Estimated Secondary Structure Propensities within V1/V2 Region of HIV gp120 Are an Important Global Antibody Neutralization Sensitivity Determinant

Maxim Totrov,Chandravanu Dash

doi:10.1371/journal.pone.0094002

Abstract

BackgroundNeutralization 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.MethodsCorrelations 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.ResultsSignificant 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.ConclusionsObserved 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.

Highlights

Neutralization sensitivity of HIV-1 virus to antibodies and anti-sera varies greatly between the isolates
This resistance is contributing to both, the inability of human immune system to control HIV infection in the vast majority of individuals and the fact that despite decades of concerted efforts to create an effective prophylactic HIV vaccine, only a rather limited success has been reported so far [1]
Overall beta-sheet propensity of V1/V2 domain correlates with neutralization sensitivity

Summary

Introduction

Neutralization sensitivity of HIV-1 virus to antibodies and anti-sera varies greatly between the isolates. Most clinical isolates of HIV-1 virus are notoriously difficult to neutralize by antibodies. This resistance is contributing to both, the inability of human immune system to control HIV infection in the vast majority of individuals and the fact that despite decades of concerted efforts to create an effective prophylactic HIV vaccine, only a rather limited success has been reported so far (vaccine trial RV144 in Thailand) [1]. Apart from the common viral resistance mechanisms of evasion via frequent mutations, HIV appears to have evolved highly efficient ways of ‘hiding’ vulnerable conserved immunogenic structures. The virus appears to disguise these vulnerable targets from the host’s immune system under a heavy glycosylation layer [5], behind highly variable elements [6], within narrow crevasses of the structure that are poorly accessible to antibodies, and using other mechanisms of epitope ‘masking’ [7] that are still poorly understood

Methods

Results

Conclusion