Functional impact of HIV coreceptor-binding site mutations

Virology
Mark J BisconeJacqueline D Reeves

Abstract

The bridging sheet region of the gp120 subunit of the HIV-1 Env protein interacts with the major virus coreceptors, CCR5 and CXCR4. We examined the impact of mutations in and adjacent to the bridging sheet region of an X4 tropic HIV-1 on membrane fusion and entry inhibitor susceptibility. When the V3-loop of this Env was changed so that CCR5 was used, the effects of these same mutations on CCR5 use were assayed as well. We found that coreceptor-binding site mutations had greater effects on CXCR4-mediated fusion and infection than when CCR5 was used as a coreceptor, perhaps related to differences in coreceptor affinity. The mutations also reduced use of the alternative coreceptors CCR3 and CCR8 to varying degrees, indicating that the bridging sheet region is important for the efficient utilization of both major and minor HIV coreceptors. As seen before with a primary R5 virus strain, bridging sheet mutations increased susceptibility to the CCR5 inhibitor TAK-779, which correlated with CCR5 binding efficiency. Bridging sheet mutations also conferred increased susceptibility to the CXCR4 ligand AMD-3100 in the context of the X4 tropic Env. However, these mutations had little effect on the rate of membrane fusion and little effect ...Continue Reading

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Citations

Jan 6, 2010·Current Opinion in HIV and AIDS·Bette Korber, S Gnanakaran
Oct 23, 2013·Scientific Reports·Terrence M DobrowskyDenis Wirtz
Jan 1, 2009·Biopolymers·Petros A GalanakisGeorgios A Spyroulias
May 27, 2014·Journal of Virological Methods·Birco SchwalbeMichael Schreiber
May 1, 2010·Viruses·Michael A LobritzEric J Arts
Jul 4, 2012·International Journal of Molecular Sciences·Marco SchiavoneGiuseppe Scala
Jun 27, 2012·The Journal of Biological Chemistry·Lusine H DemirkhanyanGregory B Melikyan
Mar 23, 2017·Assay and Drug Development Technologies·Charline GiroudGregory B Melikyan
Jan 18, 2017·Pharmacology Research & Perspectives·Christian BergMette M Rosenkilde

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