MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface
The type one interferon induced restriction factor Myxovirus resistance B (MxB) restricts HIV-1 nuclear entry evidenced by inhibition of 2-LTR but not linear forms of viral DNA. The HIV-1 capsid is the key determinant of MxB sensitivity and cofactor binding defective HIV-1 capsid mutants P90A (defec...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-06-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/56910 |
| _version_ | 1828376318193958912 |
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| author | Richard J Miles Claire Kerridge Laura Hilditch Christopher Monit David A Jacques Greg J Towers |
| author_facet | Richard J Miles Claire Kerridge Laura Hilditch Christopher Monit David A Jacques Greg J Towers |
| author_sort | Richard J Miles |
| collection | DOAJ |
| description | The type one interferon induced restriction factor Myxovirus resistance B (MxB) restricts HIV-1 nuclear entry evidenced by inhibition of 2-LTR but not linear forms of viral DNA. The HIV-1 capsid is the key determinant of MxB sensitivity and cofactor binding defective HIV-1 capsid mutants P90A (defective for cyclophilin A and Nup358 recruitment) and N74D (defective for CPSF6 recruitment) have reduced dependency on nuclear transport associated cofactors, altered integration targeting preferences and are not restricted by MxB expression. This has suggested that nuclear import mechanism may determine MxB sensitivity. Here we have use genetics to separate HIV-1 nuclear import cofactor dependence from MxB sensitivity. We provide evidence that MxB sensitivity depends on HIV-1 capsid conformation, rather than cofactor recruitment. We show that depleting CPSF6 to change nuclear import pathway does not impact MxB sensitivity, but mutants that recapitulate the effect of Cyclophilin A binding on capsid conformation and dynamics strongly impact MxB sensitivity. We demonstrate that HIV-1 primary isolates have different MxB sensitivities due to cytotoxic T lymphocyte (CTL) selected differences in Gag sequence but similar cofactor dependencies. Overall our work demonstrates a complex relationship between cyclophilin dependence and MxB sensitivity likely driven by CTL escape. We propose that cyclophilin binding provides conformational flexibility to HIV-1 capsid facilitating simultaneous evasion of capsid-targeting restriction factors including TRIM5 as well as MxB. |
| first_indexed | 2024-04-14T07:58:19Z |
| format | Article |
| id | doaj.art-63d4946b0ef442e1ae53f1f0260db612 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:58:19Z |
| publishDate | 2020-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-63d4946b0ef442e1ae53f1f0260db6122022-12-22T02:04:58ZengeLife Sciences Publications LtdeLife2050-084X2020-06-01910.7554/eLife.56910MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surfaceRichard J Miles0Claire Kerridge1Laura Hilditch2Christopher Monit3David A Jacques4https://orcid.org/0000-0002-6426-4510Greg J Towers5https://orcid.org/0000-0002-7707-0264Division of Infection and Immunity, University College London, London, United KingdomDivision of Infection and Immunity, University College London, London, United KingdomDivision of Infection and Immunity, University College London, London, United KingdomDivision of Infection and Immunity, University College London, London, United KingdomEMBL Australia Node in Single Molecule Science and ARC Centre of Excellence in Advanced Molecular Imaging, School of Medical Sciences, University of New South Wales, Sydney, AustraliaDivision of Infection and Immunity, University College London, London, United KingdomThe type one interferon induced restriction factor Myxovirus resistance B (MxB) restricts HIV-1 nuclear entry evidenced by inhibition of 2-LTR but not linear forms of viral DNA. The HIV-1 capsid is the key determinant of MxB sensitivity and cofactor binding defective HIV-1 capsid mutants P90A (defective for cyclophilin A and Nup358 recruitment) and N74D (defective for CPSF6 recruitment) have reduced dependency on nuclear transport associated cofactors, altered integration targeting preferences and are not restricted by MxB expression. This has suggested that nuclear import mechanism may determine MxB sensitivity. Here we have use genetics to separate HIV-1 nuclear import cofactor dependence from MxB sensitivity. We provide evidence that MxB sensitivity depends on HIV-1 capsid conformation, rather than cofactor recruitment. We show that depleting CPSF6 to change nuclear import pathway does not impact MxB sensitivity, but mutants that recapitulate the effect of Cyclophilin A binding on capsid conformation and dynamics strongly impact MxB sensitivity. We demonstrate that HIV-1 primary isolates have different MxB sensitivities due to cytotoxic T lymphocyte (CTL) selected differences in Gag sequence but similar cofactor dependencies. Overall our work demonstrates a complex relationship between cyclophilin dependence and MxB sensitivity likely driven by CTL escape. We propose that cyclophilin binding provides conformational flexibility to HIV-1 capsid facilitating simultaneous evasion of capsid-targeting restriction factors including TRIM5 as well as MxB.https://elifesciences.org/articles/56910HIVcapsidcyclophilin Arestriction factorMxB |
| spellingShingle | Richard J Miles Claire Kerridge Laura Hilditch Christopher Monit David A Jacques Greg J Towers MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface eLife HIV capsid cyclophilin A restriction factor MxB |
| title | MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface |
| title_full | MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface |
| title_fullStr | MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface |
| title_full_unstemmed | MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface |
| title_short | MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface |
| title_sort | mxb sensitivity of hiv 1 is determined by a highly variable and dynamic capsid surface |
| topic | HIV capsid cyclophilin A restriction factor MxB |
| url | https://elifesciences.org/articles/56910 |
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