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TRIM5alpha mediates the postentry block to N-tropic murine leukemia viruses in human cells
Michel J Perron1, Matthew Stremlau, Byeongwoon Song
1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Murine leukemia viruses (MLVs) have been classified as N-tropic (N-MLV) or B-tropic (B-MLV), depending on their ability to infect particular mouse strains. The early phase of N-MLV infection is blocked in the cells of several mammalian species, including humans. This block is mediated by a dominant host factor that targets the viral capsid soon after virus entry into the cell has been achieved. A similar block to HIV-1 in rhesus monkey cells is mediated by TRIM5alpha. Here we show that human TRIM5alpha is both necessary and sufficient for the restriction of N-MLV in human cells. Rhesus monkey TRIM5alpha, which potently blocks HIV-1 infection, exhibited only modest inhibition of N-MLV infection. B-MLV was resistant to the antiviral effects of both human and rhesus monkey TRIM5alpha; susceptibility to TRIM5alpha-mediated restriction was conferred by alteration of residue 110 of the B-MLV capsid protein to the amino acid found in the N-MLV capsid. Our results demonstrate that species-specific variation in TRIM5alpha governs its ability to block infection by diverse retroviruses.
Insights
Human TRIM5alpha restricts N-tropic murine leukemia virus (N-MLV) infection by targeting the viral capsid. Species-specific TRIM5alpha variations dictate its effectiveness against different retroviruses, including N-MLV and HIV-1.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Murine leukemia viruses (MLVs) are classified as N-tropic (N-MLV) or B-tropic (B-MLV) based on infectivity in mouse strains.
- N-MLV infection is blocked early in human cells by a host factor targeting the viral capsid.
- TRIM5alpha restricts HIV-1 in rhesus monkey cells, suggesting a role in retroviral restriction.
Purpose of the Study:
- To investigate the role of human TRIM5alpha in restricting N-MLV infection.
- To determine if TRIM5alpha species-specificity influences its antiviral activity against N-MLV and B-MLV.
- To identify specific viral capsid determinants involved in TRIM5alpha-mediated restriction.
Main Methods:
- Infection assays using human and rhesus monkey cells with N-MLV and B-MLV.
- Functional assays to assess necessity and sufficiency of human TRIM5alpha.
- Mutagenesis of B-MLV capsid protein at residue 110.
Main Results:
- Human TRIM5alpha is essential and sufficient for blocking N-MLV infection in human cells.
- Rhesus monkey TRIM5alpha showed limited N-MLV inhibition compared to its potent HIV-1 restriction.
- B-MLV resisted TRIM5alpha restriction; altering capsid residue 110 to the N-MLV form conferred susceptibility.
Conclusions:
- Species-specific TRIM5alpha variations are key determinants of retroviral restriction.
- TRIM5alpha's antiviral spectrum is shaped by interactions with viral capsid proteins.
- Understanding TRIM5alpha-retrovirus interactions offers insights into host-pathogen dynamics.
