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Journal of Virology, March 2004, p. 2722-2728, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2722-2728.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

In Vivo Evolution of X4 Human Immunodeficiency Virus Type 1 Variants in the Natural Course of Infection Coincides with Decreasing Sensitivity to CXCR4 Antagonists

Evelien H. B. Stalmeijer,1,{dagger} Ronald P. van Rij,1,{dagger},{ddagger} Brigitte Boeser-Nunnink,1 Janny A. Visser,1 Marloes A. Naarding,1,§ Dominique Schols,2 and Hanneke Schuitemaker1*

Sanquin Research at CLB and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, The Netherlands,1 Laboratory of Experimental Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium2

Received 13 August 2003/ Accepted 11 November 2003

CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) variants evolve from CCR5-restricted (R5) HIV-1 variants. Early after their first appearance in vivo, X4 HIV-1 variants additionally use CCR5. The ability to use CCR5 in addition to CXCR4 is generally lost late in infection. Here we studied whether this evolution of the coreceptor repertoire is also reflected in a changing sensitivity of X4 variants to CXCR4 antagonists such as peptide T22 and the synthetic compound AMD3100. We observed differences in the concentrations of CXCR4 antagonists needed to suppress replication of X4 HIV variants from different patients. In general, late X4 HIV variants were less sensitive to AMD3100 than were early R5X4 HIV variants. The differences between early R5X4 HIV variants and late X4 variants were less pronounced for T22-mediated inhibition. These results suggest an ongoing evolution of X4 virus variants toward more efficient usage of the cellular entry complex.

* Corresponding author. Mailing address: Department of Clinical Viro-Immunology, Sanquin Research at CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. Phone: 31-20-5123317. Fax: 31-20-5123310. E-mail: h.schuitemaker{at}sanquin.nl.

{dagger} E.H.B.S. and R.P.V.R. contributed equally to this study.

{ddagger} Present address: Department of Microbiology and Immunobiology, University of California at San Francisco, San Francisco, CA 94143-2280.

§ Present address: Department of Human Retrovirology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.

Journal of Virology, March 2004, p. 2722-2728, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2722-2728.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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