Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses
ABSTRACT The HIV-1 accessory protein Vpu enhances viral release by counteracting the restriction factor BST-2. Furthermore, Vpu promotes NK cell evasion by downmodulating cell surface NTB-A and PVR, known ligands of the NK cell receptors NTB-A and DNAM-1, respectively. While it has been established...
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American Society for Microbiology
2019
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oai:doaj.org-article:a9c7f1cd222240a497b7cabeef046a5f2021-11-15T15:55:25ZUpregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses10.1128/mBio.01113-192150-7511https://doaj.org/article/a9c7f1cd222240a497b7cabeef046a5f2019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01113-19https://doaj.org/toc/2150-7511ABSTRACT The HIV-1 accessory protein Vpu enhances viral release by counteracting the restriction factor BST-2. Furthermore, Vpu promotes NK cell evasion by downmodulating cell surface NTB-A and PVR, known ligands of the NK cell receptors NTB-A and DNAM-1, respectively. While it has been established that Vpu’s transmembrane domain (TMD) is required for the interaction and intracellular sequestration of BST-2, NTB-A, and PVR, it remains unclear how Vpu manages to target these proteins simultaneously. In this study, we show that upon upregulation, BST-2 is preferentially downregulated by Vpu over its other TMD substrates. We found that type I interferon (IFN)-mediated BST-2 upregulation greatly impairs the ability of Vpu to downregulate NTB-A and PVR. Our results suggest that occupation of Vpu by BST-2 affects its ability to downregulate other TMD substrates. Accordingly, knockdown of BST-2 increases Vpu’s potency to downmodulate NTB-A and PVR in the presence of type I IFN treatment. Moreover, we show that expression of human BST-2, but not that of the macaque orthologue, decreases Vpu’s capacity to downregulate NTB-A. Importantly, we show that type I IFNs efficiently sensitize HIV-1-infected cells to NTB-A- and DNAM-1-mediated direct and antibody-dependent NK cell responses. Altogether, our results reveal that type I IFNs decrease Vpu’s polyfunctionality, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. IMPORTANCE The restriction factor BST-2 and the NK cell ligands NTB-A and PVR are among a growing list of membrane proteins found to be downregulated by HIV-1 Vpu. BST-2 antagonism enhances viral release, while NTB-A and PVR downmodulation contributes to NK cell evasion. However, it remains unclear how Vpu can target multiple cellular factors simultaneously. Here we provide evidence that under physiological conditions, BST-2 is preferentially targeted by Vpu over NTB-A and PVR. Specifically, we show that type I IFNs decrease Vpu’s polyfunctionality by upregulating BST-2, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. This indicates that there is a hierarchy of Vpu substrates upon IFN treatment, revealing that for the virus, targeting BST-2 as part of its resistance to IFN takes precedence over evading NK cell responses. This reveals a potential weakness in HIV-1’s immunoevasion mechanisms that may be exploited therapeutically to harness NK cell responses against HIV-1.Jérémie PrévostSuzanne PickeringMitchell J. MumbyHalima MedjahedGabrielle Gendron-LepageGloria G. DelgadoBrennan S. DirkJimmy D. DikeakosChristina M. StürzelDaniel SauterFrank KirchhoffFrederic Bibollet-RucheBeatrice H. HahnMathieu DubéDaniel E. KaufmannStuart J. D. NeilAndrés FinziJonathan RichardAmerican Society for MicrobiologyarticleADCCDNAM-1HIVNK cellsNTB-APVRMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
ADCC DNAM-1 HIV NK cells NTB-A PVR Microbiology QR1-502 |
| spellingShingle |
ADCC DNAM-1 HIV NK cells NTB-A PVR Microbiology QR1-502 Jérémie Prévost Suzanne Pickering Mitchell J. Mumby Halima Medjahed Gabrielle Gendron-Lepage Gloria G. Delgado Brennan S. Dirk Jimmy D. Dikeakos Christina M. Stürzel Daniel Sauter Frank Kirchhoff Frederic Bibollet-Ruche Beatrice H. Hahn Mathieu Dubé Daniel E. Kaufmann Stuart J. D. Neil Andrés Finzi Jonathan Richard Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses |
