Dataset Information

V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and Vicriviroc.

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.

SUBMITTER: Berro R

PROVIDER: S-EPMC3320651 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and Vicriviroc.

Berro Reem R Klasse Per Johan PJ Jakobsen Martin R MR Gorry Paul R PR Moore John P JP Sanders Rogier W RW

Virology 20120316 2

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 ...[more]

PMID: 22424737

Similar Datasets

Project description:BackgroundMaraviroc (MVC) is an allosteric CCR5 inhibitor used against HIV-1 infection. While MVC-resistant viruses have been identified in patients, it still remains incompletely known how they adjust their CD4 and CCR5 binding properties to resist MVC inhibition while preserving their replicative capacity. It is thought that they maintain high efficiency of receptor binding. To date however, information about the binding affinities to receptors for inhibitor-resistant HIV-1 remains limited.ResultsHere, we show by means of viral envelope (gp120) binding experiments and virus-cell fusion kinetics that a MVC-resistant virus (MVC-Res) that had emerged as a dominant viral quasispecies in a patient displays reduced affinities for CD4 and CCR5 either free or bound to MVC, as compared to its MVC-sensitive counterpart isolated before MVC therapy. An alanine insertion within the GPG motif (G310_P311insA) of the MVC-resistant gp120 V3 loop is responsible for the decreased CCR5 binding affinity, while impaired binding to CD4 is due to sequence changes outside V3. Molecular dynamics simulations of gp120 binding to CCR5 further emphasize that the Ala insertion alters the structure of the V3 tip and weakens interaction with CCR5 ECL2. Paradoxically, infection experiments on cells expressing high levels of CCR5 also showed that Ala allows MVC-Res to use CCR5 efficiently, thereby improving viral fusion and replication efficiencies. Actually, although we found that the V3 loop of MVC-Res is required for high levels of MVC resistance, other regions outside V3 are sufficient to confer a moderate level of resistance. These sequence changes outside V3, however, come with a replication cost, which is compensated for by the Ala insertion in V3.ConclusionThese results indicate that changes in the V3 loop of MVC-resistant viruses can augment the efficiency of CCR5-dependent steps of viral entry other than gp120 binding, thereby compensating for their decreased affinity for entry receptors and improving their fusion and replication efficiencies. This study thus sheds light on unsuspected mechanisms whereby MVC-resistant HIV-1 could emerge and grow in treated patients.

Dataset Information

V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and Vicriviroc.

Publications

V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and Vicriviroc.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets