Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors.
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.
Towers
Greg J
GJ
Department of Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Hatziioannou
Theodora
T
Cowan
Simone
S
Goff
Stephen P
SP
Luban
Jeremy
J
Bieniasz
Paul D
PD
D000595:Amino Acid Sequence; D000818:Animals; D016645:Aotidae; D001665:Binding Sites; D002213:Capsid / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D021984:Cyclophilin A / Q000187:drug effects / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000187:drug effects / Q000378:metabolism; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry / Q000472:pathogenicity*; D006790:Host-Parasite Interactions; D006801:Humans; D009052:Leukemia Virus, Murine / Q000737:chemistry / Q000472:pathogenicity; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000472:pathogenicity
D002352:Carrier Proteins; C103189:Fv1 protein, mouse; D015683:Gene Products, gag; D011506:Proteins; D016572:Cyclosporine; C085108:APEX1 protein, human; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D021984:Cyclophilin A