Sequence Variations in Human Immunodeficiency Virus Type 1 Nef Are Associated with Different Stages of Disease

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Journal of Virology, July 1999, p. 5497-5508, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Sequence Variations in Human Immunodeficiency Virus Type 1 Nef Are Associated with Different Stages of Disease

Frank Kirchhoff,¹^,^* Philippa J. Easterbrook,² Nigel Douglas,³ Maxine Troop,² Thomas C. Greenough,⁴ Jonathan Weber,⁵ Silke Carl,¹ John L. Sullivan,⁴ and Rod S. Daniels³

Institute for Clinical and Molecular Virology, Friedrich-Alexander University, D-91054 Erlangen, Germany¹; HIV Epidemiology Unit, Chelsea & Westminster Hospital, Imperial College School of Medicine, London SW10 9NH,² Virology Division, National Institute for Medical Research, London NW7 1AA,³ and Imperial College School of Medicine, Jefferiss Research Trust Laboratories, London W2 1PG,⁵ United Kingdom; and Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester, Massachusetts 01605⁴

Received 1 September 1998/Accepted 5 March 1999

nef alleles derived from a large number of individuals infected with human immunodeficiency virus type 1 (HIV-1) were analyzedto investigate the frequency of disrupted nef genes and to elucidatewhether specific amino acid substitutions in Nef are associatedwith different stages of disease. We confirm that deletions orgross abnormalities in nef are rarely present. However, a comparisonof Nef consensus sequences derived from 41 long-term nonprogressorsand from 50 individuals with progressive HIV-1 infection revealedthat specific variations are associated with different stagesof infection. Five amino acid variations in Nef (T15, N51, H102,L170, and E182) were more frequently observed among nonprogressors,while nine features (an additional N-terminal PxxP motif, A15,R39, T51, T157, C163, N169, Q170, and M182) were more frequentlyfound in progressors. Strong correlations between the frequencyof these variations in Nef and both the CD4⁺-cell count and the viral load were observed. Moreover, analysisof sequential samples obtained from two progressors revealed thatseveral variations in Nef, which were more commonly observed inpatients with low CD4⁺-T-cell counts, were detected only during or after progressionto immunodeficiency. Our results indicate that sequence variationsin Nef are associated with different stages of HIV-1 infectionand suggest a link between nef gene function and the immune statusof the infectedindividual.

^* Corresponding author. Mailing address: Institute for Clinical and Molecular Virology, Friedrich-Alexander University, Schlossgarten4, D-91054 Erlangen, Germany. Phone: 49-09131-856483. Fax: 49-09131-851002.E-mail: fkkirchh{at}viro.med.uni-erlangen.de.

Journal of Virology, July 1999, p. 5497-5508, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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