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Journal of Virology, May 2003, p. 5846-5854, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5846-5854.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vivo Evolution of Human Immunodeficiency Virus Type 1 toward Increased Pathogenicity through CXCR4-Mediated Killing of Uninfected CD4 T Cells

Andreas Jekle,1* Oliver T. Keppler,1,{dagger} Erik De Clercq,2 Dominique Schols,2 Mark Weinstein,3 and Mark A. Goldsmith1,4,{ddagger}

Gladstone Institute of Virology and Immunology,1 Department of Pathology, General Hospital,3 Department of Medicine, University of California at San Francisco, San Francisco, California 94141-9100,4 Rega Institute for Medical Research, B-3000 Leuven, Belgium2

Received 4 December 2002/ Accepted 18 February 2003

The destruction of the immune system by progressive loss of CD4 T cells is the hallmark of AIDS. CCR5-dependent (R5) human immunodeficiency virus type 1 (HIV-1) isolates predominate in the early, asymptomatic stages of HIV-1 infection, while CXCR4-dependent (X4) isolates typically emerge at later stages, frequently coinciding with a rapid decline in CD4 T cells. Lymphocyte killing in vivo primarily occurs through apoptosis, but the importance of apoptosis of HIV-1-infected cells relative to apoptosis of uninfected bystander cells is controversial. Here we show that in human lymphoid tissues ex vivo, apoptosis of uninfected bystander CD4 T cells is a major mechanism of lymphocyte depletion caused by X4 HIV-1 strains but is only a minor mechanism of depletion by R5 strains. Further, X4 HIV-1-induced bystander apoptosis requires the interaction of the viral envelope glycoprotein gp120 with the CXCR4 coreceptor on CD4 T cells. These results emphasize the contribution of bystander apoptosis to HIV-1 cytotoxicity and suggest that in association with a coreceptor switch in HIV disease, T-cell killing evolves from an infection-restricted stage to generalized toxicity that involves a high degree of bystander apoptosis.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA 94141-9100. Phone: (415) 695-3803. Fax: (415) 695-1364. E-mail: ajekle{at}gladstone.ucsf.edu.

{dagger} Present address: Department of Virology, University of Heidelberg, 69120 Heidelberg, Germany.

{ddagger} Present address: Genencor International, Inc., Palo Alto, CA 94304.

Journal of Virology, May 2003, p. 5846-5854, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5846-5854.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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