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Journal of Virology, April 2005, p. 4720-4729, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4720-4729.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role of the Specific Amino Acid Sequence of the Membrane-Spanning Domain of Human Immunodeficiency Virus Type 1 in Membrane Fusion

Kosuke Miyauchi,1 Jun Komano,1 Yoshiyuki Yokomaku,2 Wataru Sugiura,3 Naoki Yamamoto,1,3 and Zene Matsuda1*

Laboratory of Virology and Pathogenesis,1 Therapeutic Research and Clinical Science Group, AIDS Research Center, National Institute of Infectious Diseases, Tokyo,3 Division of Control and Treatment of Infectious Diseases, Chiba University Hospital, Chiba, Japan2

Received 16 July 2004/ Accepted 6 December 2004

Fusion between cell and virus membranes mediated by gp41 initiates the life cycle of human immunodeficiency virus type 1. In contrast to the many studies that have elucidated the structure-function relationship of the ectodomain, the study of the membrane-spanning domain (MSD) has been rather limited. In particular, the role that the MSD's specific amino acid sequences may have in membrane fusion as well as other gp41 functions is not well understood. The MSD of gp41 contains well-conserved glycine residues that form the GXXXG motif (G, glycine; X, other amino acid residues), a motif often found at the helix-helix interface of membrane spanning {alpha}-helices. Here we examined the role that the specific amino acid sequence of the gp41 MSD has in gp41 function, particularly in membrane fusion, by making two types of MSD mutants: (i) glycine substitution mutants in which glycine residues of the MSD were mutated to alanine or leucine residues, and (ii) replacement mutants in which the entire MSD was replaced with one derived from glycophorin A or from vesicular stomatitis virus G. The substitution of glycines did not affect gp41 function. MSD-replacement mutants, however, showed severely impaired fusion activity. The assay using the Env expression vector revealed defects in membrane fusion after CD4 binding steps in the MSD-replacement mutants. In addition, the change in Env processing was noted for MSD-replacement mutants. These results suggest that the MSD of gp41 has a relatively wide but not unlimited tolerance for mutations and plays a critical role in membrane fusion as well as in other steps of Env biogenesis.

* Corresponding author. Mailing address: Laboratory of Virology and Pathogenesis, AIDS Research Center, National Institute of Infectious Diseases, 4-7-1 Gakuen Musashimurayama, Tokyo 208-0011, Japan. Phone: 81-42-561-0771-335. Fax: 81-42-562-7875. E-mail: zmatsuda{at}nih.go.jp.

Journal of Virology, April 2005, p. 4720-4729, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4720-4729.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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