title: Mutation V111I in HIV-2 reverse transcriptase increases the fitness of the nucleoside analogue-resistant K65R and Q151M viruses.
abstract: Infection with HIV-2 can ultimately lead to AIDS, although disease progression is much slower than with HIV-1. HIV-2 patients are mostly treated with a combination of nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and protease inhibitors designed for HIV-1. Many studies have described the development of HIV-1 resistance to NRTIs and identified mutations in the polymerase domain of RT. Recent studies have shown that mutations in the connection and RNase H domains of HIV-1 RT may also contribute to resistance. However, only limited information exists regarding the resistance of HIV-2 to NRTIs. In this study, therefore, we analyzed the polymerase, connection, and RNase H domains of RT in HIV-2 patients failing NRTI-containing therapies. Besides the key resistance mutations K65R, Q151M, and M184V, we identified a novel mutation, V111I, in the polymerase domain. This mutation was significantly associated with mutations K65R and Q151M. Sequencing of the connection and RNase H domains of the HIV-2 patients did not reveal any of the mutations that were reported to contribute to NRTI resistance in HIV-1. We show that V111I does not strongly affect drug susceptibility but increases the replication capacity of the K65R and Q151M viruses. Biochemical assays demonstrate that V111I restores the polymerization defects of the K65R and Q151M viruses but negatively affects the fidelity of the HIV-2 RT enzyme. Molecular dynamics simulations were performed to analyze the structural changes mediated by V111I. This showed that V111I changed the flexibility of the 110-to-115 loop region, which may affect deoxynucleoside triphosphate (dNTP) binding and polymerase activity.
  
  
  OBJECTIVE
  Mutation V111I in the HIV-2 reverse transcriptase enzyme was identified in patients failing therapies containing nucleoside analogues. We show that the V111I change does not strongly affect the sensitivity of HIV-2 to nucleoside analogues but increases the fitness of viruses with drug resistance mutations K65R and Q151M.
authors.affiliation: Department of Virology, Viroscience Laboratory, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Ilona P
authors.initials: IP
authors.lastname: Deuzing
authors.affiliation: INSERM, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Charpentier
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, London, United Kingdom Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom.
authors.forename: David W
authors.initials: DW
authors.lastname: Wright
authors.affiliation: INSERM, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France AP-HP, Hôpital Bichat, Service des Maladies Infecieuse et Tropicales, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Matheron
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, London, United Kingdom Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom.
authors.forename: Jack
authors.initials: J
authors.lastname: Paton
authors.affiliation: Department of Virology, Viroscience Laboratory, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Dineke
authors.initials: D
authors.lastname: Frentz
authors.affiliation: Department of Virology, Viroscience Laboratory, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: David A
authors.initials: DA
authors.lastname: van de Vijver
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, London, United Kingdom.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Coveney
authors.affiliation: INSERM, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Descamps
authors.affiliation: Department of Virology, Viroscience Laboratory, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Charles A B
authors.initials: CA
authors.lastname: Boucher
authors.affiliation: Department of Virology, Viroscience Laboratory, Erasmus MC, Rotterdam, the Netherlands beerens.erasmusMC@mail.com.
authors.forename: Nancy
authors.initials: N
authors.lastname: Beerens
mesh_terms: D019943:Amino Acid Substitution; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015498:HIV-2 / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D014779:Virus Replication
chemical_list: C072416:reverse transcriptase, Human immunodeficiency virus 2; D054303:HIV Reverse Transcriptase