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

Overview

Journal J Stem Cells

Specialty Cell Biology

Date 2008 Nov 26

PMID 19030112

Citations 4

Authors

I Birgitta Sundell

Prasad S Koka

Affiliations

Soon will be listed here.

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.

Citing Articles

Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection.

Baldridge M, King K, Boles N, Weksberg D, Goodell M Nature. 2010; 465(7299):793-7.

PMID: 20535209 PMC: 2935898. DOI: 10.1038/nature09135.

Biomarkers of HIV-1-associated neurocognitive disorders: challenges of proteomic approaches.

Ciborowski P Biomark Med. 2010; 3(6):771-85.

PMID: 20477714 PMC: 3544489. DOI: 10.2217/bmm.09.63.

The utilization of humanized mouse models for the study of human retroviral infections.

Van Duyne R, Pedati C, Guendel I, Carpio L, Kehn-Hall K, Saifuddin M Retrovirology. 2009; 6:76.

PMID: 19674458 PMC: 2743631. DOI: 10.1186/1742-4690-6-76.

Natural Killer Cell Receptor NKG2A/HLA-E Interaction Dependent Differential Thymopoiesis of Hematopoietic Progenitor Cells Influences the Outcome of HIV Infection.

Yunis E, Romero V, Diaz-Giffero F, Zuniga J, Koka P J Stem Cells. 2008; 2(4):237-248.

PMID: 19005583 PMC: 2581831.

References

. Valganciclovir: new preparation. CMV retinitis: a simpler, oral treatment. Prescrire Int. 2003; 12(66):133-5. View

Li Z, Nardi M, Karpatkin S . Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia. Blood. 2005; 106(2):572-6. PMC: 1895171. DOI: 10.1182/blood-2005-01-0243. View

Michael N, Nelson J, Kewalramani V, Chang G, OBrien S, Mascola J . Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32. J Virol. 1998; 72(7):6040-7. PMC: 110409. DOI: 10.1128/JVI.72.7.6040-6047.1998. View

Lannutti B, Drachman J . Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors. Blood. 2004; 103(10):3736-43. DOI: 10.1182/blood-2003-10-3566. View

Emery S, Capra W, Cooper D, Mitsuyasu R, Kovacs J, Vig P . Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease. J Infect Dis. 2000; 182(2):428-34. DOI: 10.1086/315736. View

Nicolau D, Ross J, Quintiliani R, Nightingale C . Pharmacoeconomics of Pneumocystis carinii pneumonia in HIV-infected and HIV-noninfected patients. Pharmacoeconomics. 1996; 10(1):72-8. DOI: 10.2165/00019053-199610010-00007. View

Geissler R, Ottmann O, Kleiner K, Mentzel U, Bickelhaupt A, Hoelzer D . Decreased haematopoietic colony growth in long-term bone marrow cultures of HIV-positive patients. Res Virol. 1993; 144(1):69-73. DOI: 10.1016/s0923-2516(06)80014-2. View

Uittenbogaart C, Anisman D, Zack J, Economides A, Schmid I, HAYS E . Effects of cytokines on HIV-1 production by thymocytes. Thymus. 1994; 23(3-4):155-75. View

Tambussi G, Ghezzi S, Nozza S, Vallanti G, Magenta L, Guffanti M . Efficacy of low-dose intermittent subcutaneous interleukin (IL)--2 in antiviral drug--experienced human immunodeficiency virus--infected persons with detectable virus load: a controlled study of 3 il-2 regimens with antiviral drug therapy. J Infect Dis. 2001; 183(10):1476-84. DOI: 10.1086/320188. View

10.

Carbonara S, Fiorentino G, Serio G, Maggi P, Ingravallo G, Monno L . Response of severe HIV-associated thrombocytopenia to highly active antiretroviral therapy including protease inhibitors. J Infect. 2001; 42(4):251-6. DOI: 10.1053/jinf.2001.0833. View

11.

Burbano X, Miguez M, Lecusay R, Rodriguez A, Ruiz P, Morales G . Thrombocytopenia in HIV-infected drug users in the HAART era. Platelets. 2002; 12(8):456-61. DOI: 10.1080/09537100120093956. View

12.

Murphy M, Metcalfe P, Waters A, Carne C, Weller I, Linch D . Incidence and mechanism of neutropenia and thrombocytopenia in patients with human immunodeficiency virus infection. Br J Haematol. 1987; 66(3):337-40. DOI: 10.1111/j.1365-2141.1987.tb06920.x. View

13.

Dal Negro G, Vandin L, Bonato M, Repeto P, Sciuscio D . A new experimental protocol as an alternative to the colony-forming unit-granulocyte/macrophage (CFU-GM) clonogenic assay to assess the haematotoxic potential of new drugs. Toxicol In Vitro. 2005; 20(5):750-6. DOI: 10.1016/j.tiv.2005.10.015. View

14.

Dalgleish A, Beverley P, Clapham P, Crawford D, Greaves M, Weiss R . The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984; 312(5996):763-7. DOI: 10.1038/312763a0. View

15.

Safrin S, Finkelstein D, Feinberg J, Frame P, Simpson G, Wu A . Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108.... Ann Intern Med. 1996; 124(9):792-802. DOI: 10.7326/0003-4819-124-9-199605010-00003. View

16.

Lima J, Ribera A, Garcia-Bragado F, Monteagudo M, Martin-Vega C, Bastida M . Antiplatelet antibodies in primary infection by human immunodeficiency virus. Ann Intern Med. 1987; 106(2):333. DOI: 10.7326/0003-4819-106-2-333_2. View

17.

Ramsfjell V, Borge O, Cui L, Jacobsen S . Thrombopoietin directly and potently stimulates multilineage growth and progenitor cell expansion from primitive (CD34+ CD38-) human bone marrow progenitor cells: distinct and key interactions with the ligands for c-kit and flt3, and inhibitory.... J Immunol. 1997; 158(11):5169-77. View

18.

Moir S, Malaspina A, Li Y, Chun T, Lowe T, Adelsberger J . B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells. J Exp Med. 2000; 192(5):637-46. PMC: 2193277. DOI: 10.1084/jem.192.5.637. View

19.

Kimura S, Roberts A, Metcalf D, Alexander W . Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc Natl Acad Sci U S A. 1998; 95(3):1195-200. PMC: 18717. DOI: 10.1073/pnas.95.3.1195. View

20.

Levy J . HIV-1: hitching a ride on erythrocytes. Lancet. 2002; 359(9325):2212-3. DOI: 10.1016/S0140-6736(02)09314-5. View