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Journal of Virology, December 2008, p. 11651-11668, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01762-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Profiling the Specificity of Neutralizing Antibodies in a Large Panel of Plasmas from Patients Chronically Infected with Human Immunodeficiency Virus Type 1 Subtypes B and C{triangledown} ,{dagger}

James M. Binley,1 Elizabeth A. Lybarger,2 Emma T. Crooks,1 Michael S. Seaman,3 Elin Gray,4 Katie L. Davis,5 Julie M. Decker,5 Diane Wycuff,2 Linda Harris,6 Natalie Hawkins,6 Blake Wood,6 Cory Nathe,6 Douglas Richman,7 Georgia D. Tomaras,8 Frederic Bibollet-Ruche,5 James E. Robinson,9 Lynn Morris,4 George M. Shaw,5 David C. Montefiori,8 and John R. Mascola2*

Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, California 92121,1 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, 40 Convent Drive, Bethesda, Maryland 20892,2 Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, 330 Brookline Ave., RE-204, Boston, Massachusetts 02215,3 National Institute for Communicable Diseases, Private Bag X4, Sandringham 2131, Johannesburg, South Africa,4 Division of Hematology and Oncology, University of Alabama at Birmingham, 720 20th Street South, Kaul 816, Birmingham, Alabama 35294-0024,5 Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., LE-400, Seattle, Washington 98109,6 Department of Pathology, 9500 Gilman Drive, University of California, San Diego, California 92093,7 Department of Surgery, Department of Molecular Genetics and Microbiology, and Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina 27710,8 Department of Pediatrics, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, Louisiana 701129

Received 20 August 2008/ Accepted 18 September 2008

Identifying the viral epitopes targeted by broad neutralizing antibodies (NAbs) that sometimes develop in human immunodeficiency virus type 1 (HIV-1)-infected subjects should assist in the design of vaccines to elicit similar responses. Here, we investigated the activities of a panel of 24 broadly neutralizing plasmas from subtype B- and C-infected donors using a series of complementary mapping methods, focusing mostly on JR-FL as a prototype subtype B primary isolate. Adsorption with gp120 immobilized on beads revealed that an often large but variable fraction of plasma neutralization was directed to gp120 and that in some cases, neutralization was largely mediated by CD4 binding site (CD4bs) Abs. The results of a native polyacrylamide gel electrophoresis assay using JR-FL trimers further suggested that half of the subtype B and a smaller fraction of subtype C plasmas contained a significant proportion of NAbs directed to the CD4bs. Anti-gp41 neutralizing activity was detected in several plasmas of both subtypes, but in all but one case, constituted only a minor fraction of the overall neutralization activity. Assessment of the activities of the subtype B plasmas against chimeric HIV-2 viruses bearing various fragments of the membrane proximal external region (MPER) of HIV-1 gp41 revealed mixed patterns, implying that MPER neutralization was not dominated by any single specificity akin to known MPER-specific monoclonal Abs. V3 and 2G12-like NAbs appeared to make little or no contribution to JR-FL neutralization titers. Overall, we observed significant titers of anti-CD4bs NAbs in several plasmas, but approximately two-thirds of the neutralizing activity remained undefined, suggesting the existence of NAbs with specificities unlike any characterized to date.

* Corresponding author. Mailing address: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, 40 Convent Drive, Bethesda, MD 20892. Phone: (301) 594-8484. Fax: (301) 480-2788. E-mail: jmascola{at}mail.nih.gov

{triangledown} Published ahead of print on 24 September 2008.

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

Journal of Virology, December 2008, p. 11651-11668, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01762-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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