Multiple Effector Functions Mediated by Human Immunodeficiency Virus-Specific CD4+ T-Cell Clones

doi:10.1128/JVI.75.20.9771-9779.2001

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Journal of Virology, October 2001, p. 9771-9779, Vol. 75, No. 20
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.20.9771-9779.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Multiple Effector Functions Mediated by Human Immunodeficiency Virus-Specific CD4⁺ T-Cell Clones

Philip J. Norris,¹ Marina Sumaroka,² Christian Brander,¹ Howell F. Moffett,¹ Steven L. Boswell,³ Tam Nguyen,¹ Yuri Sykulev,² Bruce D. Walker,¹ and Eric S. Rosenberg¹^,^*

Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114¹; Department of Microbiology and Immunology and Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107²; and Fenway Community Health Center, Boston, Massachusetts 02115³

Received 13 April 2001/Accepted 6 July 2001

Mounting evidence suggests that human immunodeficiency virus type 1 (HIV-1) Gag-specific T helper cells contribute to effectiveantiviral control, but their functional characteristics and theprecise epitopes targeted by this response remain to be defined.In this study, we generated CD4⁺ T-cell clones specific for Gag from HIV-1-infected persons withvigorous Gag-specific responses detectable in peripheral bloodmononuclear cells. Multiple peptides containing T helper epitopeswere identified, including a minimal peptide, VHAGPIAG (aminoacids 218 to 226), in the cyclophilin binding domain of Gag. Peptiderecognition by all clones examined induced cell proliferation,gamma interferon (IFN- $gamma$ ) secretion, and cytolytic activity. Cytolysiswas abrogated by concanamycin A and EGTA but not brefeldin A oranti-Fas antibody, implying a perforin-mediated mechanism of celllysis. Additionally, serine esterase release into the extracellularmedium, a marker for cytolytic granules, was demonstrated in anantigen-specific, dose-dependent fashion. These data indicatethat T helper cells can target multiple regions of the p24 Gagprotein and suggest that cytolytic activity may be a componentof the antiviral effect of thesecells.

^* Corresponding author. Mailing address: Massachusetts General Hospital, GRJ 504, 55 Fruit St., Boston, MA 02114. Phone: (617)724-7519. Fax: (617) 726-7416. E-mail: erosenberg1{at}partners.org.

Journal of Virology, October 2001, p. 9771-9779, Vol. 75, No. 20
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.20.9771-9779.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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