title: Naturally occurring mutations within HIV-1 V3 genomic RNA lead to antigenic variation dependent on a single amino acid substitution.
abstract: In a study on the evolution of genomic diversity of HIV-1, genomic RNA was isolated from serum of two individuals. Starting at the time of primary infection we collected six samples of serum from each patient over a period of 5 years. Ninety-four cDNA clones (50 of patient 1 and 44 of patient 495) of part of the envelope coding region including the principal neutralization domain (PND) were sequenced. Around the time of antibody seroconversion, genomic RNA levels reached a peak and the population of sequences was highly homogeneous. In the course of the infection, the number of amino acid substitutions accumulated, which led to a higher genomic diversity within successive samples and a drift in the consensus sequence, progressively differing from the first found consensus sequence. Fixation of a substitution at glycoprotein 120 amino acid 308 was observed in both patients between two time points (patient 1, H----P; patient 495, P----H). With the use of 16-meric synthetic peptides, differing only at the 308 position (H308 versus P308), antibody binding specificity was found to be dependent on this difference. In patient 495, the nonconservative (P308----H) substitution reduced the binding affinity with the patient's antibodies. Furthermore, antibody competition assays showed that the observed substitution at position 308 elicited a new antibody population, indicating antigenic variation. After the decline of V3-specific antibodies, the simultaneous increase in genomic RNA levels and progression to AIDS in patient 495, a new variant with major changes in the PND emerged, again forming a homogeneous population of sequences.
authors.affiliation: Human Retrovirus Laboratory, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: T F
authors.initials: TF
authors.lastname: Wolfs
authors.forename: G
authors.initials: G
authors.lastname: Zwart
authors.forename: M
authors.initials: M
authors.lastname: Bakker
authors.forename: M
authors.initials: M
authors.lastname: Valk
authors.forename: C L
authors.initials: CL
authors.lastname: Kuiken
authors.forename: J
authors.initials: J
authors.lastname: Goudsmit
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000276:immunology / Q000382:microbiology*; D000595:Amino Acid Sequence; D000917:Antibody Formation; D000940:Antigenic Variation; D001483:Base Sequence; D003001:Cloning, Molecular; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005814:Genes, Viral; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D006716:Homosexuality; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D001909:Leukemia Virus, Bovine / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D010455:Peptides / Q000138:chemical synthesis; D016133:Polymerase Chain Reaction / Q000379:methods; D012367:RNA, Viral / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
chemical_list: D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; D010455:Peptides; D012367:RNA, Viral