Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity
ABSTRACT HIV-1 evades antibody-dependent cellular cytotoxicity (ADCC) responses not only by controlling Env conformation and quantity at the cell surface but also by altering NK cell activation via the downmodulation of several ligands of activating and co-activating NK cell receptors. The signaling...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00789-23 |
| _version_ | 1797730241044545536 |
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| author | Lorie Marchitto Mehdi Benlarbi Jérémie Prévost Annemarie Laumaea Jade Descôteaux-Dinelle Halima Medjahed Catherine Bourassa Gabrielle Gendron-Lepage Frank Kirchhoff Daniel Sauter Beatrice H. Hahn Andrés Finzi Jonathan Richard |
| author_facet | Lorie Marchitto Mehdi Benlarbi Jérémie Prévost Annemarie Laumaea Jade Descôteaux-Dinelle Halima Medjahed Catherine Bourassa Gabrielle Gendron-Lepage Frank Kirchhoff Daniel Sauter Beatrice H. Hahn Andrés Finzi Jonathan Richard |
| author_sort | Lorie Marchitto |
| collection | DOAJ |
| description | ABSTRACT HIV-1 evades antibody-dependent cellular cytotoxicity (ADCC) responses not only by controlling Env conformation and quantity at the cell surface but also by altering NK cell activation via the downmodulation of several ligands of activating and co-activating NK cell receptors. The signaling lymphocyte activation molecule (SLAM) family of receptors, which includes NTB-A and 2B4, act as co-activating receptors to sustain NK cell activation and cytotoxic responses. These receptors cooperate with CD16 (FcγRIII) and other activating receptors to trigger NK cell effector functions. In that context, Vpu-mediated downregulation of NTB-A on HIV-1-infected CD4 T cells was shown to prevent NK cell degranulation via an homophilic interaction, thus contributing to ADCC evasion. However, less is known on the capacity of HIV-1 to evade 2B4-mediated NK cell activation and ADCC. Here, we show that HIV-1 downregulates the ligand of 2B4, CD48, from the surface of infected cells in a Vpu-dependent manner. This activity is conserved among Vpu proteins from the HIV-1/SIVcpz lineage and depends on conserved residues located in its transmembrane domain and dual phosphoserine motif. We show that NTB-A and 2B4 stimulate CD16-mediated NK cell degranulation and contribute to ADCC responses directed to HIV-1-infected cells to the same extent. Our results suggest that HIV-1 has evolved to downmodulate the ligands of both SLAM receptors to evade ADCC. IMPORTANCE Antibody-dependent cellular cytotoxicity (ADCC) can contribute to the elimination of HIV-1-infected cells and HIV-1 reservoirs. An in-depth understanding of the mechanisms used by HIV-1 to evade ADCC might help develop novel approaches to reduce the viral reservoirs. Members of the signaling lymphocyte activation molecule (SLAM) family of receptors, such as NTB-A and 2B4, play a key role in stimulating NK cell effector functions, including ADCC. Here, we show that Vpu downmodulates CD48, the ligand of 2B4, and this contributes to protect HIV-1-infected cells from ADCC. Our results highlight the importance of the virus to prevent the triggering of the SLAM receptors to evade ADCC. |
| first_indexed | 2024-03-12T11:41:25Z |
| format | Article |
| id | doaj.art-370ace319440473889660cd756045895 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-03-12T11:41:25Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-370ace319440473889660cd7560458952023-08-31T15:04:20ZengAmerican Society for MicrobiologymBio2150-75112023-08-0114410.1128/mbio.00789-23Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicityLorie Marchitto0Mehdi Benlarbi1Jérémie Prévost2Annemarie Laumaea3Jade Descôteaux-Dinelle4Halima Medjahed5Catherine Bourassa6Gabrielle Gendron-Lepage7Frank Kirchhoff8Daniel Sauter9Beatrice H. Hahn10Andrés Finzi11Jonathan Richard12Centre de Recherche du CHUM , Montreal, Quebec, CanadaCentre