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Journal of Virology, January 2009, p. 662-672, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01328-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Continuous Viral Escape and Selection by Autologous Neutralizing Antibodies in Drug-Naïve Human Immunodeficiency Virus Controllers{triangledown}

Madhumita Mahalanabis,1,{dagger} Pushpa Jayaraman,6,{ddagger} Toshiyuki Miura,5 Florencia Pereyra,5 E. Michael Chester,4 Barbra Richardson,3 Bruce Walker,5 and Nancy L. Haigwood1,2,6,§*

Departments of Microbiology,1 Pathobiology,2 Biostatistics,3 Medicine, University of Washington, Seattle, Washington 98195,4 Partners AIDS Research Center and Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129,5 Seattle Biomedical Research Institute, Seattle, Washington 981096

Received 25 June 2008/ Accepted 23 October 2008

We assessed differences in the character and specificity of autologous neutralizing antibodies (ANAbs) against individual viral variants of the quasispecies in a cohort of drug-naïve subjects with long-term controlled human immunodeficiency virus type 1 (HIV-1) infection and moderate levels of broad heterologous neutralizing antibodies (HNAb). Functional plasma virus showed continuous env evolution despite a short time frame and low levels of viral replication. Neutralization-sensitive variants dominated in subjects with intermittent viral blips, while neutralization-resistant variants predominated in elite controllers. By sequence analysis of this panel of autologous variants with various sensitivities to neutralization, we identified more than 30 residues in envelope proteins (Env) associated with resistance or sensitivity to ANAbs. The appearance of new sensitive variants is consistent with a model of continuous selection and turnover. Strong ANAb responses directed against autologous Env variants are present in long-term chronically infected individuals, suggesting a role for these responses in contributing to the durable control of HIV replication.

* Corresponding author. Mailing address: Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006. Phone: (503) 690-5500. Fax: (503) 690-5569. E-mail: haigwoon{at}ohsu.edu

{triangledown} Published ahead of print on 5 November 2008.

{dagger} Present address: Department of Biomedical Engineering, Boston University, Boston, MA 02115.

{ddagger} Present address: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.

§ Present address: Oregon National Primate Research Center, OHSU, Beaverton, OR 97006.

Journal of Virology, January 2009, p. 662-672, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01328-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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