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Journal of Virology, February 2001, p. 1672-1680, Vol. 75, No. 4
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.4.1672-1680.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Genetic and Functional Diversity of Human Immunodeficiency Virus Type 1 Subtype B Nef Primary Isolates

John L. Foster,1 Rene P. Molina,1 Tianci Luo,2 Vivek K. Arora,1 Yaoxing Huang,3 David D. Ho,3 and J. Victor Garcia1,*

Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 753901; Genetic Therapy, Inc., Gaithersburg, Maryland 208792; and Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York 100163

Received 28 August 2000/Accepted 9 November 2000

We have characterized the functional integrity of seven primary Nef isolates: five from a long-term nonprogressing human immunodeficiency virus (HIV)-infected individual and one each from two patients with AIDS. One of the seven Nefs was defective for CD4 downregulation, two others were defective for PAK-2 activation, and one Nef was defective for PAK-2 activation and major histocompatibility complex (MHC) class I downregulation. Five of the Nefs were tested and found to be functional for the enhancement of virus particle infectivity. The structural basis for each of the functional defects has been analyzed by constructing a consensus nef, followed by mutational analysis of the variant amino acid residues. Mutations A29V and F193I were deleterious to CD4 downregulation and PAK-2 activation, respectively, while S189R rendered Nef defective for both MHC class I downregulation and PAK-2 activation. A search of the literature identified HIVs from five patients with Nefs predominantly mutated at F193 and from one patient with Nefs predominantly mutated at A29. A29 is highly conserved in all HIV subtypes except for subtype E. F193 is conserved in subtype B (and possibly in the closely related subtype D), but none of the other HIV group M subtypes. Our results suggest that functional distinctions may exist between HIV subtypes.

* Corresponding author. Mailing address: Department of Internal Medicine, Division of Infectious Diseases Y9.206, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9113. Phone: (214) 648-9970. Fax: (214) 648-0231. Email: victor.garcia{at}UTsouthwestern.edu.

Journal of Virology, February 2001, p. 1672-1680, Vol. 75, No. 4
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.4.1672-1680.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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