title: Potent and broad neutralization of HIV-1 subtype C by plasma antibodies targeting a quaternary epitope including residues in the V2 loop.
abstract: The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth. CAP256 developed potent BCN activity peaking at 3 years postinfection, neutralizing 32 (76%) of 42 heterologous viruses, with titers of antibodies against some viruses exceeding 1:10,000. CAP256 showed a subtype bias, preferentially neutralizing subtype C and A viruses over subtype B viruses. CAP256 BCN serum targeted a quaternary epitope which included the V1V2 region. Further mapping identified residues F159, N160, L165, R166, D167, K169, and K171 (forming the FN/LRD-K-K motif) in the V2 region as crucial to the CAP256 epitope. However, the fine specificity of the BCN response varied over time and, while consistently dependent on R166 and K169, became gradually less dependent on D167 and K171, possibly contributing to the incremental increase in breadth over 4 years. The presence of an intact FN/LRD-K-K motif in heterologous viruses was associated with sensitivity, although the length of the adjacent V1 loop modulated the degree of sensitivity, with a shorter V1 region significantly associated with higher titers. Repair of the FN/LRD-K-K motif in resistant heterologous viruses conferred sensitivity, with titers sometimes exceeding 1:10,000. Comparison of the CAP256 epitope with that of the PG9/PG16 monoclonal antibodies suggested that these epitopes overlapped, adding to the mounting evidence that this may represent a common neutralization target that should be further investigated as a potential vaccine candidate.
authors.affiliation: National Institute for Communicable Diseases of the NHLS, Private Bag X4, Sandringham 2131, Johannesburg, South Africa. pennym@nicd.ac.za
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.forename: Elin S
authors.initials: ES
authors.lastname: Gray
authors.forename: Daniel
authors.initials: D
authors.lastname: Sheward
authors.forename: Maphuti
authors.initials: M
authors.lastname: Madiga
authors.forename: Nthabeleng
authors.initials: N
authors.lastname: Ranchobe
authors.forename: Zhong
authors.initials: Z
authors.lastname: Lai
authors.forename: William J
authors.initials: WJ
authors.lastname: Honnen
authors.forename: Molati
authors.initials: M
authors.lastname: Nonyane
authors.forename: Nancy
authors.initials: N
authors.lastname: Tumba
authors.forename: Tandile
authors.initials: T
authors.lastname: Hermanus
authors.forename: Sengeziwe
authors.initials: S
authors.lastname: Sibeko
authors.forename: Koleka
authors.initials: K
authors.lastname: Mlisana
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
authors.forename: Abraham
authors.initials: A
authors.lastname: Pinter
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood* / Q000276:immunology; D003429:Cross Reactions; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D005838:Genotype; D015483:HIV Antibodies / Q000097:blood* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology*; D006801:Humans; D009500:Neutralization Tests; D010949:Plasma / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1