Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages

Cashin, K, Roche, M, Sterjovski, J, Ellett, A, Gray, L, Cunningham, A, Ramsland, P, Churchill, M and Gorry, P 2011, 'Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages', Journal of Virology, vol. 85, no. 20, pp. 10699-10709.


Document type: Journal Article
Collection: Journal Articles

Title Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages
Author(s) Cashin, K
Roche, M
Sterjovski, J
Ellett, A
Gray, L
Cunningham, A
Ramsland, P
Churchill, M
Gorry, P
Year 2011
Journal name Journal of Virology
Volume number 85
Issue number 20
Start page 10699
End page 10709
Total pages 11
Publisher American Society for Microbiology
Abstract Macrophage tropism of human immunodeficiency virus type 1 (HIV-1) is distinct from coreceptor specificity of the viral envelope glycoproteins (Env), but the virus-cell interactions that contribute to efficient HIV-1 entry into macrophages, particularly via CXCR4, are not well understood. Here, we characterized a panel of HIV-1 Envs that use CCR5 (n = 14) or CXCR4 (n = 6) to enter monocyte-derived macrophages (MDM) with various degrees of efficiency. Our results show that efficient CCR5-mediated MDM entry by Env-pseudotyped reporter viruses is associated with increased tolerance of several mutations within the CCR5 N terminus. In contrast, efficient CXCR4-mediated MDM entry was associated with reduced tolerance of a large deletion within the CXCR4 N terminus. Env sequence analysis and structural modeling identified amino acid variants at positions 261 and 263 within the gp41-interactive region of gp120 and a variant at position 326 within the gp120 V3 loop that were associated with efficient CXCR4-mediated MDM entry. Mutagenesis studies showed that the gp41 interaction domain variants exert a significant but strain-specific influence on CXCR4-mediated MDM entry, suggesting that the structural integrity of the gp120-gp41 interface is important for efficient CXCR4-mediated MDM entry of certain HIV-1 strains. However, the presence of Ile326 in the gp120 V3 loop stem, which we show by molecular modeling is located at the gp120-coreceptor interface and predicted to interact with the CXCR4 N terminus, was found to be critical for efficient CXCR4-mediated MDM entry of divergent CXCR4-using Envs. Together, the results of our study provide novel insights into alternative mechanisms of Env-coreceptor engagement that are associated with efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages.
Subject Microbiology not elsewhere classified
DOI - identifier 10.1128/JVI.05510-11
Copyright notice Copyright © 2011, American Society for Microbiology. All Rights Reserved.
ISSN 0022-538X
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