Stem Cell Microenvironment in hiv Infection

HIV infection of stem cell microenvironments or niches causes hematopoietic inhibition and hence cytopenias [52-57]. Hematopoietic CD34+ progenitor stem cells are reported to be resistant to HIV-1 infection, in vitro, or in vivo [58, 59]. Those cells that experienced the indirect effects of HIV-1 infection exhibit inhibition of their multilineage hematopoiesis as determined by colony forming activity ex vivo [58, 60-62]. It is reported that the hematopoietic stem cell microenvironment is damaged due to the indirect effects of HIV-1 infection of the thymocytes on the CD34+ progenitor stem cells but in a reversible manner, in the human fetal Thymus/Liver conjoint hematopoietic organ of the transplanted chimeric severe combined immunodeficiency mouse (SCID-hu) model system [60, 62]. It is therefore highly plausible that this implanted human organ in the SCID-hu mouse, which serves as a niche, not only for thymocyte expansion but also supports hematopoiesis, suffers niche dysfunction due to HIV-1 infection. Continued presence of the CD34+ progenitor stem cells in the infected niche seem to suffer due to exacerbation resulting from persistent virus mediated niche disruption via infection of thymocytes and consequent interactions and signaling network of the hubs. In this microenvironment it is possible that several ARGs could produce different outcomes. This is evident from our previous observation that CCR4 and CCR5- tropic HIV-1 produce variable kinetics of inhibition of hematopoiesis [60].

Less understood is the role of different lymphoid organs in regards to the diminution of T cells in the gastrointestinal niche which is involved in HIV infection clinical outcome especially the genetic markers that contribute to AIDS progression. The intestinal mucosal immune system is an important target of HIV-1 infection and contributes to disease progression. In addition distinct gene expression profiles correlate with clinical outcome [63]. In this regard we wonder if the variable time of outcome of AIDS following HIV infection is related to several innate unknown mechanisms operating in the host. Independent of these is the fact that patients with HIV do not get diagnosed immediately after infection and the time of diagnosis could be variable taking sometimes several years. For example, we had access to the San Francisco database [46] and several individuals recruited for follow-up were first evaluated from 0 to 11 years and therefore the definition of long-term non-progression can only be analyzed after years of the date of known infection. In addition, some of such patients were censored after they had begun treatment. Only in those individuals followed from the time of infection it would be possible to demonstrate the role of genetic markers in viremia, and their participation in producing decreased CD4 counts and/or conversion to AIDS.

The transcription factors such as STAT5A are involved in stem cell self-renewal that precedes multilineage differentiation of CD34+ progenitor stem cells [64-69]. The proto-oncogene of myeloproliferative leukemia also known as thrombopoietin (Tpo) receptor proto-oncogene, c-mpl, is known to promote multi-lineage pluripotent stem cell differentiation of the CD34+ progenitor cells [70-73]. Both STAT5 and c-mpl are important target genes for control and enhancement of stem cell self-renewal and multi-lineage differentiation to reduce or prevent cytopenias induced during HIV infection [74]. We wonder if some individuals have highly regulated expression of STAT5A/B and c-mpl genes in progenitor cells and if in such individuals CD4 cells are generated in higher numbers than in those without such a regulated niche.

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