de Recherche du CHUM , Montreal, Quebec, CanadaCentre de Recherche du CHUM , Montreal, Quebec, CanadaCentre de Recherche du CHUM , Montreal, Quebec, CanadaCentre de Recherche du CHUM , Montreal, Quebec, CanadaCentre de Recherche du CHUM , Montreal, Quebec, CanadaCentre de Recherche du CHUM , Montreal, Quebec, CanadaCentre de Recherche du CHUM , Montreal, Quebec, CanadaInstitute of Molecular Virology, Ulm University Medical Center , Ulm, GermanyInstitute of Molecular Virology, Ulm University Medical Center , Ulm, GermanyDepartment of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USACentre de Recherche du CHUM , Montreal, Quebec, CanadaCentre de Recherche du CHUM , Montreal, Quebec, CanadaABSTRACT HIV-1 evades antibody-dependent cellular cytotoxicity (ADCC) responses not only by controlling Env conformation and quantity at the cell surface but also by altering NK cell activation via the downmodulation of several ligands of activating and co-activating NK cell receptors. The signaling lymphocyte activation molecule (SLAM) family of receptors, which includes NTB-A and 2B4, act as co-activating receptors to sustain NK cell activation and cytotoxic responses. These receptors cooperate with CD16 (FcγRIII) and other activating receptors to trigger NK cell effector functions. In that context, Vpu-mediated downregulation of NTB-A on HIV-1-infected CD4 T cells was shown to prevent NK cell degranulation via an homophilic interaction, thus contributing to ADCC evasion. However, less is known on the capacity of HIV-1 to evade 2B4-mediated NK cell activation and ADCC. Here, we show that HIV-1 downregulates the ligand of 2B4, CD48, from the surface of infected cells in a Vpu-dependent manner. This activity is conserved among Vpu proteins from the HIV-1/SIVcpz lineage and depends on conserved residues located in its transmembrane domain and dual phosphoserine motif. We show that NTB-A and 2B4 stimulate CD16-mediated NK cell degranulation and contribute to ADCC responses directed to HIV-1-infected cells to the same extent. Our results suggest that HIV-1 has evolved to downmodulate the ligands of both SLAM receptors to evade ADCC. IMPORTANCE Antibody-dependent cellular cytotoxicity (ADCC) can contribute to the elimination of HIV-1-infected cells and HIV-1 reservoirs. An in-depth understanding of the mechanisms used by HIV-1 to evade ADCC might help develop novel approaches to reduce the viral reservoirs. Members of the signaling lymphocyte activation molecule (SLAM) family of receptors, such as NTB-A and 2B4, play a key role in stimulating NK cell effector functions, including ADCC. Here, we show that Vpu downmodulates CD48, the ligand of 2B4, and this contributes to protect HIV-1-infected cells from ADCC. Our results highlight the importance of the virus to prevent the triggering of the SLAM receptors to evade ADCC.https://journals.asm.org/doi/10.1128/mbio.00789-23HIV-1NK cellVpuNefCD48NTB-A |
| spellingShingle | Lorie Marchitto Mehdi Benlarbi Jérémie Prévost Annemarie Laumaea Jade Descôteaux-Dinelle Halima Medjahed Catherine Bourassa Gabrielle Gendron-Lepage Frank Kirchhoff Daniel Sauter Beatrice H. Hahn Andrés Finzi Jonathan Richard Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity mBio HIV-1 NK cell Vpu Nef CD48 NTB-A |
| title | Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity |
| title_full | Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity |
| title_fullStr | Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity |
| title_full_unstemmed | Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity |
| title_short | Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity |
| title_sort | impact of hiv 1 vpu mediated downregulation of cd48 on nk cell mediated antibody dependent cellular cytotoxicity |
| topic | HIV-1 NK cell Vpu Nef CD48 NTB-A |
| url | https://journals.asm.org/doi/10.1128/mbio.00789-23 |
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