Estimated secondary structure propensities within V1/V2 region of HIV gp120 are an important global antibody neutralization sensitivity determinant.
BACKGROUND
Neutralization sensitivity of HIV-1 virus to antibodies and anti-sera varies greatly between the isolates. Significant role of V1/V2 domain as a global neutralization sensitivity regulator has been suggested. Recent X-ray structures revealed presence of well-defined tertiary structure within this domain but also demonstrated partial disorder and conformational heterogeneity.


METHODS
Correlations of neutralization sensitivity with the conformational propensities for beta-strand and alpha-helix formation over the entire folded V1/V2 domain as well as within sliding 5-residue window were investigated. Analysis was based on a set of neutralization data for 106 HIV isolates for which consistent neutralization sensitivity measurements against multiple pools of human immune sera have been previously reported.


RESULTS
Significant correlation between beta-sheet formation propensity of the folded segments of V1/V2 domain and neutralization sensitivity was observed. Strongest correlation peaks localized to the beta-strands B and C. Correlation persisted when subsets of HIV isolates belonging to clades B, C and circulating recombinant form BC where analyzed individually or in combinations.


CONCLUSIONS
Observed correlations suggest that stability of the beta-sheet structure and/or degree of structural disorder in the V1/V2 domain is an important determinant of the global neutralization sensitivity of HIV-1 virus. While specific mechanism is to yet to be investigated, plausible hypothesis is that less ordered V1/V2s may have stronger masking effect on various neutralizing epitopes, perhaps effectively occupying larger volume and thereby occluding antibody access.
Molsoft LLC, San Diego, California, United States of America.
Maxim
M
Totrov
D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000276:immunology; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments