The pathobiology of HIV mediated suppression of hematopoiesis appears to be complex and multifactorial. Direct productive HIV infection of CD34+ hematopoietic progenitors does not appear to explain the profound impairment in effective blood cell production seen in patients with AIDS. Rather, soluble mediators including the HIV envelope protein gp120 and inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) have been suggested as important inhibitors of hematopoiesis based on studies of progenitors in semisolid culture systems. Recently published data demonstrate impairment of stromal support of hematopoiesis in the more dynamic long term bone marrow culture (LTBMC) system following exposure to HIV. We propose to pursue the study of the pathogenesis of HIV mediated suppression of hematopoiesis in two novel culture systems using functionally selected primitive CD34+ hematopoietic progenitor cells: LTBMC yielding myeloid and erythroid elements and thymic stromal cultures yielding T lymphocytes. We shall focus on the effects of two categories of inhibitors, HIV proteins and myelosuppressive cytokines, in these systems. The LTBMC and thymic stromal culture systems will then be exploited to assess three potential strategies to augment hematopoiesis suppressed by HIV: (a) early acting hematopoietic growth factors which stimulate progenitor development; (b) anti-cytokine and anti-cytokine receptor antibodies; and (c) gene therapy using adeno-associated virus (AAV) vectors. AAV vectors appear to have a high transduction efficiency for resting target cells such as CD34 + progenitors, monocyte-macrophages and mature T lymphocytes. This integrated approach of characterizing candidate inhibitors of hematopoiesis and potential novel therapeutic interventions in culture systems of CD34+ progenitors should provide insights into both the mechanisms of impaired blood cell production and strategies to restore such production in patients with AIDS.
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