V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and Vicriviroc |
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Authors: | Berro Reem Klasse Per Johan Jakobsen Martin R Gorry Paul R Moore John P Sanders Rogier W |
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Affiliation: | a Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USAb Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands |
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Abstract: | HIV-1 develops resistance to CCR5 antagonists such as Maraviroc (MVC) and Vicriviroc (VVC) both in vitro and in vivo, with most changes arising in the gp120 V3 region. Both compounds bind to the same hydrophobic cavity in CCR5 in subtly different ways. Here, we investigated which V3 sequence changes are most associated with MVC and VVC resistance and how they affect the interaction between gp120 and the CCR5 NT. We found that VVC- and MVC-selected amino acid changes map to different V3 locations and involve residues that interact with the CCR5 NT in different ways. Changes in VVC-selected, but not MVC-selected, variants often involve charged residues. Although the overall V3 charge tends not to change, the introduction or removal of charged residues at specific positions affects the local electrostatic potential and could have structural and functional implications. In summary, VVC and MVC trigger the evolution of distinct HIV-1 resistance patterns in V3. |
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Keywords: | CCR5 Small molecule CCR5 inhibitors V3 sequence Drug resistance CCR5 NT Maraviroc Vicriviroc |
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