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

病毒和免疫干预对口腔 SIV 感染后早期事件的影响

• 批准号: 10628249
• 负责人: D. Noah Sather
• 金额: $ 95.71万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628249
• 关键词: Address; Breast Feeding; Collaborations; Consumption; Country; Data; Disease Outcome; Dyes; Early Intervention; Early identification; Event; Future; Gastrointestinal tract structure; Goals; HIV; HIV Infections; HIV therapy; HIV vaccine; Hour; Human Milk; Immune; Immune response; Immunity; Immunologics; Individual; Indocyanine Green; Infant; Infant Health; Infection; Injections; Interferons; Intervention; Laboratories; Location; Lymphatic; Lymphoid; Macaca; Macaca mulatta; Modeling; Morbidity - disease rate; Mothers; Mucous Membrane; National Institute of Dental and Craniofacial Research; Operative Surgical Procedures; Oral; Oral mucous membrane structure; Outcome; Rectum; Research; Resources; Risk; Route; SIV; SIV Vaccines; Sampling; Seminal fluid; Site; Specificity; Surface; Techniques; Therapeutic; Tissues; Vaccination; Vaccines; Vagina; Viral; Virus; Virus Diseases; Virus Replication; Woman; adaptive immune response; antiretroviral therapy; design; draining lymph node; epidemiology study; experimental study; immunological intervention; improved; improved outcome; innovation; insight; intraepithelial; lymph nodes; mortality; mucosal site; novel; novel therapeutics; oral HIV; penis; rectal; response; therapeutic evaluation; therapy design; transmission process; vaccine delivery; vaccine evaluation; viral DNA; viral RNA; viral transmission

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.

大多数HIV感染发生在粘膜表面，包括直肠、阴道、阴茎或口腔 粘膜口服艾滋病毒传播发生在两种不同的情况下， 艾滋病毒感染的妇女和接受性的口腔接触精液从艾滋病毒感染的伙伴。艾滋病毒阳性母亲 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， 每年仍有约15万婴儿感染艾滋病毒。此外，流行病学研究提供了 明确的证据表明，艾滋病毒可以通过接受性口交传播。迄今为止，评估 粘膜SIV传播受到与不确切知道何时和 在那里发生了传输事件。例如，在评估口服SIV传播时，我们 先前在24和48小时时在全身淋巴结中鉴定出SIV DNA和RNA， 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处 消化道该提案通过使用我们开发的创新技术来解决这个问题 并优化了HIV疫苗的递送和引流淋巴结的变化评估， 上皮内（IEp）疫苗注射到口腔粘膜。在这里，我们利用IEp注射来传递SIV病毒 直接进入IEp空间，这是与粘膜感染后SIV进入和复制相关的位置。 这种精确粘膜感染（PMI）模型使我们能够知道粘膜感染的确切位置。在 根据我们的初步数据，我们已经成功地使用PMI启动口腔和直肠粘膜感染， 猕猴重要的是，通过精确定义感染部位，使我们能够通过以下方式开发淋巴追踪： 吲哚菁绿色染料（LTI），以精确的特异性识别第一个接触SIV病毒的引流淋巴结。 我们假设，第一个接触SIV的淋巴结是抗SIV的启动、广度和强度的关键。 SIV免疫反应，以及旨在刺激先天性或适应性免疫反应的早期干预措施 有可能改善这种最初的淋巴反应。这三种干预策略将 评价的是：A.抗逆转录病毒治疗（ART），B。1型干扰素（IFN 1）和C. SIV-Env疫苗。三 该提案的目的是重点对受感染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）、进入消化道（目标2）和全身（目标3）。这项研究使 使用由Smedley博士开创的新型靶向感染和采样技术， 对感染部位和原发引流淋巴结取样。该研究具有以下潜力：1。 提供对SIV感染后最早事件的了解。2.指导确定治疗方法，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PMI和LTI的建立 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新颖的 针对HIV阳性个体的治疗，旨在改善HIV感染后的结果。