The Journal of Experimental Medicine
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Published online 5 June 2000.
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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. Rileya, Katia Schliengera, Patrick J. Blairb, Beatriz Carrenoc, Nancy Craigheadb, Daniel Kimd, Richard G. Carrolla, and Carl H. Junea

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
Department of Molecular and Cellular Engineering, University of Pennsylvania, BRB II/III, Rm. 554, 421 Curie Blvd., Philadelphia, PA 19104-6160.215-573-8590215-573-5745

cjune{at}mail.med.upenn.edu

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

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

Abbreviations used in this paper: allo, allogeneic; CCR5, CC chemokine receptor 5; CTLA-4, CTL antigen 4; CXCR4, CXC chemokine receptor 4; DC, dendritic cell; RANTES, regulated on activation, normal T cell expressed and secreted; MIP, macrophage inflammatory protein; RT, reverse transcriptase; TCID50, half-maximal tissue culture infectious dose; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; TT, tetanus toxoid.

© 2000 The Rockefeller University Press


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