UCLA

Multilineage hematopoiesis suffers in the presence of HIV infection. While the hallmark of HIV infection is the massive loss of CD4+ T-cells, a number of studies have shown that the development of all blood phenotypes is disturbed through the course of infection. However, antiretroviral drugs, opportunistic infections, and the drugs used to treat them all impair hematopoiesis and confound the study of the mechanism of hematopoietic impairment in HIV-infected patient samples. These factors underscore the need to develop controlled in vitro and in vivo models to study the impact of HIV infection in the bone marrow. Here we present data that demonstrate intermediate hematopoietic progenitors are susceptible to infection both in vitro and in vivo and direct infection in part impairs hematopoietic lineage development. Further, these results were supported using the BLT humanized mouse model thus demonstrating its utility as a model to study HIV associated bone marrow pathogenesis. Innate HIV restriction factors are popular targets for manipulating infection from hematopoietic stem cells. Of the known HIV restriction factors, APOBEC3G(A3G) is unique in that it is expressed in early hematopoiesis and whose expression fluctuates significantly throughout the process of hematopoiesis. When A3G is knocked down by siRNA in hematopoietic progenitors, hematopoietic lineage commitment is clearly skewed. Erythroid and megakaryocyte lineages are impaired while granulocyte and macrophage lineages are enriched. This phenotype is maintained in a humanized mouse model. When human hematopoietic progenitors are isolated from the bone marrow of BLT mice that are reconstituted with stable A3G knockdown vectors, they show a similar skewing of hematopoietic lineage commitment. Microarray analysis of A3G knockdown in the common myeloid progenitor confirms that a number of hematopoiesis-specific genes are dysregulated when A3G expression is diminished. Further analysis suggests A3G may be exerting its effects through the cellular mRNA editing machinery.