Recognition by Human Monoclonal Antibodies of Free and Complexed Peptides Representing the Prefusogenic and Fusogenic Forms of Human Immunodeficiency Virus Type 1 gp41

doi:10.1128/JVI.74.13.6186-6192.2000

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Journal of Virology, July 2000, p. 6186-6192, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Recognition by Human Monoclonal Antibodies of Free and Complexed Peptides Representing the Prefusogenic and Fusogenic Forms of Human Immunodeficiency Virus Type 1 gp41

Miroslaw K. Gorny¹ and Susan Zolla-Pazner¹^,²^,^*

Department of Pathology, New York University School of Medicine, New York, New York 10016,¹ and Research Center for AIDS and HIV Infection, Veterans Affairs Medical Center, New York, New York 10010²

Received 10 December 1999/Accepted 30 March 2000

Human immunodeficiency virus type 1 (HIV-1) entry into target cells appears to be triggered when two heptad repeat regionsin the ectodomain of gp41 associate, converting the prefusogenicform of gp41 to a fusogenic form. Peptides from these two heptadrepeat regions, designated N51 and C43, form a coiled coil consistingof an $alpha$ -helical trimer of heterodimers which approximates thecore of the fusogenic form of gp41. To understand the antigenicstructures of gp41 in these two configurations, and to examinethe specificity of anti-gp41 antibodies produced by HIV-1-infectedindividuals, human anti-gp41 monoclonal antibodies (MAbs) weretested for their reactivity against N51, C43, and the complexformed by these peptides. Of 11 MAbs, 7 reacted with the complexbut with neither of the parent peptides. These MAbs reacted optimallywith the N51-C43 complex prepared at a 1:1 ratio and appearedto recognize the fusogenic form of gp41 in which the two heptadrepeat regions are associated to form the coiled coil. The existenceof antibodies from HIV-infected humans that exclusively recognizethe N51-C43 complex constitutes the first proof that the coiled-coilconformation of gp41 exists in vivo and is immunogenic. Two ofthe 11 MAbs were specific for the hydrophilic loop region of gp41and failed to react with either peptide alone or with the peptidecomplex, while the remaining 2 MAbs reacted with peptide C43.One of these two latter MAbs, 98-6, also reacted well with theequimolar N51-C43 complex, while reactivity with C43 by the otherMAb, 2F5, was inhibited by even small amounts of N51, suggestingthat the interaction of these peptides occludes or disrupts theepitope recognized by MAb 2F5. MAbs 98-6 and 2F5 are also unusualamong the MAbs tested in their ability to neutralize multipleprimary HIV isolates, although 2F5 displays more broad and potentactivity. The data suggest that anti-gp41 neutralizing activityis associated with specificity for a region in C43 which participatesin complex formation withN51.

^* Corresponding author. Mailing address: Veterans Affairs Medical Center, 423 East 23rd St., Room 18124N, New York, NY 10010.Phone: (212) 951-3211. Fax: (212) 951-6321. E-mail: zollas01{at}popmail.med.nyu.edu.

Journal of Virology, July 2000, p. 6186-6192, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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