Experimental Treatment of SIV-Infected Macaques via Autograft of CCR5 -Disrupted Hematopoietic Stem and Progenitor Cells.

Hematopoietic stem cell (HSC)-based gene therapy targeting represents a promising way to cure human immunodeficiency virus type 1 (HIV-1) infection. Yet the preclinical animal model with transplantation of autologous -ablated HSCs remains to be optimized. In this study, four Chinese rhesus macaques of simian immunodeficiency virus (SIV) chronic infection were given long-term antiretroviral therapy (ART), during which peripheral CD34 hematopoietic stem and progenitor cells (HSPCs) were purified and infected with -specific CRISPR/Cas9 lentivirus (three monkeys) or GFP lentivirus (one monkey). After non-myeloablative conditioning, the -modified or GFP-labeled HSPCs were autotransplanted to four recipients, and ART was withdrawn following engraftment. All of the recipients survived the process of transplantation. The purified CD34 HSPCs harbored an undetectable level of integrated SIV DNA. The efficiency of disruption in HSPCs ranges from 6.5% to 15.6%. Animals experienced a comparable level of hematopoietic reconstuction and displayed a similar physiological homeostasis Despite the low-level editing of (0.3%-1%), the -disrupted cells in peripheral CD4 Effector Memory T cell (TEM) subsets were enriched 2- to 3-fold after cessation of ART. Moreover, two of the three treated monkeys displayed a delayed viral rebound and a moderately recovered immune function 6 months after ART withdrawal. This study highlights the importance of improving the -editing efficacy and augmenting the virus-specific immunity for effective treatment of HIV-1 infection.