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HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication
Torsten Schaller1, Karen E Ocwieja, Jane Rasaiyaah
1Division of Infection and Immunity, University College London Medical Research Council Centre for Medical Molecular Virology, London, United Kingdom.
Plos Pathogens
|December 17, 2011
Summary
Human immunodeficiency virus type 1 (HIV-1) capsid proteins bind to Nup358/RanBP2, influencing viral integration and replication. This interaction is key to understanding HIV-1 nuclear import and infection mechanisms.
Area of Science:
- Virology
- Cell Biology
- Structural Biology
Background:
- Lentiviruses like HIV-1 infect non-dividing cells by crossing nuclear pore complexes (NPCs).
- The NPC protein Nup358/RanBP2 is a known HIV-1 co-factor, but its precise role remains unclear.
- Understanding HIV-1 nuclear import is crucial for developing antiviral strategies.
Purpose of the Study:
- To elucidate the interaction between HIV-1 capsid (CA) and Nup358/RanBP2.
- To investigate the role of this interaction in HIV-1 replication and integration targeting.
- To develop novel inhibitors of HIV-1 replication based on these interactions.
Main Methods:
- Direct binding assays to characterize HIV-1 CA and Nup358/RanBP2 cyclophilin domain interaction.
- Creation of a novel TRIM5-based inhibitor incorporating the Nup358/RanBP2 cyclophilin domain.
- Analysis of HIV-1 integration site preferences using cyclophilin and Nup358/RanBP2 binding mutants.
- Assessment of viral replication efficiency in cell lines and primary macrophages.
Main Results:
- HIV-1 CA directly binds to the cyclophilin domain of Nup358/RanBP2.
- A TRIM5-Nup358/RanBP2 cyclophilin domain fusion protein inhibits HIV-1 replication.
- Nup358 binding is distinct from cyclophilin A (CypA) binding and cyclosporine-insensitive.
- HIV-1 CA mutants affecting Nup358/TRN-SR2 binding show altered integration site preferences.
- Both CypA and Nup358 interactions influence HIV-1 integration targeting and replication efficiency.
Conclusions:
- HIV-1 capsid interactions with cyclophilins, including Nup358/RanBP2, are critical for regulating viral integration site selection.
- These interactions also play a significant role in the overall efficiency of HIV-1 replication.
- The findings provide insights into conserved mechanisms of viral cyclophilin recruitment and offer potential targets for antiviral therapies.
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