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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 analyzed to investigate the frequency of disrupted nef genes and to elucidate whether specific amino acid substitutions in Nef are associated with different stages of disease. We confirm that deletions or gross abnormalities in nef are rarely present. However, a comparison of Nef consensus sequences derived from 41 long-term nonprogressors and from 50 individuals with progressive HIV-1 infection revealed that specific variations are associated with different stages of 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 frequently found in progressors. Strong correlations between the frequency of these variations in Nef and both the CD4+-cell count and the viral load were observed. Moreover, analysis of sequential samples obtained from two progressors revealed that several variations in Nef, which were more commonly observed in patients with low CD4+-T-cell counts, were detected only during or after progression to immunodeficiency. Our results indicate that sequence variations in Nef are associated with different stages of HIV-1 infection and suggest a link between nef gene function and the immune status of the infected individual.

* Corresponding author. Mailing address: Institute for Clinical and Molecular Virology, Friedrich-Alexander University, Schlossgarten 4, 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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