| description |
ABSTRACT The HIV-1 accessory protein Vpu enhances viral release by counteracting the restriction factor BST-2. Furthermore, Vpu promotes NK cell evasion by downmodulating cell surface NTB-A and PVR, known ligands of the NK cell receptors NTB-A and DNAM-1, respectively. While it has been established that Vpu’s transmembrane domain (TMD) is required for the interaction and intracellular sequestration of BST-2, NTB-A, and PVR, it remains unclear how Vpu manages to target these proteins simultaneously. In this study, we show that upon upregulation, BST-2 is preferentially downregulated by Vpu over its other TMD substrates. We found that type I interferon (IFN)-mediated BST-2 upregulation greatly impairs the ability of Vpu to downregulate NTB-A and PVR. Our results suggest that occupation of Vpu by BST-2 affects its ability to downregulate other TMD substrates. Accordingly, knockdown of BST-2 increases Vpu’s potency to downmodulate NTB-A and PVR in the presence of type I IFN treatment. Moreover, we show that expression of human BST-2, but not that of the macaque orthologue, decreases Vpu’s capacity to downregulate NTB-A. Importantly, we show that type I IFNs efficiently sensitize HIV-1-infected cells to NTB-A- and DNAM-1-mediated direct and antibody-dependent NK cell responses. Altogether, our results reveal that type I IFNs decrease Vpu’s polyfunctionality, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. IMPORTANCE The restriction factor BST-2 and the NK cell ligands NTB-A and PVR are among a growing list of membrane proteins found to be downregulated by HIV-1 Vpu. BST-2 antagonism enhances viral release, while NTB-A and PVR downmodulation contributes to NK cell evasion. However, it remains unclear how Vpu can target multiple cellular factors simultaneously. Here we provide evidence that under physiological conditions, BST-2 is preferentially targeted by Vpu over NTB-A and PVR. Specifically, we show that type I IFNs decrease Vpu’s polyfunctionality by upregulating BST-2, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. This indicates that there is a hierarchy of Vpu substrates upon IFN treatment, revealing that for the virus, targeting BST-2 as part of its resistance to IFN takes precedence over evading NK cell responses. This reveals a potential weakness in HIV-1’s immunoevasion mechanisms that may be exploited therapeutically to harness NK cell responses against HIV-1. |
| format |
article |
| author |
Jérémie Prévost Suzanne Pickering Mitchell J. Mumby Halima Medjahed Gabrielle Gendron-Lepage Gloria G. Delgado Brennan S. Dirk Jimmy D. Dikeakos Christina M. Stürzel Daniel Sauter Frank Kirchhoff Frederic Bibollet-Ruche Beatrice H. Hahn Mathieu Dubé Daniel E. Kaufmann Stuart J. D. Neil Andrés Finzi Jonathan Richard |
| author_facet |
Jérémie Prévost Suzanne Pickering Mitchell J. Mumby Halima Medjahed Gabrielle Gendron-Lepage Gloria G. Delgado Brennan S. Dirk Jimmy D. Dikeakos Christina M. Stürzel Daniel Sauter Frank Kirchhoff Frederic Bibollet-Ruche Beatrice H. Hahn Mathieu Dubé Daniel E. Kaufmann Stuart J. D. Neil Andrés Finzi Jonathan Richard |
| author_sort |
Jérémie Prévost |
| title |
Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses |
| title_short |
Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses |
| title_full |
Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses |
| title_fullStr |
Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses |
| title_full_unstemmed |
Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses |
| title_sort |
upregulation of bst-2 by type i interferons reduces the capacity of vpu to protect hiv-1-infected cells from nk cell responses |
| publisher |
American Society for Microbiology |
| publishDate |
2019 |
| url |
https://doaj.org/article/a9c7f1cd222240a497b7cabeef046a5f |
| work_keys_str_mv |
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