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Journal of Virology, October 1998, p. 8061-8072, Vol. 72, No. 10
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Molecular and Cellular Analysis of Human Immunodeficiency Virus-Induced Apoptosis in Lymphoblastoid T-Cell-Line-Expressing Wild-Type and Mutated CD4 Receptors

Laure Moutouh,1 Jérôme Estaquier,2 Douglas D. Richman,1,3 and Jacques Corbeil1,*

Departments of Pathology and Medicine, University of California San Diego, La Jolla, California 92093-06791; INSERM CJF 97-07, Groupe Hospitalier Claude-Bernard Bichat, 75877 Paris, France2; and San Diego Veterans Affairs Medical Center, San Diego, California 921613

Received 13 January 1998/Accepted 17 June 1998

We have previously shown that the presence of the CD4 cytoplasmic tail is critical for human immunodeficiency virus (HIV)-induced apoptosis (J. Corbeil, M. Tremblay, and D. D. Richman, J. Exp. Med. 183:39-48, 1996). We have pursued our investigation of the role of the CD4 transduction pathway in HIV-induced apoptosis. To do this, wild-type and mutant forms of the CD4 cytoplasmic tail were stably expressed in the lymphoblastoid T-cell line A2.01. Apoptosis was prevented when CD4 truncated at residue 402 was expressed; however, cells expressing mutated receptors that do not associate with p56lck (mutated at the dicysteine motif and truncated at residue 418) but which conserved proximal domains of the cytoplasmic tail underwent apoptosis like wild-type CD4. The differences between wild-type and mutated receptors in the induction of apoptosis were not related to levels of p56lck or NF-kappa B activation. Initial signaling through the CD4 receptor played a major role in the sensitization of HIV-infected T cells to undergo apoptosis. Incubation of HIV-infected cells with monoclonal antibody (MAb) 13B8-2, which binds to CD4 in a region critical for dimerization of the receptor, prevented apoptosis without inhibiting HIV replication. Moreover, the apoptotic process was not related to Fas-Fas ligand interaction; however, an antagonistic anti-Fas MAb (ZB-4) enhanced apoptosis in HIV-infected cells without inducing apoptosis in uninfected cells. These observations demonstrate that CD4 signaling mediates HIV-induced apoptosis by a mechanism independent of Fas-Fas ligand interaction, does not require p56lck signaling, and may involve a critical region for CD4 dimerization.

* Corresponding author. Mailing address: Department of Medicine, University of California San Diego, Clinical Sciences Bldg., Rm. 325, 9500 Gilman Dr., La Jolla, CA 92093-0679. Phone: (619) 552-4339. Fax: (619) 552-7445. E-mail: jcorbeil{at}ucsd.edu.

Journal of Virology, October 1998, p. 8061-8072, Vol. 72, No. 10
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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