Strain-specific differences in the impact of human TRIM5alpha, different TRIM5alpha alleles, and the inhibition of capsid-cyclophilin A interactions on the infectivity of HIV-1.
HIV-1 infectivity is strongly restricted by TRIM5α from certain primate species but has been described as being only marginally susceptible to human TRIM5α. In this study, we evaluated the effects of the modulation of human TRIM5α activity (pretreatment of target cells with alpha interferon, expression of a pre-miRNA targeting TRIM5α, and/or overexpression of TRIM5γ), the inhibition of cyclophilin A (CypA)-CA interactions, and the expression of different allelic variants of human TRIM5α on the infectivity of a series of recombinant viruses carrying different patient-derived Gag-protease sequences. We show that HIV-1 displays virus-specific differences in its sensitivity to human TRIM5α and in its sensitivity to different TRIM5α alleles. The effect of inhibiting CypA-CA interactions is also strain specific, and blocking these interactions can either inhibit or improve viral infectivity, depending on the isolate studied. The inhibition of CypA-CA interactions also modulates viral sensitivity to human TRIM5α. In the absence of CypA-CA interactions, most viruses displayed increased sensitivity to the inhibitory effects of TRIM5α on viral replication, but one isolate showed a paradoxical decrease in sensitivity to TRIM5α. Taken together, these findings support a model in which three interlinked factors--capsid sequence, CypA levels, and TRIM5α--interact to determine capsid stability and therefore viral infectivity.
Battivelli
Emilie
E
INSERM U941, Institut Universitaire d’Hématologie, Université Paris Diderot, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75475 Paris cedex 10, France.
Lecossier
Denise
D
Matsuoka
Saori
S
Migraine
Julie
J
Clavel
François
F
Hance
Allan J
AJ
D000483:Alleles; D000090103:Antiviral Restriction Factors; D001483:Base Sequence; D002213:Capsid / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D021984:Cyclophilin A / Q000032:analysis / Q000378:metabolism*; D015683:Gene Products, gag / Q000235:genetics; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D013045:Species Specificity; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D014779:Virus Replication
D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D015683:Gene Products, gag; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases; D021984:Cyclophilin A