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Journal of Virology, November 2001, p. 10766-10778, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.10766-10778.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

CD4-Independent Use of Rhesus CCR5 by Human Immunodeficiency Virus Type 2 Implicates an Electrostatic Interaction between the CCR5 N Terminus and the gp120 C4 Domain

George Lin,1 Benhur Lee,2 Beth S. Haggarty,1 Robert W. Doms,3 and James A. Hoxie1,*

Department of Medicine, Hematology-Oncology Division,1 and Department of Microbiology,3 University of Pennsylvania, Philadelphia, Pennsylvania 19104, and Department of Microbiology, Immunology, and Molecular Genetics, UCLA AIDS Institute, University of California-Los Angeles, Los Angeles, California 900952

Received 16 May 2001/Accepted 31 July 2001

Envelope glycoproteins (Envs) of human immunodeficiency virus type 2 (HIV-2) are frequently able to use chemokine receptors, CXCR4 or CCR5, in the absence of CD4. However, while these Envs are commonly dual-tropic, no isolate has been described to date that is CD4 independent on both CXCR4 and CCR5. In this report we show that a variant of HIV-2/NIHz, termed HIV-2/vcp, previously shown to utilize CXCR4 without CD4, is also CD4 independent on rhesus (rh) CCR5, but requires CD4 to fuse with human (hu) CCR5. The critical determinant for this effect was an acidic amino acid at position 13 in the CCR5 N terminus, which is an asparagine in huCCR5 and an aspartic acid in rhCCR5. Transferring the huCCR5 N terminus with an N13D substitution to CCR2b or CXCR2 was sufficient to render these heterologous chemokine receptors permissive for CD4-independent fusion. Chimeric Envs between HIV-2/vcp and a CD4-dependent clone of HIV-2/NIHz as well as site-directed Env mutations implicated a positively charged amino acid (lysine or arginine) at position 427 in the C4 region of the HIV-2/vcp env gene product (VCP) gp120 as a key determinant for this phenotype. Because CD4-independent use of CCR5 mapped to a negatively charged amino acid in the CCR5 N terminus and a positively charged amino acid in the gp120 C4 domain, an electrostatic interaction between these residues or domains is likely. Although not required for CD4-dependent fusion, this interaction may serve to increase the binding affinity of Env and CCR5 and/or to facilitate subsequent conformational changes that are required for fusion. Because the structural requirements for chemokine receptor use by HIV are likely to be more stringent in the absence of CD4, CD4-independent viruses should be particularly useful in dissecting molecular events that are critical for viral entry.

* Corresponding author. Mailing address: Biomedical Research Building II/III, Room 356, University of Pennsylvania, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-0261. Fax: (215) 573-7356. E-mail: hoxie{at}mail.med.upenn.edu.

Journal of Virology, November 2001, p. 10766-10778, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.10766-10778.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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