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Journal of Virology, January 2008, p. 115-125, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.00927-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 gp41 Antibodies That Mask Membrane Proximal Region Epitopes: Antibody Binding Kinetics, Induction, and Potential for Regulation in Acute Infection{triangledown}

S. Munir Alam,1* Richard M. Scearce,1 Robert J. Parks,1 Kelly Plonk,1 Steven G. Plonk,1 Laura L. Sutherland,1 Miroslaw K. Gorny,2 Susan Zolla-Pazner,2 Stacie VanLeeuwen,1 M. Anthony Moody,1 Shi-Mao Xia,1 David C. Montefiori,1 Georgia D. Tomaras,1 Kent J. Weinhold,1 Salim Abdool Karim,3 Charles B. Hicks,1 Hua-Xin Liao,1 James Robinson,4 George M. Shaw,5 and Barton F. Haynes1

Duke Human Vaccine Institute and Departments of Medicine and Immunology, Duke University School Medicine, Durham, North Carolina 27710,1 New York University School of Medicine, New York, New York 15016,2 University of KwaZulu-Natal, Durban, South Africa,3 Tulane University School of Medicine, New Orleans, Louisiana,4 University of Alabama at Birmingham; Birmingham, Alabama 35294-00245

Received 30 April 2007/ Accepted 2 October 2007

Two human monoclonal antibodies (MAbs) (2F5 and 4E10) against the human immunodeficiency virus type 1 (HIV-1) envelope g41 cluster II membrane proximal external region (MPER) broadly neutralize HIV-1 primary isolates. However, these antibody specificities are rare, are not induced by Env immunization or HIV-1 infection, and are polyspecific and also react with lipids such as cardiolipin or phosphatidylserine. To probe MPER anti-gp41 antibodies that are produced in HIV-1 infection, we have made two novel murine MAbs, 5A9 and 13H11, against HIV-1 gp41 envelope that partially cross-blocked 2F5 MAb binding to Env but did not neutralize HIV-1 primary isolates or bind host lipids. Competitive inhibition assays using labeled 13H11 MAb and HIV-1-positive patient plasma samples demonstrated that cluster II 13H11-blocking plasma antibodies were made in 83% of chronically HIV-1 infected patients and were acquired between 5 to 10 weeks after acute HIV-1 infection. Both the mouse 13H11 MAb and the three prototypic cluster II human MAbs (98-6, 126-6, and 167-D) blocked 2F5 binding to gp41 epitopes to variable degrees; the combination of 98-6 and 13H11 completely blocked 2F5 binding. These data provide support for the hypothesis that in some patients, B cells make nonneutralizing cluster II antibodies that may mask or otherwise down-modulate B-cell responses to immunogenic regions of gp41 that could be recognized by B cells capable of producing antibodies like 2F5.

* Corresponding author. Mailing address: Human Vaccine Institute, Box 3258, Duke University Medical Center, MSRBII Bldg., Room 4042, Durham, NC 27710. Phone: (919) 684-5384. Fax: (919) 681-8992. E-mail: alam0004{at}mc.duke.edu

{triangledown} Published ahead of print on 17 October 2007.

Journal of Virology, January 2008, p. 115-125, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.00927-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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