HIV-1 Is Restricted prior to Integration of Viral DNA in Primary

Certain cells have the ability to block retroviral infection at specific stages of the viral cycle by the activities of well-characterized factors and transcriptional silencing machinery. Infection of murine stem cells (MSCs) by the murine leukemia viruses (MLVs) is profoundly blocked postintegration by transcriptional silencing. Here, we show that a dominant point of restriction of HIV-1 in human CD34 cells is prior to integration of viral DNA and that HIV-1 restriction by human CD34 cells is fundamentally different fromMLV restriction by mouse cells. There is currently significant controversy regarding whetherhuman hematopoietic stem cells (HSCs) can become infected withHIV-1; some but not all investigators have detectedHIV-1 in human HSCs of infected patients (1, 2). Lentiviruses do success-fully infect nondividing cells, butHIV-1 infection of humanHSCs in culture is inefficient compared to that in activated T cells (3–5). A significant body of work has identified postintegration silencing as a major mechanism employed by murine stem cells (MSCs) to restrict retroviruses, but humanHSCsmay be different. The point in the retroviral replication cycle at which retroviruses are blocked in human HSCs remains unknown, and whether this involves