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Novel Escape Mutants Suggest an Extensive TRIM5α Binding Site
Spanning the Entire Outer Surface of the Murine Leukemia Virus Capsid
Protein


After entry into target cells, retroviruses encounter the host restriction

factors such as Fv1 and TRIM5α. While it is clear that these factors target

retrovirus capsid proteins (CA), recognition remains poorly defined in the

absence of structural information. To better understand the binding interaction

between TRIM5α and CA, we selected a panel of novel N-tropic murine

leukaemia virus (N-MLV) escape mutants by a serial passage of replication

competent N-MLV in rhesus macaque TRIM5α (rhTRIM5α)-positive cells using

a small percentage of unrestricted cells to allow multiple rounds of virus

replication. The newly identified mutations, many of which involve changes in

charge, are distributed over the outer ‘top’ surface of N-MLV CA,

including the N-terminal β-hairpin, and map up to 29 Ao apart.

Biological characterisation with a number of restriction factors revealed that

only one of the new mutations affects restriction by human TRIM5α,

indicating significant differences in the binding interaction between N-MLV and

the two TRIM5αs, whereas three of the mutations result in dual sensitivity

to Fv1n and Fv1b. Structural studies of two mutants show

that no major changes in the overall CA conformation are associated with escape

from restriction. We conclude that interactions involving much, if not all, of

the surface of CA are vital for TRIM5α binding.


Vyšlo v časopise: Novel Escape Mutants Suggest an Extensive TRIM5α Binding Site Spanning the Entire Outer Surface of the Murine Leukemia Virus Capsid Protein. PLoS Pathog 7(3): e32767. doi:10.1371/journal.ppat.1002011
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002011

Souhrn

After entry into target cells, retroviruses encounter the host restriction

factors such as Fv1 and TRIM5α. While it is clear that these factors target

retrovirus capsid proteins (CA), recognition remains poorly defined in the

absence of structural information. To better understand the binding interaction

between TRIM5α and CA, we selected a panel of novel N-tropic murine

leukaemia virus (N-MLV) escape mutants by a serial passage of replication

competent N-MLV in rhesus macaque TRIM5α (rhTRIM5α)-positive cells using

a small percentage of unrestricted cells to allow multiple rounds of virus

replication. The newly identified mutations, many of which involve changes in

charge, are distributed over the outer ‘top’ surface of N-MLV CA,

including the N-terminal β-hairpin, and map up to 29 Ao apart.

Biological characterisation with a number of restriction factors revealed that

only one of the new mutations affects restriction by human TRIM5α,

indicating significant differences in the binding interaction between N-MLV and

the two TRIM5αs, whereas three of the mutations result in dual sensitivity

to Fv1n and Fv1b. Structural studies of two mutants show

that no major changes in the overall CA conformation are associated with escape

from restriction. We conclude that interactions involving much, if not all, of

the surface of CA are vital for TRIM5α binding.


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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


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