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Journal of Virology, June 2007, p. 6548-6562, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02749-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors{triangledown}

Amandeep K. Dhillon,1,{dagger} Helen Donners,1,2,{dagger} Ralph Pantophlet,1 Welkin E. Johnson,3 Julie M. Decker,5 George M. Shaw,5 Fang-Hua Lee,6 Douglas D. Richman,4 Robert W. Doms,6 Guido Vanham,2 and Dennis R. Burton1*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037,1 Department of Microbiology, Institute of Tropical Medicine, B-2000, Antwerp, Belgium,2 New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01722,3 Center for AIDS Research, University of California, San Diego, California 92093-0679, and VA San Diego Healthcare System, La Jolla, California 92161,4 Department of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, 35294,5 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 191046

Received 13 December 2006/ Accepted 25 March 2007

Attempts to elicit broadly neutralizing antibody responses by human immunodeficiency virus type 1 (HIV-1) vaccine antigens have been met with limited success. To better understand the requirements for cross-neutralization of HIV-1, we have characterized the neutralizing antibody specificities present in the sera of three asymptomatic individuals exhibiting broad neutralization. Two individuals were infected with clade B viruses and the third with a clade A virus. The broadly neutralizing activity could be exclusively assigned to the protein A-reactive immunoglobulin G (IgG) fraction of all three donor sera. Neutralization inhibition assays performed with a panel of linear peptides corresponding to the third hypervariable (V3) loop of gp120 failed to inhibit serum neutralization of a panel of HIV-1 viruses. The sera also failed to neutralize chimeric simian immunodeficiency virus (SIV) and HIV-2 viruses displaying highly conserved gp41-neutralizing epitopes, suggesting that antibodies directed against these epitopes likely do not account for the broad neutralizing activity observed. Polyclonal IgG was fractionated on recombinant monomeric clade B gp120, and the neutralization capacities of the gp120-depleted samples were compared to that of the original polyclonal IgG. We found that the gp120-binding antibody population mediated neutralization of some isolates, but not all. Overall, the data suggest that broad neutralization results from more than one specificity in the sera but that the number of these specificities is likely small. The most likely epitope recognized by the monomeric gp120 binding neutralizing fraction is the CD4 binding site, although other epitopes, such as the glycan shield, cannot be excluded.

* Corresponding author. Mailing address: The Scripps Research Institute, Department of Immunology (IMM-2), 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-9298. Fax: (858) 784-8360. E-mail: burton{at}scripps.edu

{triangledown} Published ahead of print on 4 April 2007.

{dagger} These authors contributed equally to this work.

Journal of Virology, June 2007, p. 6548-6562, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02749-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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