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.
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.
Rong
Rong
R
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, Atlanta, GA 30329, USA.
Gnanakaran
S
S
Decker
Julie M
JM
Bibollet-Ruche
Frederic
F
Taylor
Jesse
J
Sfakianos
Jeffrey N
JN
Mokili
John L
JL
Muldoon
Mark
M
Mulenga
Joseph
J
Allen
Susan
S
Hahn
Beatrice H
BH
Shaw
George M
GM
Blackwell
Jerry L
JL
Korber
Bette T
BT
Hunter
Eric
E
Derdeyn
Cynthia A
CA
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
D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120