Modulation of Susceptibility to HIV-1 Infection by the Cytotoxic T Lymphocyte Antigen 4 Costimulatory Molecule

doi:10.1084/jem.191.11.1987

Published online 6 June 1999.

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© The Rockefeller University Press, 0022-1007/2000/6/1987/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 11, June 5, 2000 1987-1998

Original Article

Modulation of Susceptibility to HIV-1 Infection by the Cytotoxic T Lymphocyte Antigen 4 Costimulatory Molecule

James L. Riley^a, Katia Schlienger^a, Patrick J. Blair^b, Beatriz Carreno^c, Nancy Craighead^b, Daniel Kim^d, Richard G. Carroll^a, and Carl H. June^a
^a Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104
^b Transplant and Autoimmunity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20889
^c Genetics Institute, Incorporated, Cambridge, Massachusetts 02140
^d Division of Retrovirology, Walter Reed Army Institute of Research and Henry M. Jackson Foundation, Rockville, Maryland 20850

Correspondence to: Carl H. June, Department of Molecular and Cellular Engineering, University of Pennsylvania, BRB II/III, Rm. 554, 421 Curie Blvd., Philadelphia, PA 19104-6160. Tel:215-573-5745 Fax:215-573-8590 E-mail:cjune{at}mail.med.upenn.edu.

CD4 T cells activated in vitro by anti-CD3/28–coated beadsare resistant to infection by CC chemokine receptor 5 (CCR5)-dependentHIV-1 isolates. In vivo, antigen-presenting cells (APCs) activateCD4 T cells in part by signaling through the T cell receptorand CD28, yet cells stimulated in this manner are susceptibleto HIV-1 infection. We show that cytotoxic T lymphocyte antigen4 (CTLA-4) engagement counteracts the CD28 antiviral effects,and that the ratio of CTLA-4 to CD28 engagement determines thesusceptibility of HIV-1 infection. Furthermore, unopposed CTLA-4signaling provided by CD28 blockade promotes vigorous HIV-1replication, despite minimal T cell proliferation. Finally,CTLA-4 antibodies decrease the susceptibility of antigen-activatedCD4 T cells to HIV, suggesting a potential approach to preventor limit viral spread in HIV-1–infected individuals.

Key Words: HIV, costimulation, T cells, chemokine receptors, chemokines

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