Cytopenias in HIV Infection: Mechanisms and Alleviation of Hematopoietic Inhibition

Hematopoietic abnormalities including anemia, cytopenias, and alterations of the stem cell plasticity in the bone marrow microenvironment commonly occur in HIV infected patients. These observations suggest that HIV-1 infection may affect processes important during early stages of hematopoiesis or stem cell differentiation. Hematopoietic abnormalities may be caused by altered stem cell differentiation possibly due to abnormal lineage specific expression of certain cellular genes such as cytokines relevant to hematopoiesis. These cytokines could affect regulatory signals important in hematopoiesis. However, in HIV infected individuals, it is not only the virus but also the highly active antiretroviral therapy (HAART) that both contribute to persistent hematopoietic suppression and ensuing cytopenias. Even if a lowering of HIV replication by HAART were to occur in infected individuals, prolonged HAART by itself and/or appearance of drug resistant mutants can contribute to hematopoietic suppression and resulting cytopenias. However, confounding factors such as opportunistic infections, immune mediated effects, or the consequences of prolonged physiological stress, which could contribute to decreased hematopoiesis in patients or other individuals, make the causative role of HIV in vivo, uncertain. The severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues (SCID-hu) is a small animal model which mimics HIV infection in humans, and is useful to determine the mechanisms of HIV-1 induced hematopoietic inhibition and development of drug therapies for interventions of stem cell differentiation. Further, SCID mouse serves as a useful small animal recipient of human progenitor cells and also allows us to study the differentiation of these cells in vivo. Results from our studies are expected to provide relief for HIV infected individuals from hematopoietic inhibition and ensuing cytopenias.