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Journal of Virology, December 2003, p. 13376-13388, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13376-13388.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Improved Coreceptor Usage Prediction and Genotypic Monitoring of R5-to-X4 Transition by Motif Analysis of Human Immunodeficiency Virus Type 1 env V3 Loop Sequences

Mark A. Jensen,1* Fu-Sheng Li,1,{dagger} Angélique B. van ’t Wout,1 David C. Nickle,1 Daniel Shriner,1 Hong-Xia He,1 Sherry McLaughlin,1 Raj Shankarappa,2 Joseph B. Margolick,3 and James I. Mullins1

Department of Microbiology, University of Washington, Seattle, Washington 98195-8070,1 Allegheny-Singer Research Institute, Pittsburgh, Pennsylvania,2 Department of Molecular Microbiology and Immunology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland3

Received 10 February 2003/ Accepted 11 September 2003

Early in infection, human immunodeficiency virus type 1 (HIV-1) generally uses the CCR5 chemokine receptor (along with CD4) for cellular entry. In many HIV-1-infected individuals, viral genotypic changes arise that allow the virus to use CXCR4 (either in addition to CCR5 or alone) as an entry coreceptor. This switch has been associated with an acceleration of both CD3+ T-cell decline and progression to AIDS. While it is well known that the V3 loop of gp120 largely determines coreceptor usage and that positively charged residues in V3 play an important role, the process of genetic change in V3 leading to altered coreceptor usage is not well understood. Further, the methods for biological phenotyping of virus for research or clinical purposes are laborious, depend on sample availability, and present biosafety concerns, so reliable methods for sequence-based "virtual phenotyping" are desirable. We introduce a simple bioinformatic method of scoring V3 amino acid sequences that reliably predicts CXCR4 usage (sensitivity, 84%; specificity, 96%). This score (as determined on the basis of position-specific scoring matrices [PSSM]) can be interpreted as revealing a propensity to use CXCR4 as follows: known R5 viruses had low scores, R5X4 viruses had intermediate scores, and X4 viruses had high scores. Application of the PSSM scoring method to reconstructed virus phylogenies of 11 longitudinally sampled individuals revealed that the development of X4 viruses was generally gradual and involved the accumulation of multiple amino acid changes in V3. We found that X4 viruses were lost in two ways: by the dying off of an established X4 lineage or by mutation back to low-scoring V3 loops.

* Corresponding author. Mailing address: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195-8070. Phone: (206) 732-6102. Fax: (206) 732-6167. E-mail: majensen{at}u.washington.edu.

{dagger} Present address: Fred Hutchinson Cancer Research Center, MW-500, Seattle, WA 98109.

Journal of Virology, December 2003, p. 13376-13388, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13376-13388.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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