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Correlation of naturally occurring HIV-1 resistance to DEB025 with capsid amino acid polymorphisms

Academic Article
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Overview

authors

  • Gallay, Philippe
  • Ptak, R. G.
  • Bobardt, M. D.
  • Dumont, J. M.
  • Vuagniaux, G.
  • Rosenwirth, B.

publication date

  • March 2013

journal

  • Viruses-Basel  Journal

abstract

  • DEB025 (alisporivir) is a synthetic cyclosporine with inhibitory activity against human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV). It binds to cyclophilin A (CypA) and blocks essential functions of CypA in the viral replication cycles of both viruses. DEB025 inhibits clinical HIV-1 isolates in vitro and decreases HIV-1 virus load in the majority of patients. HIV-1 isolates being naturally resistant to DEB025 have been detected in vitro and in nonresponder patients. By sequence analysis of their capsid protein (CA) region, two amino acid polymorphisms that correlated with DEB025 resistance were identified: H87Q and I91N, both located in the CypA-binding loop of the CA protein of HIV-1. The H87Q change was by far more abundant than I91N. Additional polymorphisms in the CypA-binding loop (positions 86, 91 and 96), as well as in the N-terminal loop of CA were detected in resistant isolates and are assumed to contribute to the degree of resistance. These amino acid changes may modulate the conformation of the CypA-binding loop of CA in such a way that binding and/or isomerase function of CypA are no longer necessary for virus replication. The resistant HIV-1 isolates thus are CypA-independent.

subject areas

  • Amino Acid Sequence
  • Anti-HIV Agents
  • Capsid
  • Capsid Proteins
  • Cyclosporine
  • Drug Resistance, Viral
  • HIV Infections
  • HIV-1
  • Humans
  • Molecular Sequence Data
  • Mutation, Missense
  • Polymorphism, Genetic
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Research

keywords

  • DEB025
  • HIV capsid
  • HIV/retroviruses
  • alisporivir
  • cyclophilin inhibitors
  • cyclosporines
  • natural resistance
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Identity

PubMed Central ID

  • PMC3705307

International Standard Serial Number (ISSN)

  • 1999-4915

Digital Object Identifier (DOI)

  • 10.3390/v5030981

PubMed ID

  • 23524389
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Additional Document Info

start page

  • 981

end page

  • 997

volume

  • 5

issue

  • 3

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