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Journal of Virology, January 2009, p. 757-769, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.02036-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection{triangledown}

D. Noah Sather,1 Jakob Armann,1,2 Lance K. Ching,1,3 Angeliki Mavrantoni,1,4 George Sellhorn,1 Zachary Caldwell,1 Xuesong Yu,5 Blake Wood,5 Steve Self,5 Spyros Kalams,6 and Leonidas Stamatatos1,3*

Seattle Biomedical Research Institute, Seattle, Washington 98109,1 Ludwig-Maximilians-University, Munich, Germany,2 Department of Global Health, University of Washington, Seattle, Washington 98109,3 Department of Molecular Biology and Genetics, Democritus University of Thrace, Thrace, Greece,4 Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,5 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 372326

Received 26 September 2008/ Accepted 24 October 2008

The characterization of the cross-reactive, or heterologous, neutralizing antibody responses developed during human immunodeficiency virus type 1 (HIV-1) infection and the identification of factors associated with their generation are relevant to the development of an HIV vaccine. We report that in healthy HIV-positive, antiretroviral-naïve subjects, the breadth of plasma heterologous neutralizing antibody responses correlates with the time since infection, plasma viremia levels, and the binding avidity of anti-Env antibodies. Anti-CD4-binding site antibodies are responsible for the exceptionally broad cross-neutralizing antibody responses recorded only in rare plasma samples. However, in most cases examined, antibodies to the variable regions and to the CD4-binding site of Env modestly contributed in defining the overall breadth of these responses. Plasmas with broad cross-neutralizing antibody responses were identified that targeted the gp120 subunit, but their precise epitopes mapped outside the variable regions and the CD4-binding site. Finally, although several plasmas were identified with cross-neutralizing antibody responses that were not directed against gp120, only one plasma with a moderate breadth of heterologous neutralizing antibody responses contained cross-reactive neutralizing antibodies against the 4E10 epitope, which is within the gp41 transmembrane subunit. Overall, our study indicates that more than one pathway leads to the development of broad cross-reactive neutralizing antibodies during HIV infection and that the virus continuously escapes their action.

* Corresponding author. Mailing address: Seattle Biomedical Research Institute, 307 Westlake Avenue North, Seattle, WA 98109. Phone: (206) 256-7200. Fax: (206) 256-7229. E-mail: leo.stamatatos{at}sbri.org

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

Journal of Virology, January 2009, p. 757-769, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.02036-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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