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Journal of Virology, April 2002, p. 3852-3864, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3852-3864.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Variability in the Human Immunodeficiency Virus Type 1 gp120 Env Protein Linked to Phenotype-Associated Changes in the V3 Loop

Noah G. Hoffman,1,2 Francoise Seillier-Moiseiwitsch,2,3,{dagger} JaeHyung Ahn,3 Jason M. Walker,2 and Ronald Swanstrom1,2*

Department of Microbiology and Immunology,1 UNC Center for AIDS Research,2 Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-72953

Received 13 July 2001/ Accepted 21 December 2001

Isolates of human immunodeficiency virus type 1 (HIV-1) are classified according to the chemokine receptor (coreceptor) used in conjunction with CD4 to target and enter cells: viruses using CCR5 and CXCR4 are classified as R5 and X4, respectively. The major determinant of entry-related HIV-1 phenotypes is known to reside in the third variable region of gp120 (V3). It is clear, however, that positions outside of V3 play some role in influencing phenotype, although marked context dependence and extensive variability among HIV-1 isolates have made the identification of these positions difficult. We used the presence of previously described substitutions in V3 to classify a large set of HIV-1 subtype B gp120 sequences available in public databases as X4-like or R5-like. Using these classifications, we searched for positions outside of V3 where either amino acid composition or variability differed significantly among sequences of different inferred phenotypes. Our approach took the epidemiological relationships among sequences into account. A cluster of positions linked to changes in V3 was identified between amino acids 190 and 204 of gp120, immediately C-terminal of V2; changes at position 440 in C4 were also linked to inferred phenotype. Structural data place these positions at the coreceptor-binding face of gp120 in a surface-exposed location. We also noted a significant increase in net positive charge in a highly variable region of V2. This study both confirms previous observations and predicts specific positions that contribute to a functional relationship between V3, V2, and C4.

* Corresponding author. Mailing address: 22-006 LCCC CB# 7295, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295. Phone: (919) 966-5710. Fax: (919) 966-8212. E-mail: risunc{at}med.unc.edu.

{dagger} Present address: Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Md.

Journal of Virology, April 2002, p. 3852-3864, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3852-3864.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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