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Journal of Virology, October 2006, p. 9519-9529, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00575-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Selection on the Human Immunodeficiency Virus Type 1 Proteome following Primary Infection§

Yi Liu,1,{dagger} John McNevin,4,{dagger} Jianhong Cao,4 Hong Zhao,1 Indira Genowati,1 Kim Wong,1 Sherry McLaughlin,1 Matthew D. McSweyn,4 Kurt Diem,2 Claire E. Stevens,2 Janine Maenza,2 Hongxia He,1 David C. Nickle,1 Daniel Shriner,1,{ddagger} Sarah E. Holte,5 Ann C. Collier,2 Lawrence Corey,1,2,3,4 M. Juliana McElrath,2,3,4 and James I. Mullins1,2,3*

Departments of Microbiology,1 Medicine,2 Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington 98195,3 Program in Infectious Diseases,4 Program in Biostatistics and Biomathematics, Fred Hutchinson Cancer Research Center, Seattle, Washington 981095

Received 20 March 2006/ Accepted 8 July 2006

Typically during human immunodeficiency virus type 1 (HIV-1) infection, a nearly homogeneous viral population first emerges and then diversifies over time due to selective forces that are poorly understood. To identify these forces, we conducted an intensive longitudinal study of viral genetic changes and T-cell immunity in one subject at ≤17 time points during his first 3 years of infection, and in his infecting partner near the time of transmission. Autologous peptides covering amino acid sites inferred to be under positive selection were powerful for identifying HIV-1-specific cytotoxic-T-lymphocyte (CTL) epitopes. Positive selection and mutations resulting in escape from CTLs occurred across the viral proteome. We detected 25 CTL epitopes, including 14 previously unreported. Seven new epitopes mapped to the viral Env protein, emphasizing Env as a major target of CTLs. One-third of the selected sites were associated with epitopic mutational escapes from CTLs. Most of these resulted from replacement with amino acids found at low database frequency. Another one-third represented acquisition of amino acids found at high database frequency, suggesting potential reversions of CTL epitopic sites recognized by the immune system of the transmitting partner and mutation toward improved viral fitness in the absence of immune targeting within the recipient. A majority of the remaining selected sites occurred in the envelope protein and may have been subjected to humoral immune selection. Hence, a majority of the amino acids undergoing selection in this subject appeared to result from fitness-balanced CTL selection, confirming CTLs as a dominant selective force in HIV-1 infection.

* Corresponding author. Mailing address: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195-8070. Phone: (206) 732-6163. Fax: (206) 732-6167. E-mail: jmullins{at}u.washington.edu.

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

{dagger} These authors contributed equally to this work.

{ddagger} Present address: University of Alabama, RPHB 327, 1530 3rd Ave. S, Birmingham, AL 35294-0022.

Journal of Virology, October 2006, p. 9519-9529, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00575-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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