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Journal of Virology, March 2002, p. 2683-2691, Vol. 76, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.6.2683-2691.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Truncation of the Cytoplasmic Domain Induces Exposure of Conserved Regions in the Ectodomain of Human Immunodeficiency Virus Type 1 Envelope Protein

Terri G. Edwards,1 Stéphanie Wyss,2 Jacqueline D. Reeves,1 Susan Zolla-Pazner,3,4 James A. Hoxie,2 Robert W. Doms,1* and Frédéric Baribaud1

Department of Microbiology,1 Hematology-Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,2 New York University School of Medicine, New York, New York 10016,3 Research Center for AIDS and HIV Infection, New York Harbor Veterans Affairs Medical Center, New York, New York 100104

Received 17 August 2001/ Accepted 12 December 2001

We have described a CD4-independent variant of HXBc2, termed 8x, that binds directly to CXCR4 and mediates CD4-independent virus infection. Determinants for CD4 independence map to residues in the V3 and V4-C4 domains together with a single nucleotide deletion in the transmembrane domain which introduces a frameshift (FS) at position 706. This FS results in a truncated cytoplasmic domain of 27 amino acids. We demonstrate here that while introduction of the 8x FS mutation into heterologous R5, X4, or R5X4 Env proteins did not impart CD4 independence, it did affect the conformation of the gp120 surface subunit, exposing highly conserved domains involved in both coreceptor and CD4 binding. In addition, antigenic changes in the gp41 ectodomain were also observed, consistent with the idea that the effects of cytoplasmic domain truncation must in some way be transmitted to the external gp120 subunit. Truncation of gp41 also resulted in the marked neutralization sensitivity of all Env proteins tested to human immunodeficiency virus-positive human sera and monoclonal antibodies directed against the CD4 or coreceptor-binding sites. These results demonstrate a structural interdependence between the cytoplasmic domain of gp41 and the ectodomain of the Env protein. They also may help explain why the length of the gp41 cytoplasmic domain is retained in vivo and may provide a way to genetically trigger the exposure of neutralization determinants in heterologous Env proteins that may prove useful for vaccine development.

* Corresponding author. Mailing address: Department of Microbiology, University of Pennsylvania, 225 Johnson Pavilion, 36th and Hamilton Walk, Philadelphia, PA 19104. Phone: (215) 898-0890. Fax: (215) 898-9557. E-mail: doms{at}mail.med.upenn.edu.

Journal of Virology, March 2002, p. 2683-2691, Vol. 76, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.6.2683-2691.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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