HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency (original) (raw)
Figure 7
Model for CypA-dependent/-independent HIV-1 nuclear entry pathways.
A, Wild type (WT) HIV-1 capsids are bound by cytoplasmic cyclophilin A (CypA) molecules that direct the capsid to use a specific nuclear entry pathway. The nuclear entry pathway involves CA binding to the cyclophilin domain of the cytoplasmic nuclear pore complex (NPC) component Nup358. Nup358 may mediate uncoating directly at the nuclear pore, liberating the pre-integration complex, which will interact with TRN-SR2 and the nuclear NPC component Nup153. B, Inhibition of CypA-CA interaction by the drug cyclosporine (Cs) or by substitution of CA residues that abolish CypA binding directs the virus into a less productive CypA-independent nuclear entry pathway that displays impaired dependence on Nup358 and Nup153. This route of nuclear entry results in virus integration preferences in areas of higher density of transcription units and associated features. C, HIV-1 capsid mutants that are less sensitive to Nup358, Nup153 or TRN-SR2 RNAi (HIV-1 CA N57A or N74D) enter the nucleus through a different pathway that directs their integration into genome areas of lower density of transcription units. D, Depletion of Nup358 by RNAi reduces viral nuclear entry via the Nup358-dependent pathway and the virus gains access via an Nup358-independent alternative pathway resulting in phenotypically similar integration site selection as observed for the CA mutants N74D or N57A. Alternative nuclear entry pathways disturb HIV-1 integration site selection, possibly contributing to sub-optimal replication of the virus in spreading infection assays.