With 34 million people currently living with HIV, stopping the HIV epidemic remains imperative. Combination antiretroviral therapy (cART) limits viral replication, but is not curative. Thus, there is an urgent need to design a functional cure va elimination of the viral reservoir. There are now 3 HIV patients who remain HIV free in the absence of cART following leukemia-related, MHC-matched, allogeneic hematopoietic stem cell transplantation (HSCT). The mechanisms underlying this functional cure are not known, but may depend on graft-versus-host immunity in the transplant recipients. Non-human primates are the best model of HIV infection, but the majority of studies focus on autologous or MHC-mismatched allogeneic HSCT due to the complexity of non-human primate MHC. Thus, no studies have directly assessed the role of graft-versus-host immunity in the clearance of the HIV reservoir following MHC-matched, allogeneic HSCT. We intend to define the contribution of graft-versus-host immunity to HIV clearance following HSCT using a novel, Mauritian Cynomolgus macaque (MCM) model. MCM have extremely simplified genetics due to a recent bottleneck approximately 500 years ago. Therefore, we are able to readily identify fully MHC-matched animals, a situation akin to the MHC-matching most often performed in human HSCT.
In specific aim 1, we will establish a safe and effective nonmyeoablative regimen in SIV-infected MCMs.
In specific aim 2, we will perform MHC-matched HSCT, measure graft-versus host immunity, and correlate it to SIV rebound in the plasma and tissues. Overall, this study will build a new model of MHC-matched, allogeneic HSCT in non-human primates and use this model to assess the role of graft-versus-host immunity in HIV clearance following HSCT.
The development of curative approaches for HIV infection is now recognized as both a necessary and attainable goal. Hematopoietic stem cell transplantation has been shown to functionally cure HIV infection in three separate patients. Therefore, we propose here to build a novel non-human primate model of hematopoietic stem cell transplantation and use it to elucidate the mechanisms of HIV clearance.
|Burwitz, Benjamin J; Wu, Helen L; Abdulhaqq, Shaheed et al. (2017) Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes. Nat Commun 8:1418|
|Sacha, Jonah B; Ndhlovu, Lishomwa C (2016) Strategies to target non-T-cell HIV reservoirs. Curr Opin HIV AIDS 11:376-82|