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Journal of Virology, November 2001, p. 10113-10117, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10113-10117.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

CD4 Down-Modulation by Human Immunodeficiency Virus Type 1 Nef Correlates with the Efficiency of Viral Replication and with CD4+ T-Cell Depletion in Human Lymphoid Tissue Ex Vivo

Svetlana Glushakova,1 Jan Münch,2,dagger Silke Carl,2 Thomas C. Greenough,3 John L. Sullivan,3 Leonid Margolis,1,* and Frank Kirchhoff2,dagger ,*

The Laboratory of Molecular and Cellular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892,1 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605,3 and Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany2

Received 20 June 2001/Accepted 1 August 2001

The human immunodeficiency virus type 1 (HIV-1) Nef protein is an important virulence factor. Nef has several functions, including down-modulation of CD4 and class I major histocompatibility complex cell surface expression, enhancement of virion infectivity, and stimulation of viral replication in peripheral blood mononuclear cells. Nef also increases HIV-1 replication in human lymphoid tissue (HLT) ex vivo. We analyzed recombinant and primary nef alleles with highly divergent activity in different in vitro assays to clarify which of these Nef activities are functionally linked. Our results demonstrate that Nef activity in CD4 down-regulation correlates significantly with the efficiency of HIV-1 replication and with the severity of CD4+ T-cell depletion in HLT. In conclusion, HIV-1 Nef variants with increased activity in CD4 down-modulation would cause severe depletion of CD4+ T cells in lymphoid tissues and accelerate AIDS progression.

* Corresponding author. Mailing address for Frank Kirchhoff: Abteilung Virologie---Universitätsklinikum, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Phone: 49-731-50023344. Fax: 49-731-50023337. E-mail: frank.kirchhoff{at}medizin.uni-ulm.de. Mailing address for Leonid Margolis: National Institutes of Health, Building 10, Room 10D14, Bethesda, MD 20892. Phone: (301) 594-2476. Fax: (301) 480-0857. E-mail: margolis{at}helix.nih.gov.

dagger Present address: Abteilung Virologie---Universitätsklinikum, Albert-Einstein-Allee 11, 89081 Ulm, Germany.

Journal of Virology, November 2001, p. 10113-10117, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10113-10117.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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