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Journal of Virology, February 2006, p. 1311-1320, Vol. 80, No. 3
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.3.1311-1320.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Dynamic Evolution of the Human Immunodeficiency Virus Type 1 Pathogenic Factor, Nef{dagger}

Eduardo O'Neill,1 Lillian S. Kuo,1 John F. Krisko,1 Diana R. Tomchick,2 J. Victor Garcia,1* and John L. Foster1

Department of Internal Medicine, Division of Infectious Diseases,1 Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 753902

Received 15 September 2005/ Accepted 27 October 2005

The human immunodeficiency virus type 1 (HIV-1) early gene product Nef is a multifunctional protein that alters numerous pathways of T-cell function, including endocytosis, signal transduction, vesicular trafficking, and immune modulation, and is a major determinant of pathogenesis. Individual Nef functions include PAK-2 activation, CD4 downregulation, major histocompatibility complex (MHC) class I downregulation, and enhancement of viral particle infectivity. How Nef accomplishes its multiple tasks presents a difficult problem of mechanistic analysis because of the complications associated with multiple, overlapping functional domains in the context of significant sequence variability. To address these issues we determined the conservation of each Nef residue based on 1,643 subtype B Nef sequences. Mutational analysis based on conservative substitutions and Nef sequence data allowed us to search for amino acids on the surface of Nef that are specifically required for PAK-2 activation. We found residues 85, 89, and 191 to be highly significant determinants for Nef's PAK-2 activation function but functionally unlinked to CD4 and MHC class I downregulation or enhancement of infectivity. These residues are not conserved across HIV-1 subtypes but are confined to separate sets of surface elements within a subtype. Thus, L85/H89/F191 and F85/F89/R191 are dominant in subtype B and subtype E or C, respectively. Our results provide support for developing subtype-specific interventions in HIV-1 disease.

* 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. E-mail: victor.garcia{at}utsouthwestern.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, February 2006, p. 1311-1320, Vol. 80, No. 3
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.3.1311-1320.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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