Effects of HIV on the Development and Function of Bone Marrow Cells

Hematologic abnormalities occur with high frequency (up to 70% of patients) in human immunodeficiency virus (HIV) infected individuals. The pathogenesis of these abnormalities is not currently understood, although both an abnormal bone marrow environment (e.g., altered growth factor production) and direct infection and dysfunction of progenitor cells themselves have been postulated. Under the current protocol we have studied bone marrow precursor cells from both HIV infected and uninfected individuals and have shown not only that these cells are infectable in vitro with HIV but also infected in vivo in a subpopulation of seropositive individuals. While the effects of HIV infection of precursor cells on subsequent hematopoietic potential is not completely understood, we could not show a clear correlation between in vivo infection of these cells and suppressed hematopoiesis. It seems clear from this study and others that other alterations within the bone marrow environment must play a role in the clinically observed hematologic abnormalities. We therefore wish to continue our studies to elucidate the relative contributions of direct infection of myeloid progenitor cells and alterations in bone marrow environment in the pathology seen in HIV infected individuals. Understanding the pathogenesis of abnormal hematopoiesis in HIV infection will allow investigators to design appropriate therapeutic strategies. Using recently developed techniques we also wish to use bone marrow cells from HIV infected individuals to establish antibody libraries. This will allow the study of immunologically important epitopes on the HIV virion with potential impact on the subsequent design of HIV vaccines or introduction of passive immunotherapy. Thirdly, research in the field of HIV has been hampered by the lack of an appropriate animal model. One promising approach is the use of human bone marrow to reconstitute lethally irradiated Balb/c mice. Once the human hematopoietic system is established in the mouse, it may be possible to infect these animals with HIV and study in an in vivo model the effects of infection on hematopoiesis.