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.