One of the greatest therapeutic challenges in HIV research and care is the goal of viral eradication. Any strategy aimed at HIV eradication in chronic infection will need to address the persistence of virus in secondary lymphoid organs. Eradicating virus from these sites is complicated. Lymph nodes (LN) are rapidly infected in early infection, and maintain residual level of activation/inflammation during ART that may potentiate infection of susceptible cells to sustain the latent reservoir. LN are sites at which penetration of otherwise effective antiretroviral drugs appears limited. A third critical complication is that cytolytic effector T cels are typically excluded from LN by their movement across a concentration gradient of the lysophospholipid sphingosine-1 phosphate (S1P). As a result, lymphoid tissues that constitute critical sites of HIV persistence are relatively protected from HIV-specific cytolytic cells. Based on these findings, we propose a novel approach to retain cytolytic cells in lymphoid tissues by administration of the S1P receptor agonist FTY720. We hypothesize that sustained exposure to cytolytic cells will promote a more inflammatory LN environment, will accelerate the stochastic bursts of SIV replication that play a role in sustaining HIV reservoirs, and will allow cytolytic clls to recognize and destroy virus expressing cells directly in lymphoid tissues. We will test this model in the well-established model of SIV infection of rhesus macaques (RMs) using the S1P receptor agonist FTY720, a molecule approved by the FDA for the treatment of multiple sclerosis that blocks the interaction of S1P with its receptors and results in significant circulatng lymphopenia as a consequence of lymphocyte sequestration in LN. Crucial for this proposal, we developed a fully suppressive ART regimen for SIV-infected RMs, thus validating this model for studies of HIV eradication and cure. In the R21 phase of this proposal, we will assess the safety and activity of two different doses of FTY720 in retaining cytolytic cells in lymphoid tissues in ART-suppressed SIV-infected RMs. If successful, these studies will pave the way for the R33 phase, in which we will determine how FTY720 - at the dose showing the best activity/safety profile in the R21 studies - affects (i) antiviral cytotoxic responses and residual inflammation an (ii) HIV persistence in lymphoid tissues. The longitudinal design will allow analyses of blood, LN and rectal biopsies before and during FTY720 treatment. Elective necropsy after the last dose of FTY720 will give us the unprecedented opportunity to address the effects of FTY720 in many other anatomic locations including spleen, lung and brain.
Using a well-established model of HIV infection, we will test a novel intervention with a drug already approved by the FDA for another indication. These features make our approach very translational. If our results are successful, FTY720 would ultimately be tested in clinical trials aimed at achieving a functional cure of HIV infection in humans.
|Ryan, Emily S; Micci, Luca; Fromentin, RÃ©mi et al. (2016) Loss of Function of Intestinal IL-17 and IL-22 Producing Cells Contributes to Inflammation and Viral Persistence in SIV-Infected Rhesus Macaques. PLoS Pathog 12:e1005412|