title: Unique mutational patterns in the envelope alpha 2 amphipathic helix and acquisition of length in gp120 hypervariable domains are associated with resistance to autologous neutralization of subtype C human immunodeficiency virus type 1.
abstract: Autologous neutralizing antibodies (NAb) against human immunodeficiency virus type 1 generate viral escape variants; however, the mechanisms of escape are not clearly defined. In a previous study, we determined the susceptibilities of 48 donor and 25 recipient envelope (Env) glycoproteins from five subtype C heterosexual transmission pairs to NAb in donor plasma by using a virus pseudotyping assay, thereby providing an ideal setting to probe the determinants of susceptibility to neutralization. In the present study, acquisition of length in the Env gp120 hypervariable domains was shown to correlate with resistance to NAb in donor plasma (P = 0.01; Kendall's tau test) but not in heterologous plasma. Sequence divergence in the gp120 V1-to-V4 region also correlated with resistance to donor (P = 0.0002) and heterologous (P = 0.001) NAb. A mutual information analysis suggested possible associations of nine amino acid positions in V1 to V4 with NAb resistance to the donor's antibodies, and five of these were located within an 18-residue amphipathic helix (alpha2) located on the gp120 outer domain. High nonsynonymous-to-synonymous substitution (dN/dS) ratios, indicative of positive selection, were also found at these five positions in subtype C sequences in the database. Nevertheless, exchange of the entire alpha2 helix between resistant donor Envs and sensitive recipient Envs did not alter the NAb phenotype. The combined mutual information and dN/dS analyses suggest that unique mutational patterns in alpha2 and insertions in the V1-to-V4 region are associated with NAb resistance during subtype C infection but that the selected positions within the alpha2 helix must be linked to still other changes in Env to confer antibody escape. These findings suggest that subtype C viruses utilize mutations in the alpha2 helix for efficient viral replication and immune avoidance.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, Atlanta, GA 30329, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Rong
authors.forename: S
authors.initials: S
authors.lastname: Gnanakaran
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.forename: Jesse
authors.initials: J
authors.lastname: Taylor
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Sfakianos
authors.forename: John L
authors.initials: JL
authors.lastname: Mokili
authors.forename: Mark
authors.initials: M
authors.lastname: Muldoon
authors.forename: Joseph
authors.initials: J
authors.lastname: Mulenga
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Blackwell
authors.forename: Bette T
authors.initials: BT
authors.lastname: Korber
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
mesh_terms: D000595:Amino Acid Sequence; D015483:HIV Antibodies / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009500:Neutralization Tests; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120