HIV-1 escape from the CCR5 antagonist maraviroc associated with an altered and less-efficient mechanism of gp120-CCR5 engagement that attenuates macrophage tropism
MetadataShow full item record
Maraviroc (MVC) inhibits the entry of human immunodeficiency virus type 1 (HIV-1) by binding to and modifying the conformation of the CCR5 extracellular loops (ECLs). Resistance to MVC results from alterations in the HIV-1 gp120 envelope glycoproteins (Env) enabling recognition of the drug-bound conformation of CCR5. To better understand the mechanisms underlying MVC resistance, we characterized the virus-cell interactions of gp120 from in vitro-generated MVC-resistant HIV-1 (MVC-Res Env), comparing them with those of gp120 from the sensitive parental virus (MVC-Sens Env). In the absence of the drug, MVC-Res Env maintains a highly efficient interaction with CCR5, similar to that of MVC-Sens Env, and displays a relatively modest increase in dependence on the CCR5 N terminus. However, in the presence of the drug, MVC-Res Env interacts much less efficiently with CCR5 and becomes critically dependent on the CCR5 N terminus and on positively charged elements of the drug-modified CCR5 ECL1 and ECL2 regions (His88 and His181, respectively). Structural analysis suggests that the Val323 resistance mutation in the gp120 V3 loop alters the secondary structure of the V3 loop and the buried surface area of the V3 loop-CCR5 N terminus interface. This altered mechanism of gp120-CCR5 engagement dramatically attenuates the entry of HIV-1 into monocyte-derived macrophages (MDM), cell-cell fusion activity in MDM, and viral replication capacity in MDM. In addition to confirming that HIV-1 escapes MVC by becoming heavily dependent on the CCR5 N terminus, our results reveal novel interactions with the drug-modified ECLs that are critical for the utilization of CCR5 by MVC-Res Env and provide additional insights into virus-cell interactions that modulate macrophage tropism. © 2011, American Society for Microbiology.
Showing items related by title, author, creator and subject.
A common mechanism of clinical HIV-1 resistance to the CCR5 antagonist maraviroc despite divergent resistance levels and lack of common gp120 resistance mutationsRoche, M.; Salimi, H.; Duncan, R.; Wilkinson, B.; Chikere, K.; Moore, M.; Webb, N.; Zappi, H.; Sterjovski, J.; Flynn, J.; Ellett, A.; Gray, L.; Lee, B.; Jubb, B.; Westby, M.; Ramsland, Paul; Lewin, S.; Payne, R.; Churchill, M.; Gorry, P. (2013)Background: The CCR5 antagonist maraviroc (MVC) inhibits human immunodeficiency virus type 1 (HIV-1) entry by altering the CCR5 extracellular loops (ECL), such that the gp120 envelope glycoproteins (Env) no longer recognize ...
Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophagesCashin, K.; Roche, M.; Sterjovski, J.; Ellett, A.; Gray, L.; Cunningham, A.; Ramsland, Paul; Churchill, M.; Gorry, P. (2011)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 ...
Modelling the co-occurence of Streptococcus pneumoniae with other bacterial and viral pathogens in the upper respiratory tractJacoby, P.; Watson, K.; Bowman, J.; Taylor, A.; Riley, T.; Smith, D.; Lehmann, Deborah (2007)Go to ScienceDirect® Home Skip Main Navigation Links Brought to you by: The University of Western Australia Library Login: + Register Athens/Institution Login Not Registered? - User Name: Password: ...