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G541R within the 4070A TM protein regulates fusion in murine leukemia viruses
Lucille O'Reilly1, Monica J Roth
1Department of Biochemistry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Abstract:
The mutation G541R within the ectodomain of TM was isolated in three independent chimeric enveloped murine leukemia virus (MuLV) viral populations originally impaired in viral passage and in wild-type 4070A. Isolation of G541R in multiple populations suggested it played a critical role in viral envelope function. Using a viral vector system, the observed effects of the G541R mutation within MuLV envelope proteins were pleiotropic and included effects on the regulation of SU-TM interactions and membrane fusion. G541R suppresses enhanced cell-cell fusion events attributable to the absence of the R-peptide yet does not adversely affect virus titers. The ability to suppress cell-cell fusion is dependent on the presence of the C terminus of the amphotropic 4070A SU protein. Within the wild-type 4070A envelope background, the mutation results in a decreased level of Env at the cell surface that is mirrored in the virion. The TM mutation alters recognition of the SU C terminus by a monoclonal antibody, suggestive of an altered conformation. The presence of G541R allowed the virus to achieve a balance between cytopathogenicity and replication and restored productive viral entry.
Insights
The G541R mutation in murine leukemia virus (MuLV) envelope proteins is critical for viral function, regulating cell fusion and restoring productive viral entry. This discovery balances viral pathogenicity and replication.
Area of Science:
- Virology
- Molecular Biology
- Structural Biology
Background:
- Murine leukemia virus (MuLV) envelope proteins (Env) mediate viral entry and cell fusion.
- Specific mutations within Env can significantly impact viral infectivity and tropism.
- The role of the G541R mutation in MuLV envelope function was previously uncharacterized.
Purpose of the Study:
- To investigate the functional impact of the G541R mutation in MuLV envelope proteins.
- To elucidate the mechanisms by which G541R affects viral entry, cell-cell fusion, and viral replication.
- To determine the structural consequences of the G541R mutation on Env conformation.
Main Methods:
- Isolation and characterization of MuLV viral populations with the G541R mutation.
- Utilizing a viral vector system to assess the pleiotropic effects of G541R.
- Analyzing SU-TM interactions, membrane fusion, cell surface Env levels, and viral titers.
- Employing monoclonal antibody binding assays to probe Env conformation.
Main Results:
- The G541R mutation was isolated in multiple independent MuLV populations, indicating its critical role in viral envelope function.
- G541R pleiotropically affects MuLV envelope proteins, regulating SU-TM interactions and membrane fusion.
- The mutation suppresses R-peptide-deficient cell-cell fusion without reducing virus titers, dependent on the 4070A SU C terminus.
- G541R leads to decreased cell surface and virion Env levels and alters SU C terminus recognition by antibodies, suggesting conformational changes.
- G541R restores productive viral entry by balancing cytopathogenicity and replication.
Conclusions:
- The G541R mutation is a key determinant of MuLV envelope function, impacting viral entry and replication.
- This mutation modulates cell-cell fusion and Env display, offering insights into viral tropism and infectivity.
- G541R represents a potential target for modulating MuLV pathogenesis and developing novel viral vectors.
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