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Journal of Virology, February 2001, p. 1152-1164, Vol. 75, No. 3
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.3.1152-1164.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Partial Activation and Induction of Apoptosis in CD4+ and CD8+ T Lymphocytes by Conformationally Authentic Noninfectious Human Immunodeficiency Virus Type 1†

Mark T. Esser,1 Julian W. Bess Jr.,1 Kalachar Suryanarayana,1,Dagger Elena Chertova,1 Darlene Marti,2 Mary Carrington,2 Larry O. Arthur,1 and Jeffrey D. Lifson1,*

AIDS Vaccine Program1 and Intramural Research Support Program,2 SAIC-Frederick, National Cancer Institute Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

Received 23 August 2000/Accepted 6 November 2000

Increased levels of apoptosis are seen in human immunodeficiency virus (HIV) infection, and this has been proposed as an important mechanism contributing to HIV pathogenesis. However, interpretation of in vitro studies aimed at understanding HIV-related apoptosis has been complicated by the use of high concentrations of recombinant proteins or by direct cytopathic effects of replicating virus. We have developed an inactivation procedure that destroys retroviral infectivity while preserving the structural and functional integrity of the HIV surface proteins. These noninfectious virions interact authentically with target cells, providing a powerful tool to dissect mechanisms of HIV pathogenesis that do or do not require viral replication. Noninfectious CXCR4-tropic HIV-1 virions, but not microvesicles, partially activated freshly isolated CD4+ and CD8+ peripheral blood mononuclear cell T lymphocytes to express FasL and Fas, but not CD69 or CD25 (interleukin-2 receptor alpha) and eventually die via apoptosis starting 4 to 6 days postexposure. These effects required conformationally intact virions, as heat-denatured virions or equivalent amounts of recombinant gp120 did not induce apoptosis. The maximal apoptotic effect was dependent on major histocompatibility complex (MHC) class II proteins being present on the virion, but was not MHC restricted. The results suggest that the immunopathogenesis of HIV infection may not depend solely on direct cytopathic effects of HIV replication, but that effects due to noninfectious HIV-1 virions may also contribute importantly.

* Corresponding author, Mailing address: Building 535, Room 509, Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, MD 21702. Phone: (301) 846 5019. Fax: (301) 846 5588. E-mail: lifson{at}avpvx1.ncifcrf.gov.

dagger This paper is dedicated in loving memory of Kalachar Suryanarayana.

Dagger Deceased.

Journal of Virology, February 2001, p. 1152-1164, Vol. 75, No. 3
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.3.1152-1164.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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