Combinatorial hematopoietic stem cell transplantation and vaccination reduces viral pathogenesis following SHIV89.6P-challenge.

Abstract

Development of curative approaches for HIV-1 infected patients requires novel approaches aimed at eliminating viral reservoirs and replacing potential target cells with infection-resistant immune cell populations. We have previously shown that autologous transplantation of genetically modified hematopoietic stem cells (HSCs) with lentiviral vectors encoding the mC46-fusion inhibitor results in a significant reduction in viral pathogenesis following challenge with the highly pathogenic dual tropic, SHIV89.6P strain. In this study, we used a combinatorial approach in which following engraftment of genetically modified HSCs, pigtailed macaques were vaccinated with a previously developed vaccinia-based vaccine expressing SIV-Gag, Pol. Using this dual therapy approach, lower viremia was detected in both the acute and chronic phase of disease with levels reaching near the lower limits of detection. In comparison with macaques receiving HSCT only, the combination approach resulted in a further log decrease in plasma viremia. Similar to our previous studies, positive selection of all CD4(+) T-cell subsets was observed; however, higher gene-modified CD4(+) T-cell levels were observed during the chronic phase when vaccination was included suggesting that combining vaccination with HSCT may lower the necessary threshold for achieving viremic control.