Lorenzo Bulli, Luis Apolonia, Juliane Kutzner, Darja Pollpeter, Caroline Goujon, Nikolas Herold, Sarah-Marie Schwarz, Yannick Giernat, Oliver Till Keppler, Michael H. Malim, Torsten Schaller
- Type I interferons (IFNs), including IFN-α, upregulate an array of IFN-stimulated genes (ISGs) and potently suppress Human immunodeficiency virus type 1 (HIV-1) infectivity in CD4(+) T cells, monocyte-derived macrophages, and dendritic cells. Recently, we and others identified ISG myxovirus resistance 2 (MX2) as an inhibitor of HIV-1 nuclear entry. However, additional antiviral blocks exist upstream of nuclear import, but the ISGs that suppress infection, e.g., prior to (or during) reverse transcription, remain to be defined. We show here that the HIV-1 CA mutations N74D and A105T, both of which allow escape from inhibition by MX2 and the truncated version of cleavage and polyadenylation specific factor 6 (CPSF6), as well as the cyclophilin A (CypA)-binding loop mutation P90A, all increase sensitivity to IFN-α-mediated inhibition. Using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology, we demonstrate that the IFN-α hypersensitivity of these mutants in THP-1 cells is independent of MX2 or CPSF6. As expected, CypA depletion had no additional effect on the behavior of the P90A mutant but modestly increased the IFN-α sensitivity of wild-type virus. Interestingly, the infectivity of wild-type or P90A virus could be rescued from the MX2-independent IFN-α-induced blocks in THP-1 cells by treatment with cyclosporine (Cs) or its nonimmunosuppressive analogue SDZ-NIM811, indicating that Cs-sensitive host cell cyclophilins other than CypA contribute to the activity of IFN-α-induced blocks. We propose that cellular interactions with incoming HIV-1 capsids help shield the virus from recognition by antiviral effector mechanisms. Thus, the CA protein is a fulcrum for the dynamic interplay between cell-encoded functions that inhibit or promote HIV-1 infection.
MetadatenAuthor: | Lorenzo Bulli, Luis Apolonia, Juliane Kutzner, Darja Pollpeter, Caroline Goujon, Nikolas Herold, Sarah-Marie Schwarz, Yannick Giernat, Oliver Till KepplerORCiDGND, Michael H. Malim, Torsten Schaller |
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URN: | urn:nbn:de:hebis:30:3-426016 |
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DOI: | https://doi.org/10.1128/JVI.00458-16 |
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ISSN: | 1098-5514 |
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ISSN: | 0022-538X |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/27279606 |
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Parent Title (English): | Journal of virology |
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Publisher: | American Society for Microbiology |
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Place of publication: | Baltimore, Md. |
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Contributor(s): | W. I. Sundquist |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2017/05/11 |
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Year of first Publication: | 2016 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/05/11 |
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Volume: | 90 |
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Issue: | 16 |
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Page Number: | 12 |
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First Page: | 7469 |
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Last Page: | 7480 |
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Note: | Copyright © 2016 Bulli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. |
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HeBIS-PPN: | 423734121 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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