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, th...

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Veröffentlicht in:	Nature medicine Jg. 9; H. 9; S. 1138 - 1143
Hauptverfasser:	Towers, Greg J, Hatziioannou, Theodora, Cowan, Simone, Goff, Stephen P, Luban, Jeremy, Bieniasz, Paul D
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.09.2003 Nature Publishing Group
Schlagworte:	Amino Acid Sequence Animal models Animals Aotidae Binding Sites Biomedical and Life Sciences Biomedicine Cancer Research 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 Infectious Diseases Leukemia Virus, Murine - chemistry Leukemia Virus, Murine - pathogenicity Mammals Metabolic Diseases Mice Molecular Medicine Molecular Sequence Data Mutation Neurosciences Proteins - drug effects Proteins - metabolism Sequence Homology, Amino Acid Simian Immunodeficiency Virus - drug effects Simian Immunodeficiency Virus - pathogenicity
ISSN:	1078-8956, 1546-170X
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	1078-8956 1546-170X
DOI:	10.1038/nm910