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