G-104 Defining the earliest targets of SIV susceptibility after mucosal challenge in the Rhesus Macaque Model

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Abstract

Background:

Macaque mucosal challenge via vaginal or rectal exposure with SIV is utilized to reproduce the circumstances of HIV transmission in humans. This model has provided insights into HIV transmission, but the critical window of the earliest events taking place after mucosal exposure remains undefined.

Methods:

We have recently developed a SIV-based dual reporter expression vector that facilitates the efficient identification of transmission susceptible sites in the rhesus macaque FRT after vaginal exposure. This system demonstrated that initial infection events can be widespread throughout the female reproductive tract (FRT), highly variable in their localization, and that T cells are the primary target in initial infection. We have extended this approach in 2 ways to gain additional insights into the earliest aspects of mucosal transmission. First, after rectal challenge with the SIV-based dual reporter expression vector, we can identify the location and phenotype of the cells infected by the inoculum of exposure. Additionally, because this system efficiently identifies regions of susceptibility to infection in the FRT, we have determined that we can identify small foci of SIVmac239 infection 48 hours after vaginal challenge with a mixture of wildtype SIVmac239 and the LICh dual reporter. Utilizing this novel approach to SIV challenge, we routinely identify SIVmac239 infected cells revealing their localization and fates in the FRT 48 hours after vaginal challenge.

Results:

Foci of infection with SIVmac239 are found throughout the female reproductive tract, from labia to ovary. We find that T cells are the major targets, and there is a strong bias for those with a Th17 phenotype. Infection of immature dendritic cells and macrophages is also observed representing approximately 25% of infected cells. Initial studies after rectal challenge also reveal that Th17 cells and immature dendritic cells are the primary target cells susceptible to the initial inoculum. Unexpectedly, we find that transmission can also take place in anal tissue which is protected by a squamous epithelium similar to the vaginal vault.

Conclusions:

Defining the location and phenotype of cells susceptible to SIV infection after vaginal or rectal challenge informs the development of interventions designed to decrease HIV acquisition. We find that there is great similarity relating to the initial targets of infection by the inoculum of exposure. In both cases, we find preferential infection of Th17-like cells and immature dendritic cells in contexts protected by both squamous and columnar epithelial mucosal barriers. Both of these cell types are involved in continuous immune surveillance at mucosal surfaces and could partially explain the known conditions that increase HIV acquisition, including sexually transmitted infections and bacterial vaginosis. How these conditions precisely influence mucosal barrier function or the density of target cells remains to be determined. However, the system presented here provides the ability to study and sample these foci at the portal of entry, facilitating the ability to characterize the earliest host responses to SIV/HIV infection.

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