20962083
not annotated - annotated - LINNAEUS only
Small-molecule inhibition of human immunodeficiency virus type 1 infection by virus capsid destabilization.
Human immunodeficiency virus type 1 (HIV-1) infection is dependent on the proper disassembly of the viral capsid, or "uncoating," in target cells. The HIV-1 capsid consists of a conical multimeric complex of the viral capsid protein (CA) arranged in a hexagonal lattice. Mutations in CA that destabilize the viral capsid result in impaired infection owing to defects in reverse transcription in target cells. We describe here the mechanism of action of a small molecule HIV-1 inhibitor, PF-3450074 (PF74), which targets CA. PF74 acts at an early stage of HIV-1 infection and inhibits reverse transcription in target cells. We show that PF74 binds specifically to HIV-1 particles, and substitutions in CA that confer resistance to the compound prevent binding. A single point mutation in CA that stabilizes the HIV-1 core also conferred strong resistance to the virus without inhibiting compound binding. Treatment of HIV-1 particles or purified cores with PF74 destabilized the viral capsid in vitro. Furthermore, the compound induced the rapid dissolution of the HIV-1 capsid in target cells. PF74 antiviral activity was promoted by binding of the host protein cyclophilin A to the HIV-1 capsid, and PF74 and cyclosporine exhibited mutual antagonism. Our data suggest that PF74 triggers premature HIV-1 uncoating in target cells, thereby mimicking the activity of the retrovirus restriction factor TRIM5alpha. This study highlights uncoating as a step in the HIV-1 life cycle that is susceptible to small molecule intervention.
Ann file
T1 Species 29 64 human immunodeficiency virus type 1
N1 Reference T1 Taxonomy:11676
T2 Species 110 145 Human immunodeficiency virus type 1
N2 Reference T2 Taxonomy:11676
T3 Species 147 152 HIV-1
N3 Reference T3 Taxonomy:11676
T4 Species 271 276 HIV-1
N4 Reference T4 Taxonomy:11676
T5 Species 590 595 HIV-1
N5 Reference T5 Taxonomy:11676
T6 Species 675 680 HIV-1
N6 Reference T6 Taxonomy:11676
T7 Species 783 788 HIV-1
N7 Reference T7 Taxonomy:11676
T8 Species 930 935 HIV-1
N8 Reference T8 Taxonomy:11676
T9 Species 1037 1042 HIV-1
N9 Reference T9 Taxonomy:11676
T10 Species 1184 1189 HIV-1
N10 Reference T10 Taxonomy:11676
T11 Species 1303 1308 HIV-1
N11 Reference T11 Taxonomy:11676
T12 Species 1418 1423 HIV-1
N12 Reference T12 Taxonomy:11676
T13 Species 1580 1585 HIV-1
N13 Reference T13 Taxonomy:11676