The ability of multimerized cyclophilin A to restrict retrovirus infection.
In owl monkeys, the typical retroviral restriction factor of primates, TRIM5alpha, is replaced by TRIMCyp. TRIMCyp consists of the TRIM5 RING, B-box 2 and coiled-coil domains, as well as the intervening linker regions, fused with cyclophilin A. TRIMCyp restricts infection of retroviruses, such as human immunodeficiency virus (HIV-1) and feline immunodeficiency virus (FIV), with capsids that can bind cyclophilin A. The TRIM5 coiled coil promotes the trimerization of TRIMCyp. Here we show that cyclophilin A that is oligomeric as a result of fusion with a heterologous multimer exhibits substantial antiretroviral activity. The addition of the TRIM5 RING, B-box 2 and Linker 2 to oligomeric cyclophilin A generated a protein with antiretroviral activity approaching that of wild-type TRIMCyp. Multimerization increased the binding of cyclophilin A to the HIV-1 capsid, promoting accelerated uncoating of the capsid and restriction of infection.
Javanbakht
Hassan
H
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.
Diaz-Griffero
Felipe
F
Yuan
Wen
W
Yeung
Darwin F
DF
Li
Xing
X
Song
Byeongwoon
B
Sodroski
Joseph
J
D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016645:Aotidae; D036022:Capsid Proteins / Q000378:metabolism; D002460:Cell Line; D021984:Cyclophilin A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D019281:Dimerization; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D008969:Molecular Sequence Data; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D019380:Anti-HIV Agents; D036022:Capsid Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D021984:Cyclophilin A