A comparison of murine leukemia viruses that escape from human and rhesus macaque TRIM5αs
Sadayuki Ohkura1, Jonathan P Stoye
1Division of Virology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.
Abstract:
To better understand the binding mechanism of TRIM5α to retrovirus capsid, we had previously selected N-tropic murine leukemia virus (N-MLV) mutants escaping from rhesus macaque TRIM5α (rhTRIM5α) by passaging the virus in rhTRIM5α-expressing cells and selecting for nonrestricted variants. To test the commonality of the findings from the rhTRIM5α study, we have now employed a similar genetic approach using human TRIM5α (huTRIM5α). Consistent with the rhTRIM5α study, the mapped huTRIM5α escape mutations were distributed across the capsid exterior, confirming the extended binding surface between virus and restriction factor. Compared to the results of the previous study, fewer escape mutations were identified, with particular mutants being repeatedly selected. Three out four huTRIM5α escape variants showed resistance to all primate TRIM5αs tested, but two of them sacrificed viral fitness, observations that were not made in the rhTRIM5α study. Moreover, differences in amino acid changes associated with escape from hu- and rhTRIM5αs suggested a charge dependence of the restriction by different TRIM5αs. Taken together, these results suggest that the recognition of the entire capsid surface is a general strategy for TRIM5α to restrict MLV but that significantly different specific interactions are involved in the binding of TRIM5α from different species to the MLV capsid core.
Insights
Human TRIM5α (huTRIM5α) and rhesus macaque TRIM5α (rhTRIM5α) restrict N-tropic murine leukemia virus (N-MLV) by binding its capsid. Escape mutations reveal conserved and species-specific interactions, highlighting TRIM5α
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Trimerco-5 alpha (TRIM5α) is a key antiviral protein that restricts retroviral infection.
- Understanding TRIM5α's interaction with retroviral capsids is crucial for developing antiviral strategies.
- Previous studies identified N-tropic murine leukemia virus (N-MLV) escape mutants from rhesus macaque TRIM5α (rhTRIM5α).
Purpose of the Study:
- To investigate the binding mechanism of human TRIM5α (huTRIM5α) to N-MLV capsid.
- To compare escape mutations from huTRIM5α with those previously identified for rhTRIM5α.
- To determine the commonality and specificity of TRIM5α-mediated restriction across different primate species.
Main Methods:
- Genetic approach involving passaging N-MLV in cells expressing huTRIM5α.
- Selection of N-MLV variants that escape huTRIM5α restriction.
- Mapping of escape mutations within the N-MLV capsid protein.
Main Results:
- huTRIM5α escape mutations were distributed across the capsid exterior, indicating an extended binding surface.
- Fewer escape mutations were identified for huTRIM5α compared to rhTRIM5α, with some mutants repeatedly selected.
- Three of four huTRIM5α escape variants showed resistance to multiple primate TRIM5αs, but two exhibited reduced viral fitness.
Conclusions:
- TRIM5α broadly recognizes the N-MLV capsid surface, but specific interactions vary between human and rhesus macaque TRIM5α.
- Species-specific differences in amino acid changes suggest a charge-dependent interaction mechanism.
- While TRIM5α binding is a general restriction strategy, the precise molecular interactions are distinct across primate species.
