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Journal of Virology, January 2004, p. 1026-1031, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.1026-1031.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Regulation of Human Immunodeficiency Virus Type 1 Env-Mediated Membrane Fusion by Viral Protease Activity

Tsutomu Murakami,1* Sherimay Ablan,2,{dagger} Eric O. Freed,2,{dagger} and Yuetsu Tanaka1

Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan,1 Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 208922

Received 18 July 2003/ Accepted 1 October 2003

We and others have presented evidence for a direct interaction between the matrix (MA) domain of the human immunodeficiency virus type 1 (HIV-1) Gag protein and the cytoplasmic tail of the transmembrane envelope (Env) glycoprotein gp41. In addition, it has been postulated that the MA domain of Gag undergoes a conformational change following Gag processing, and the cytoplasmic tail of gp41 has been shown to modulate Env-mediated membrane fusion activity. Together, these results raise the possibility that the interaction between the gp41 cytoplasmic tail and MA is regulated by protease (PR)-mediated Gag processing, perhaps affecting Env function. To examine whether Gag processing affects Env-mediated fusion, we compared the ability of wild-type (WT) HIV-1 Env and a mutant lacking the gp41 cytoplasmic tail to induce fusion in the context of an active (PR+) or inactive (PR-) viral PR. We observed that PR- virions bearing WT Env displayed defects in cell-cell fusion. Impaired fusion did not appear to be due to differences in the levels of virion-associated Env, in CD4-dependent binding to target cells, or in the formation of the CD4-induced gp41 six-helix bundle. Interestingly, truncation of the gp41 cytoplasmic tail reversed the fusion defect. These results suggest that interactions between unprocessed Gag and the gp41 cytoplasmic tail suppress fusion.

* Corresponding author. Mailing address: Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan. Phone: 81-98-895-1200. Fax: 81-98-895-1200. E-mail: tmura{at}med.u-ryukyu.ac.jp.

{dagger} Present address: HIV Drug Resistance Program, NCI-Frederick, Frederick, MD 21702.

Journal of Virology, January 2004, p. 1026-1031, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.1026-1031.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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