预战略将是 评估的疫苗包括：a.抗逆转录病毒疗法(ART)、b.1型干扰素(IFN1)和C.SIV-Env疫苗。三位一体 该提案的目的是对受影响的不同组织部位进行免疫学和病毒学评估 SIV感染粘膜(目标1)、进入淋巴管(目标2)和全身(目标3)。这项研究使 使用斯梅德利博士首创的新的靶向感染和采样技术，允许连续 感染部位和原发引流淋巴结的取样。这项研究具有以下潜力：1. 提供对SIV感染后最早事件的洞察。2.指导识别治疗方法以减少 与经口传播艾滋病毒有关的发病率和死亡率。3.指导建立PMI和LTI 用于将来在其他粘膜部位进行SIV感染实验。我们的长期总体目标是开发小说 为HIV+患者设计的治疗方法，旨在改善艾滋病毒感染后的结果。

A majority of HIV infections occur at a mucosal surface, which can include the rectal, vaginal, penile or oral mucosa. Oral HIV transmission occurs in two distinct settings, breast milk consumption by infants born to HIV-infected women and receptive oral contact with semen from an HIV-infected partner. For HIV+ mothers the benefits of breastfeeding to infant health often outweigh the risk of HIV transmission, and as a result, ~150,000 infants are still infected with HIV each year. Additionally, epidemiological studies have provided clear evidence that HIV can be transmitted through receptive oral intercourse. To date, studies assessing mucosal SIV transmission have been impeded by the difficulties associated with not knowing exactly when and where the transmission event has taken place. For example, when evaluating oral SIV transmission, we previously identified SIV DNA and RNA in lymph nodes throughout the body at 24 and 48 hours but were unable to determine if the transmission event occurred at one or multiple locations throughout the upper digestive tract. This proposal addresses this issue through the use of innovative techniques that we developed and optimized for HIV vaccine delivery and evaluation of changes in the draining lymph nodes following an intraepithelial (IEp) vaccine injection to the oral mucosa. Here we utilize IEp injection to deliver the SIV virus directly into the IEp space, a location associated with SIV entry and replication following mucosal infection. This Precision Mucosal Infection (PMI) model allows us to know the exact location of the mucosal infection. In our preliminary data, we have used PMI successfully to initiate both oral and rectal mucosal infections in macaques. Importantly, by precisely defining the site of infection, enabled us to develop Lymphatic Tracking by Indocyanine green dye (LTI) to identify with exquisite specificity the first draining LNs to contact the SIV virus. We hypothesize that the first LNs to contact SIV are key to the initiation, breadth and magnitude of the anti- SIV immune response, and early interventions designed to stimulate the innate or adaptive immune response has the potential to improve this initial lymphatic response. The three intervention strategies that will be evaluated are: A. Anti-retroviral therapy (ART), B. Type-1 interferons (IFN1) and C. SIV-Env vaccine. The three aims of the proposal focus on immunological and virological assessments of different tissue sites impacted by the SIV infection mucosa (Aim 1), entry to the lymphatics (Aim 2) and systemically (Aim 3). This study makes use of novel targeted infection and sampling techniques pioneered by Dr. Smedley that allow for serial sampling of the site of infection and primary draining lymph nodes. The research has the potential to: 1. Provide insight into the earliest events following SIV infection. 2. Guide identification of therapies to reduce morbidity and mortality associated with oral transmission of HIV. 3. Guide the establishment of PMI and LTI for future SIV infection experiments at other mucosal sites. Our long-term overall goal is to develop novel therapies for HIV+ individuals designed to improve outcome following an HIV infection.