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Introduction
Hematopoietic stem cells which are present in bone marrow, cord blood and liver, terminally differentiate into multiple lineages of blood cell types and thus have applications in bone marrow transplantation. The determination of alleviation of cytopenias in HIV infection in vivo [severe combined immuno deficient transplanted with human fetal thymus and liver tissues, SCID-hu] has been utilized through assay of inhibition of hematopoietic stem cell colony formation ex vivo.1
Cytopenias or hematopoietic inhibition (decreased blood cells formation) is a common occurrence in HIV infected patients both due to the virus but also caused in synergistic manner by the antiretroviral drugs (AZT or Zidovudine, ddI, certain protease inhibitors).2 Experimental observations for the indirect inhibition of the hematopoietic CD34+ stem cell colony forming activity by HIV infected T-cells were previously proposed or reported by us elsewhere in 1990’sand also bysome other investigators, from other institutions.1
The potential biologically occurring which is non-specific to a single species, Sulfatide (3-O-sulfogalactosylceramide), has already been chemically synthesized and tested for its efficacy in severe combined immuno deficient mice transplanted with human fetal thymus and liver tissues (SCID-hu Thy/Liv).3 This includes both the pre-clinical observations of not only containment of replication of HIV-1, but also relevant to the in vivo developed implant derived hematopoietic CD34+ stem cells is the reduction of cytopenias, as assayed through inhibition of colony formation, ex vivo (Figure 1).
Figure 1 HIV-1 target CD4+ cellinfection and infection resistant CD34+ cell colony forming activity in HIV-1 infected human thymus/liver implant in SCID mice.
Figure 1: HIV-1 target CD4+ cellinfection and infection resistant CD34+ cell colony forming activity in HIV-1 infected human thymus/liver implant in SCID mice. Left row: HIV-1 infection; middle row: HIV-1+AZT; right row: HIV-1+sufatide treatment. First column: CD4+ cells; second column: megakaryocytic colonies; third column: erythroid colonies; fourth column: myeloid colonies. Koka et al.3 PMID: 23550344,4 Sulfatide = 3-O-sulfogalactosylceramide.
Further characterization and isoform chemical synthesis or isolation of biologically available candidate drug (3-O-sulfogalactosylceramide) for clinical trials without the side effects of the anti-HIV drugs in AIDS patients that also cause cytopenias, is required prior to its commercial development andproduction. Different isoforms of this drug would or should be tested at least in vitro or in collaboration for the possible detection of the most efficacious isoform of 3-O-sulfogalactosylceramide, to alleviate the cytopeniasin affected patients.
Although these studies were carried out in immuno deficient animals, the inter-species nature of sulfatide consists of at least partial or significant structure homology and thus could have a longer half-life in the circulatory system of immunocompetent humans. Even otherwise when some of the efficacious isoforms are chemically synthesized, it is a well- known fact that such drugs are commonly used in patients to treat various diseases despite side effects. The only possible expected side effect of excessive sulfatide is susceptibility to clotting for which an intake of aspirin could be co-prescribed with the sulfatide.4
This co-administration of sulfatide-aspirin combination could be part of the clinical trials with appropriate negative controls to determine the blood platelet levels and clotting factors as well, besides the CD4/CD8 ratios and deriving of CD34+ cells from bone marrow for the colony assays. However this invasive procedure would not be necessary since any changes in blood cell levels for the cytopenic conditions are detected through the CBC. In this regard, it is also noteworthy that at least a low dose aspirin is commonly suggested even for individuals beyond 45 years age despite no apparent evidence of heart disease to prevent unexpected heart attacks.
Clinical trials on this anti-cytopenic candidate drug, 3-O-sulfogalactosylceramide, would lead to patient treatments and thus commercialization of its (single most efficacious isoform), or their (multiple efficacious isoforms) through pharmaceutical manufacture for availability and access to affected patients. Thus these results comprise of translational research and applicable to (bench to bedside) translational medicine.
Acknowledgments
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Conflicts of interest
None.
References
- Koka PS, Kitchen CMR, Reddy ST (2004) Targeting c-Mpl for revival of human immunodeficiency virus type 1-induced he matopoietic inhibition when CD34+ progenitor cells are re-engrafted into a fresh stromal microenvironment in vivo. J Virol 78(20):11385-11392.
- Withers-Ward ES, Amado RG, Koka PS, Jamieson BD, Kaplan AH, et al. (1997) Transient renewal of thymopoiesis in HIV-infected human thymic implants following antiviral therapy. Nat Med 3(10):1102-1109.
- Sundell IB, Halder R, Zhang M, Maricic I, Koka PS, et al. (2005) Sulfatide administration leads to HIV-1 replication and enhances hematopoiesis. J Stem Cells 2005:5(1):33-42.
- Sundell IB, Cortado RV, Koka PS (2012) Sulfatide-A new candidate for ART treatment in HIV-1 infection. J Stem Cells 7(1):61-72.
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