Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors

Nat Med. 2003 Sep;9(9):1138-43. doi: 10.1038/nm910. Epub 2003 Aug 3.


Many mammalian species express restriction factors that confer host resistance to retroviral infection. Here we show that HIV-1 sensitivity to restriction factors is modulated by cyclophilin A (CypA), a host cell protein that binds the HIV-1 capsid protein (CA). In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding. Conversely, disruption of CA-CypA interaction in human cells reveals that CypA protects HIV-1 from the Ref-1 restriction factor. These findings suggest that HIV-1 has co-opted a host cell protein to counteract restriction factors expressed by human cells and that this adaptation can confer sensitivity to restriction in unnatural hosts. Manipulation of HIV-1 CA recognition by restriction factors promises to advance animal models and new therapeutic strategies for HIV-1 and AIDS.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aotidae
  • Binding Sites
  • Capsid / drug effects
  • Capsid / metabolism
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Cyclophilin A / drug effects
  • Cyclophilin A / metabolism*
  • Cyclosporine / pharmacology
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / drug effects
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism
  • Gene Products, gag / genetics
  • Gene Products, gag / metabolism
  • HIV-1 / chemistry
  • HIV-1 / pathogenicity*
  • Host-Parasite Interactions
  • Humans
  • Leukemia Virus, Murine / chemistry
  • Leukemia Virus, Murine / pathogenicity
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Proteins / drug effects
  • Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Simian Immunodeficiency Virus / drug effects
  • Simian Immunodeficiency Virus / pathogenicity


  • Carrier Proteins
  • Fv1 protein, mouse
  • Gene Products, gag
  • Proteins
  • Cyclosporine
  • APEX1 protein, human
  • Apex1 protein, mouse
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • Cyclophilin A