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Journal of Virology, January 1999, p. 728-737, Vol. 73, No. 1
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Intrinsic Human Immunodeficiency Virus Type 1 Resistance of Hematopoietic Stem Cells Despite Coreceptor Expression

Hongmei Shen,1 Tao Cheng,1 Frederick I. Preffer,1 David Dombkowski,1 Michael H. Tomasson,2 David E. Golan,2 Otto Yang,1 Wolfgang Hofmann,3 Joseph G. Sodroski,3 Andrew D. Luster,1 and David T. Scadden1,*

AIDS Research Center, MGH Cancer Center, Divisions of Infectious Diseases and Hematology/Oncology, Massachusetts General Hospital, Department of Medicine,1 Division of Hematology/Oncology, Brigham and Women's Hospital, Department of Biological Chemistry and Molecular Pharmacology,2 and Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology,3 Harvard Medical School, Boston, Massachusetts

Received 17 September 1998/Accepted 12 October 1998

Interactions of human immunodeficiency virus type 1 (HIV-1) with hematopoietic stem cells may define restrictions on immune reconstitution following effective antiretroviral therapy and affect stem cell gene therapy strategies for AIDS. In the present study, we demonstrated mRNA and cell surface expression of HIV-1 receptors CD4 and the chemokine receptors CCR-5 and CXCR-4 in fractionated cells representing multiple stages of hematopoietic development. Chemokine receptor function was documented in subsets of cells by calcium flux in response to a cognate ligand. Productive infection by HIV-1 via these receptors was observed with the notable exception of stem cells, in which case the presence of CD4, CXCR-4, and CCR-5, as documented by single-cell analysis for expression and function, was insufficient for infection. Neither productive infection, transgene expression, nor virus entry was detectable following exposure of stem cells to either wild-type HIV-1 or lentivirus constructs pseudotyped in HIV-1 envelopes of macrophage-tropic, T-cell-tropic, or dualtropic specificity. Successful entry into stem cells of a vesicular stomatitis virus G protein-pseudotyped HIV-1 construct demonstrated that the resistance to HIV-1 was mediated at the level of virus-cell membrane fusion and entry. These data define the hematopoietic stem cell as a sanctuary cell which is resistant to HIV-1 infection by a mechanism independent of receptor and coreceptor expression that suggests a novel means of cellular protection from HIV-1.

* Corresponding author. Mailing address: AIDS Research Center, Massachusetts General Hospital, Bldg. 149, 13th St., Rm. 5212D, Boston, MA 02129. Phone: (617) 726-5615. Fax: (617) 726-4691. E-mail: scadden.david{at}mgh.harvard.edu.

Journal of Virology, January 1999, p. 728-737, Vol. 73, No. 1
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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