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HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration

Nature Neuroscience volume 6, pages 1064–1071 (2003)Cite this article

Abstract

The mechanisms of neurodegeneration that result in human immunodeficiency virus (HIV) type 1 dementia have not yet been identified. Here, we report that HIV-infected macrophages secrete the zymogen matrix metalloproteinase-2 (MMP-2), which is activated by exposure to MT1-MMP on neurons. Stromal cell–derived factor 1α (SDF-1), a chemokine overexpressed by astrocytes during HIV infection, was converted to a highly neurotoxic protein after precise proteolytic processing by active MMP-2, which removed the N-terminal tetrapeptide. Implantation of cleaved SDF-1(5–67) into the basal ganglia of mice resulted in neuronal death and inflammation with ensuing neurobehavioral deficits that were abrogated by neutralizing antibodies to SDF-1 and an MMP inhibitor drug. Hence, this study identifies a new in vivo neurotoxic pathway in which cleavage of a chemokine by an induced metalloproteinase results in neuronal apoptosis that leads to neurodegeneration.

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Figure 1: HIV infection of human macrophages induces neurotoxicity depending on input titer and HIV env expression and sequence.
Figure 2: Neurotoxic effects of MMP-2 and conditioned medium from HIV-infected macrophages.
Figure 3: SDF-1 is expressed by neurons and astrocytes and is neurotoxic.
Figure 4: In vivo neurological damage and neurobehavioral changes caused by SDF-1(5–67).

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Acknowledgements

This work is dedicated to the memory of I. Clark-Lewis (1955–2002). We thank J. Ethier, S. Henry and A. Hood for technical assistance and V.W. Yong and S. Robbins for helpful discussions. K.Z. is a Henri Toupin Medical Foundation Fellow. G.A.M. was supported by a National Cancer Institute of Canada studentship and J.B.J. was supported by an Alberta Heritage Foundation for Medical Research (AHFMR) studentship. I.C.L. was a Canadian Institutes of Health Research (CIHR) Investigator. C.M.O. holds a Canada Research Chair in Metalloproteinase Biology. C.P. is an AHFMR Scholar/CIHR Investigator. These studies were supported by the CIHR, Canadian Arthritis Network of Centers of Excellence, and Canadian Foundation for AIDS Research.

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Authors and Affiliations

  1. Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, Alberta, Canada

    Kunyan Zhang, Claudia Silva, James B Johnston & Christopher Power

  2. Departments of Biochemistry and Molecular Biology, University of British Columbia, 2199 Westbrook Mall, Vancouver, V6T 1Z3, British Columbia, Canada

    G Angus McQuibban, Ian Clark-Lewis & Christopher M Overall

  3. Departments of Oral Biological and Medical Sciences, University of British Columbia, 2199 Westbrook Mall, Vancouver, V6T 1Z3, British Columbia, Canada

    Georgina S Butler & Christopher M Overall

  4. Department of Pathology, University of British Columbia, 2199 Westbrook Mall, Vancouver, V6T 1Z3, British Columbia, Canada

    Janet Holden

  5. Department of Biomedical Research Centre, University of British Columbia, 2199 Westbrook Mall, Vancouver, V6T 1Z3, British Columbia, Canada

    Ian Clark-Lewis

  6. Department of Microbiology and Infectious Diseases, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, Alberta, Canada

    Christopher Power

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Zhang, K., McQuibban, G., Silva, C. et al. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat Neurosci 6, 1064–1071 (2003). https://doi.org/10.1038/nn1127

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