title: Limited neutralizing antibody specificities drive neutralization escape in early HIV-1 subtype C infection.
abstract: We previously showed that HIV-1 subtype C viruses elicit potent but highly type-specific neutralizing antibodies (nAb) within the first year of infection. In order to determine the specificity and evolution of these autologous nAbs, we examined neutralization escape in four individuals whose responses against the earliest envelope differed in magnitude and potency. Neutralization escape occurred in all participants, with later viruses showing decreased sensitivity to contemporaneous sera, although they retained sensitivity to new nAb responses. Early nAb responses were very restricted, occurring sequentially and targeting only two regions of the envelope. In V1V2, limited amino acid changes often involving indels or glycans, mediated partial or complete escape, with nAbs targeting the V1V2 region directly in 2 cases. The alpha-2 helix of C3 was also a nAb target, with neutralization escape associated with changes to positively charged residues. In one individual, relatively high titers of anti-C3 nAbs were required to drive genetic escape, taking up to 7 weeks for the resistant variant to predominate. Thereafter titers waned but were still measurable. Development of this single anti-C3 nAb specificity was associated with a 7-fold drop in HIV-1 viral load and a 4-fold rebound as the escape mutation emerged. Overall, our data suggest the development of a very limited number of neutralizing antibody specificities during the early stages of HIV-1 subtype C infection, with temporal fluctuations in specificities as escape occurs. While the mechanism of neutralization escape appears to vary between individuals, the involvement of limited regions suggests there might be common vulnerabilities in the HIV-1 subtype C transmitted envelope.
authors.affiliation: AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa.
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.forename: Nthabeleng
authors.initials: N
authors.lastname: Ranchobe
authors.forename: Bronwen E
authors.initials: BE
authors.lastname: Lambson
authors.forename: Elin S
authors.initials: ES
authors.lastname: Gray
authors.forename: Eleanor
authors.initials: E
authors.lastname: Cave
authors.forename: Melissa-Rose
authors.initials: MR
authors.lastname: Abrahams
authors.forename: Gama
authors.initials: G
authors.lastname: Bandawe
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: Lynn
authors.initials: L
authors.lastname: Morris
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000916:Antibody Diversity; D002460:Cell Line; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D014779:Virus Replication / Q000502:physiology
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D012367:RNA, Viral; C514793:gp120 protein, Human immunodeficiency virus 1