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Journal of Virology, November 2006, p. 11019-11030, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01382-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Fusion-Induced Apoptosis Contributes to Thymocyte Depletion by a Pathogenic Human Immunodeficiency Virus Type 1 Envelope in the Human Thymus{triangledown}

Eric G. Meissner,1,2 Liguo Zhang,1,2 S. Jiang,3 and Lishan Su1,2*

Department of Microbiology and Immunology,1 The Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599,2 The Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 100213

Received 30 June 2006/ Accepted 30 August 2006

The mechanisms of CD4+ T-cell depletion during human immunodeficiency virus type 1 (HIV-1) infection remain incompletely characterized. Of particular importance is how CD4+ T cells are depleted within the lymphoid organs, including the lymph nodes and thymus. Herein we characterize the pathogenic mechanisms of an envelope from a rapid progressor (R3A Env) in the NL4-3 backbone (NL4-R3A) which is able to efficiently replicate and deplete CD4+ thymocytes in the human fetal-thymus organ culture (HF-TOC). We demonstrate that uninterrupted replication is required for continual thymocyte depletion. During depletion, NL4-R3A induces an increase in thymocytes which uptake 7AAD, a marker of cell death, and which express active caspase-3, a marker of apoptosis. While 7AAD uptake is observed predominantly in uninfected thymocytes (p24–), active caspase-3 is expressed in both infected (p24+) and uninfected thymocytes (p24–). When added to HF-TOC with ongoing infection, the protease inhibitor saquinavir efficiently suppresses NL4-R3A replication. In contrast, the fusion inhibitors T20 and C34 allow for sustained HIV-1 production. Interestingly, T20 and C34 effectively prevent thymocyte depletion in spite of this sustained replication. Apoptosis of both p24– and p24+ thymocytes appears to be envelope fusion dependent, as T20, but not saquinavir, is capable of reducing thymocyte apoptosis. Together, our data support a model whereby pathogenic envelope-dependent fusion contributes to thymocyte depletion in HIV-1-infected thymus, correlated with induction of apoptosis in both p24+ and p24– thymocytes.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, CB#7295, Chapel Hill, NC 27599. Phone: (919) 966-6654. Fax: (919) 966-8212. E-mail: lsu{at}med.unc.edu.

{triangledown} Published ahead of print on 6 September 2006.

Journal of Virology, November 2006, p. 11019-11030, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01382-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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