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Journal of Virology, October 2004, p. 11385-11392, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.11385-11392.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Targeting c-Mpl for Revival of Human Immunodeficiency Virus Type 1-Induced Hematopoietic Inhibition When CD34+ Progenitor Cells Are Re-Engrafted into a Fresh Stromal Microenvironment In Vivo

Prasad S. Koka,1* Christina M. R. Kitchen,2 and Srinivasa T. Reddy1,3

Department of Molecular and Medical Pharmacology,1 Department of Biostatistics,2 Division of Cardiology, Department of Medicine, David Geffen School of Medicine and UCLA AIDS Institute, University of California, Los Angeles, California3

Received 8 April 2004/ Accepted 10 June 2004

The inhibition of multilineage hematopoiesis which occurs in the severe combined immunodeficiency mouse with transplanted human fetal thymus and liver tissues (SCID-hu Thy/Liv) due to human immunodeficiency virus type 1 (HIV-1) infection is also accompanied by a severe loss of c-Mpl expression on these progenitor cells. Inhibition of colony-forming activity (CFA) of the CD34+ progenitor cells is partially revived to about 40% of mock-infected Thy/Liv implants, following reconstitution of the CD34+ cells that were exposed to HIV-1 infection, in a new Thy/Liv stromal microenvironment of irradiated secondary SCID-hu recipients at 3 weeks post-re-engraftment. In addition, in these reconstituted animals, the proportion of c-Mpl+ CD34+ cells relative to c-Mpl– CD34+ cells increased by about 25%, to 35% of mock-infected implants, suggesting a reacquirement of c-Mpl phenotype by the c-Mpl– CD34+ cells. These results suggest a correlation between c-Mpl expression and multilineage CFA of the human CD34+ progenitor cells that have experienced the effects of HIV-1 infection. Treatment of the secondary-recipient animals with the c-Mpl ligand, thrombopoietin (Tpo), further increased c-Mpl expression and CFA of re-engrafted CD34+ cells previously exposed to virus in the primary implants to about 50 to 70% over that of those re-engrafted CD34+ cells derived from implants of untreated animals. Blocking of c-Mpl with anti-c-Mpl monoclonal antibody in vivo by injecting the SCID-hu animals resulted in the reduction or loss of CFA. Thus, inhibition, absence, or loss of c-Mpl expression as in the c-Mpl– CD34+ subset of cells is the likely cause of CFA inhibition. Further, CFA of the CD34+ cells segregates with their c-Mpl expression. Therefore, c-Mpl may play a role in hematopoietic inhibition during HIV-1 infection, and control of its expression levels may aid in hematopoietic recovery and thereby reduce the incidence of cytopenias occurring in infected individuals.

* Corresponding author. Mailing address: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, 23-120 CHS, 10833 Le Conte Ave., Los Angeles, CA 90095-1735. Phone: (310) 267-2750. Fax: (310) 825-6267. E-mail: pkoka{at}ucla.edu.

Journal of Virology, October 2004, p. 11385-11392, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.11385-11392.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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