Infection of Hematopoietic Progenitor Cells by HIV-1.

Abstract

HIV causes a chronic infection characterized by depletion of CD4+ T lymphocytes and, at late stages, severe bone marrow abnormalities. Despite the development of drugs that inhibit viral spread, HIV infection is difficult to eradicate because of uncharacterized cellular reservoirs that are resistant to antiretroviral therapy and the immune response. One possible mechanism that could account for viral persistence and hematopoietic dysfunction is the direct infection of hematopoietic progenitor cells (HPCs) by HIV. For this reason, we sought to determine if HPCs can be infected by HIV, and to understand the role of HPC infection in disease pathogenesis. Surprisingly, we found that a subset of HPCs became actively infected following in vitro exposure to HIV. Actively infected HPCs up-regulated apoptosis markers and were rapidly lost from culture. Moreover, HIV infection was detected in primitive, multipotent HPCs. In some HPCs, HIV became latent and stably persisted in cell culture until viral gene expression was activated by differentiation factors. A novel reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. In light of these findings, we initiated studies to evaluate the infection of HPCs in HIV-infected individuals. We found that some subjects had actively infected HPCs that were detectable by flow cytometry immediately following isolation. Conversely, other subjects did not have detectable active HPC infection after isolation, but virus could be activated from the cells by treatment with differentiation factors. Finally, we wished to determine if different HIV isolates differed in their ability to infect HPCs. We found that virus isolates that utilize CXCR4 as an entry co-receptor were capable of infecting primitive HPCs, whereas viral isolates that utilize CCR5 were not. This finding is especially interesting considering that the emergence of CXCR4-utilizing isolates corresponds with clinical disease progression. Studies in mouse model systems are currently underway to determine if CXCR4-utilizing HIV is capable of infecting hematopoietic stem cells. These findings have important implications for understanding HIV bone marrow pathology and viral persistence.