Partial rescue of V1V2 mutant infectivity by HIV-1 cell-cell transmission supports the domain’s exceptional capacity for sequence variation

Retrovirology

Alexandra Trkola²  Roland R Regoes³  Huldrych F Günthard¹  Jürg Böni²  Jacqueline Weber²  Carsten Magnus²  Peter Rusert²  Oliver F Brandenberg² 

[1] University Hospital Zurich, Division of Infectious Diseases, Zurich, Switzerland;Institute of Medical Virology, University of Zurich, Zurich, Switzerland;Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland

关键词: Antibody escape;    Neutralization;    Entry;    V1V2;    Cell-cell transmission;    HIV;   

Others  :  1152290
DOI  :  10.1186/s12977-014-0075-y

 received in 2014-06-18, accepted in 2014-08-13,  发布年份 2014

【 摘 要 】

Background

Variable loops 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 perform two key functions: ensuring envelope trimer entry competence and shielding against neutralizing antibodies. While preserving entry functionality would suggest a high need for V1V2 sequence optimization and conservation, shielding efficacy is known to depend on a high flexibility of V1V2 giving rise to its substantial sequence variability. How entry competence of the trimer is maintained despite the continuous emergence of antibody escape mutations within V1V2 has not been resolved. Since HIV cell-cell transmission is considered a highly effective means of virus dissemination, we investigated whether cell-cell transmission may serve to enhance infectivity of V1V2 variants with debilitated free virus entry.

Results

In a detailed comparison of wt and V1V2 mutant envelopes, V1V2 proved to be a key factor in ascertaining free virus infectivity, with V1V2 mutants displaying significantly reduced trimer integrity. Despite these defects, cell-cell transmission was able to partially rescue infectivity of V1V2 mutant viruses. We identified two regions, encompassing amino acids 156 to 160 (targeted by broadly neutralizing antibodies) and 175 to 180 (encompassing the ?4?7 binding site) which were particularly prone to free virus infectivity loss upon mutation but maintained infectivity in cell-cell transmission. Of note, V1V2 antibody shielding proved important during both free virus infection and cell-cell transmission.

Conclusions

Based on our data we propose a model for V1V2 evolution that centers on cell-cell transmission as a salvage pathway for virus replication. Escape from antibody neutralization may frequently result in V1V2 mutations that reduce free virus infectivity. Cell-cell transmission could provide these escape viruses with sufficiently high replication levels that enable selection of compensatory mutations, thereby restoring free virus infectivity while ensuring antibody escape. Thus, our study highlights the need to factor in cell-cell transmission when considering neutralization escape pathways of HIV-1.

【 授权许可】

   
2014 Brandenberg et al.; licensee BioMed Central Ltd.

【 图 表 】

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