Chimeric SCID-hu Model as a Human Hematopoietic Stem Cell Host That Recapitulates the Effects of HIV-1 on Bone Marrow Progenitors in Infected Patients

Abstract

The chimeric small animal model system wherein the severe combined immunodeficient mouse is transplanted with human fetal thymus and liver tissues (SCID-hu Thy/Liv) has been used in different areas of experimental research [1]. A living model system offers the advantage that studies of longer duration than in vitro can be performed. Here we discuss the importance of experimental in vivo studies and how well the data generated using this model system correlates with epidemiological studies from HIV-positive humans. Patients with HIV-1 infection often suffer from cytopenias, with thrombocytopenia typically having an earlier onset than anemia and neutropenia. The cytopenias in patients may be caused by virus effects at the stem cell level, or the mature blood cell level, or by other factors like medications used to treat the infection. Several studies preformed in SCID-hu animals show that the function of human hematopoietic progenitor stem cells are indirectly affected by HIV-1 infection. Colony forming activity (CFA) assays on hematopoietic progenitor cells derived from SCID-hu animals and human bone marrow have been performed as a measure of progenitor cellular function, and HIV-1 infection decreased CFA in multiple lineages that include megakaryoid, erythroid and myeloid types. Highly active antiretroviral therapy (HAART) partially and transiently reduces the inhibition of multilineage CFA and data suggest that HIV-1 indirectly affects stem cell differentiation into multiple lineages. The cojoint human hematopoietic organ of this small animal model system recapitulates the inhibitory effects of HIV-1 infection on the function of progenitor cells of the human bone marrow. Thus the SCID-hu (Thy/Liv) model is a useful in vivo system for preclinical translational research towards development of stem cell therapies in HIV infection.

Figure 1

Mature cells appearing in the blood of healthy humans.

Figure 2

Mature white blood cells in the blood of healthy humans. The mature T-cells are CD4+ lymphocytes, the CD8+ cells are less mature. The CD4+ cells are depleted by HIV-1 infection.

Figure 3

HIV-1 infection depletes the CD4+ T-cells, when there are fewer than 200 CD4⁺ T cells/μL of blood the diagnosis is AIDS is set. Progression of HIV-1 to AIDS can be slow even in the absence of antiretroviral therapy. The median time of progression from HIV infection to AIDS is 9 to 10 years, but the median survival time after developing AIDS is less than 1 year. When HIV can be treated with anti-viral therapy, treatment is recommended to commence when the CD4+ cells decrease below 200 cells/uL blood.

Figure 4

Platelets contribute to blood clotting by adhering to other platelets, and by secreting substances that activates plasma protein. A blood clot consists of platelets in a fibrin mesh net. The fibrin mesh can be dissolved by the process of fibrinolysis prior the maturation. Thrombocytopenia increases the risk for bleeding.

Figure 5

Megakaryocytes are bone marrow cells that produce platelets. Megakaryocytes do not divide as their DNA content increase. Megakaryocytes with a ploidy over 16N can produce platelets.