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Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4

Nature volume 395, pages 189–194 (1998)Cite this article

Abstract

CD8-positive T cells are thought to play an important role in the control of infection by human immunodeficiency virus (HIV) as a result of their cytotoxic activity and by releasing soluble factors1,2. In AIDS patients, the absolute number of CD8+ T lymphocytes is decreased in peripheral blood3,4 and their turnover rate is increased, suggesting that there is more cell renewal and cell death occurring5. Anti-retroviral therapy raises CD8+ T-cell counts in HIV-infected patients6,7,8. Here we report that the death rate of CD8+ T cells by apoptosis increased markedly during HIV infection of peripheral blood mononuclear cells in vitro. Apoptosis is induced in a dose-dependent manner by recombinant envelope glycoprotein gp120 from HIV strain X4, or by stromal-derived factor-1 (SDF-1), the physiological ligand of the chemokine receptor CXCR4. Apoptosis is mediated by the interaction between tumour-necrosis factor-α bound to the membrane of macrophages (mbTNF) and a receptor on CD8+ T cells (TNF-receptor II, or TNFRII). The expression of both of these cell-surface proteins is upregulated by HIV infection or by treatment with recombinant gp120 or SDF-1. Apoptosis of CD8+ T cells isolated from HIV-infected patients is also mediated by macrophages through the interaction between mbTNF and TNFRII. These results indicate that the increased turnover of CD8+ T cells in HIV-infected subjects is mediated by the HIV envelope protein through the CXCR4 chemokine receptor.

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Figure 1: HIV-1 infection enhances macrophage-mediated apoptosis of CD8+ T lymphocytes.
Figure 2: Recombinant gp120 activates macrophages via CXCR4 to kill CD8+ T lymphocytes.
Figure 3: Induction of CD8+-T-cell apoptosis during HIV infection or in response to rgp120 and SDF-1 is dependent on interaction between TNF and TNF receptor II.
Figure 4: Induction of mbTNF expression in macrophages by HIV infection or envelope is mediated by CXCR4 or CCR5.
Figure 5: Selective induction of TNF receptor II on CD8+ T cells by CXCR4 activation.

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Acknowledgements

We thank C. Amella for help with RT assays; D. Schepp for blood from HIV-infected patients; M. Grell, J. Nichols, N. Roberts, H. Schmidmayerova and B. Sherry for discussion; N. Shea for graphics; G. Howard and S. Ordway for editing the manuscript; and the AIDS Research and Reference Reagent Program (NIAID, NIH, PHS) for reagents. This work was supported in part by grants from the NIH of the US Public Health Service (to E.V.), by institutional funds from the Picower Institute for Medical Research, the University of Texas Medical Branch, and the Gladstone Institute of Virology and Immunology.

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Authors and Affiliations

  1. The Picower Institute for Medical Research, Manhasset, 11010, New York, USA

    Georges Herbein, Ulrich Mahlknecht & Eric Verdin

  2. Department of Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, 77555, Texas, USA

    Georges Herbein, Todd Pappas, John Butler & William A. O'Brien

  3. Division of Biology and Human Genetics, Department of Medicine, North Shore University Hospital/Cornell University Medical College, Manhasset, 11030, New York, USA

    Franak Batliwalla & Peter Gregersen

  4. The Gladstone Institute of Virology and Immunology, PO Box 419100

    Eric Verdin

  5. University of California at San Francisco, California, 94141-9100, USA

    Eric Verdin

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Correspondence to Eric Verdin.

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Herbein, G., Mahlknecht, U., Batliwalla, F. et al. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature 395, 189–194 (1998). https://doi.org/10.1038/26026

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