title: Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody.
abstract: To guide vaccine design, we assessed whether human monoclonal antibodies (MAbs) b12 and b6 against the CD4 binding site (CD4bs) on HIV-1 gp120 and F240 against an immundominant epitope on gp41 could prevent vaginal transmission of simian HIV (SHIV)-162P4 to macaques. The two anti-gp120 MAbs have similar monomeric gp120-binding properties, measured in vitro, but b12 is strongly neutralizing and b6 is not. F240 is nonneutralizing. Applied vaginally at a high dose, the strongly neutralizing MAb b12 provided sterilizing immunity in seven of seven animals, b6 in zero of five animals, and F240 in two of five animals. Compared with control animals, the protection by b12 achieved statistical significance, whereas that caused by F240 did not. For two of three unprotected F240-treated animals there was a trend toward lowered viremia. The potential protective effect of F240 may relate to the relatively strong ability of this antibody to capture infectious virions. Additional passive transfer experiments also indicated that the ability of the administered anti-gp120 MAbs to neutralize the challenge virus was a critical influence on protection. Furthermore, when data from all of the experiments were combined, there was a significant increase in the number of founder viruses establishing infection in animals receiving MAb b6, compared with other nonprotected macaques. Thus, a gp120-binding, weakly neutralizing MAb to the CD4bs was, at best, completely ineffective at protection. A nonneutralizing antibody to gp41 may have a limited capacity to protect, but the results suggest that the central focus of HIV-1 vaccine research should be on the induction of potently neutralizing antibodies.
authors.affiliation: Department of Immunology and Microbial Science and International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. burton@scripps.edu
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Hessell
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ketas
authors.forename: Brian
authors.initials: B
authors.lastname: Moldt
authors.forename: D Cameron
authors.initials: DC
authors.lastname: Dunlop
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.forename: Lara A
authors.initials: LA
authors.lastname: Doyle
authors.forename: Lisa
authors.initials: L
authors.lastname: Cavacini
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D057134:Antibodies, Neutralizing / Q000008:administration & dosage*; D005260:Female; D015483:HIV Antibodies / Q000008:administration & dosage*; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000276:immunology; D008969:Molecular Sequence Data; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D014621:Vagina / Q000276:immunology / Q000821:virology; D014759:Viral Envelope Proteins / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D008562:Membrane Glycoproteins; D018449:SAIDS Vaccines; D014759:Viral Envelope Proteins; C514793:gp120 protein, Human immunodeficiency virus 1; C069623:gp120 protein, Simian immunodeficiency virus; C514787:gp41 protein, Human immunodeficiency virus 1