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Journal of Virology, April 2002, p. 3338-3349, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3338-3349.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mutation of the Dominant Endocytosis Motif in Human Immunodeficiency Virus Type 1 gp41 Can Complement Matrix Mutations without Increasing Env Incorporation

John T. West,1 Sally K. Weldon,1 Stephanie Wyss,2 Xiaoxu Lin,1 Qin Yu,1 Markus Thali,3 and Eric Hunter1*

Department of Microbiology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-2170,1 Department of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,2 Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 954053

Received 10 August 2001/ Accepted 21 December 2001

The human immunodeficiency virus type 1 transmembrane glycoprotein (TM) is efficiently endocytosed in a clathrin-dependent manner. Internalization is mediated by a tyrosine-containing motif within the cytoplasmic domain, and replacement of the cytoplasmic tyrosine by cysteine or phenylalanine increased expression of mutant glycoprotein on the surface of transfected cells by as much as 2.5-fold. Because interactions between the cytoplasmic domain of Env and the matrix protein (MA) have been suggested to mediate incorporation of Env in virus particles, we examined whether perturbation of endocytosis would alter incorporation. Proviruses were constructed to contain the wild-type or mutant Env in conjunction with point mutations in MA that had previously been shown to block Env incorporation. These constructs were used to evaluate the effect of glycoprotein endocytosis on incorporation into virus particles and to test the necessity for a specific interaction between Env and MA to mediate incorporation. Viruses produced from transfected 293T cells were used to infect various cell lines, including MAGI, H9, and CEMx174. Viruses encoding both a disrupted endocytosis motif signal and mutations within MA were significantly more infectious in MAGI cells than their counterparts encoding a mutant MA and wild-type Env. This complementation of infectivity for the MA incorporation mutant viruses was not due to increased glycoprotein incorporation into particles but instead reflected an enhanced fusogenicity of the mutated Env proteins. Our findings further support the concept that a specific interaction between the long cytoplasmic domain of TM and MA is required for efficient incorporation of Env into assembling virions. Alteration of the endocytosis signal of Env, and the resulting increase in cell surface glycoprotein, has no effect on incorporation despite demonstrable effects on fusion, virus entry, and infectivity.

* Corresponding author. Mailing address: Department of Microbiology, The University of Alabama at Birmingham, BBRB 256, 1530 3rd Ave. S, Birmingham, AL 35294-2170. Phone: (205) 934-4321. Fax: (205) 934-1640. E-mail: ehunter{at}uab.edu.

Journal of Virology, April 2002, p. 3338-3349, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3338-3349.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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