HIV-1-RELATED MECHANISMS OF SUPPRESSION OF CD34+ HEMATOPOIETIC PROGENITORS

Peripheral blood cytopenias and bone marrow abnormalities are frequent ly observed in HIV-1-seropositive subjects. Two major mechanisms have been proposed to explain the hematopoietic failure often observed in p atients with advanced HIV-1 disease: (i) infection of cells composing the bone marrow microenvironment with a deranged production of hematop oietic growth factors; (ii) direct suppression of hematopoietic progen itor cells mediated by HIV-1 virions and/or viral proteins. In vivo an d in vitro experimental evidence supports a combination of both mechan isms. In fact, it has been shown that: (i) infection with HIV-1 and/or exposure of bone marrow accessory cells to envelope glycoprotein 120 (env gp 120) increases the production of inhibitory cytokines such as tumor necrosis factor alpha; (ii) a subset of CD34+ hematopoietic prog enitor cells co-expresses the CD4 antigen and may be infected in vivo with HIV-1; (iii) HIV-1 virions or immune complexes containing env gp1 20 are able to induce apoptosis of uninfected CD34+ hematopoietic prog enitors. This last inhibitory effect appears to be mediated by the upr egulation of transforming growth factor beta(1), which is endogenously produced by hematopoietic progenitors. Both the load and the biologic al characteristics of the virus play an important role in causing thes e suppressive effects, since different HIV-1 isolates display varying abilities to suppress hematopoiesis, and some isolates are not cytopat hic at all.