title: The development of CD4 binding site antibodies during HIV-1 infection.
abstract: Broadly neutralizing antibodies to the CD4 binding site (CD4bs) of gp120 are generated by some HIV-1-infected individuals, but little is known about the prevalence and evolution of this antibody response during the course of HIV-1 infection. We analyzed the sera of 113 HIV-1 seroconverters from three cohorts for binding to a panel of gp120 core proteins and their corresponding CD4bs knockout mutants. Among sera collected between 99 and 258 weeks post-HIV-1 infection, 88% contained antibodies to the CD4bs and 47% contained antibodies to resurfaced stabilized core (RSC) probes that react preferentially with broadly neutralizing CD4bs antibodies (BNCD4), such as monoclonal antibodies (MAbs) VRC01 and VRC-CH31. Analysis of longitudinal serum samples from a subset of 18 subjects revealed that CD4bs antibodies to gp120 arose within the first 4 to 16 weeks of infection, while the development of RSC-reactive antibodies was more varied, occurring between 10 and 152 weeks post-HIV-1 infection. Despite the presence of these antibodies, serum neutralization mediated by RSC-reactive antibodies was detected in sera from only a few donors infected for more than 3 years. Thus, CD4bs antibodies that bind a VRC01-like epitope are often induced during HIV-1 infection, but the level and potency required to mediate serum neutralization may take years to develop. An improved understanding of the immunological factors associated with the development and maturation of neutralizing CD4bs antibodies during HIV-1 infection may provide insights into the requirements for eliciting this response by vaccination.
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Lynch
authors.forename: Lillian
authors.initials: L
authors.lastname: Tran
authors.forename: Mark K
authors.initials: MK
authors.lastname: Louder
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: Myron
authors.initials: M
authors.lastname: Cohen
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dersimonian
authors.forename: Zelda
authors.initials: Z
authors.lastname: Euler
authors.forename: Elin S
authors.initials: ES
authors.lastname: Gray
authors.forename: Salim
authors.initials: S
authors.lastname: Abdool Karim
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kirchherr
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Sengeziwe
authors.initials: S
authors.lastname: Sibeko
authors.forename: Kelly
authors.initials: K
authors.lastname: Soderberg
authors.forename: Georgia
authors.initials: G
authors.lastname: Tomaras
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Yang
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.forename: Hanneke
authors.initials: H
authors.lastname: Schuitemaker
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D005260:Female; D055786:Gene Knockout Techniques; D015483:HIV Antibodies / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D008297:Male
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1