Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity.
Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity.
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HIV-1不仅通过控制细胞表面的Env构象和数量，而且通过下调活化和共活化NK细胞受体的几种配体来改变NK细胞活化，从而逃避抗体依赖性细胞毒性（ADCC）应答。信号淋巴细胞活化分子（SLAM）受体家族（包括NTB-A和2B 4）充当共活化受体以维持NK细胞活化和细胞毒性应答。这些受体与CD 16（FcγRIII）和其他活化受体协同作用，触发NK细胞效应子功能。在该背景下，显示Vpu介导的HIV-1感染的CD 4 T细胞上NTB-A的下调通过嗜同性相互作用防止NK细胞脱粒，从而有助于ADCC逃避。然而，对HIV-1逃避2B 4介导的NK细胞活化和ADCC的能力知之甚少。在这里，我们表明，HIV-1下调2B 4的配体，CD 48，从感染细胞表面的Vpu依赖性的方式。这种活性在来自HIV-1/SIVcpz谱系的Vpu蛋白中是保守的，并且依赖于位于其跨膜结构域和双磷酸丝氨酸基序中的保守残基。我们发现NTB-A和2B 4刺激CD 16介导的NK细胞脱粒，并在相同程度上促进针对HIV-1感染细胞的ADCC反应。我们的研究结果表明，HIV-1已经进化到下调两种SLAM受体的配体以逃避ADCC。抗体依赖性细胞毒性（ADCC）可有助于消除HIV-1感染细胞和HIV-1储库。深入了解HIV-1逃避ADCC的机制可能有助于开发减少病毒库的新方法。信号淋巴细胞活化分子（SLAM）受体家族的成员，如NTB-A和2B 4，在刺激NK细胞效应子功能（包括ADCC）中发挥关键作用。在这里，我们发现Vpu下调2B 4的配体CD 48，这有助于保护HIV-1感染的细胞免受ADCC的影响。我们的研究结果强调了病毒在防止触发SLAM受体以逃避ADCC方面的重要性。
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. 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.
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影响因子：
16.6
作者：
Bruel T;Guivel-Benhassine F;Amraoui S;Malbec M;Richard L;Bourdic K;Donahue DA;Lorin V;Casartelli N;Noël N;Lambotte O;Mouquet H;Schwartz O
通讯作者：
Schwartz O
影响因子：
7.3
作者：
Beltrán D;López-Vergès S
通讯作者：
López-Vergès S
影响因子：
5.4
作者：
Ding, Shilei;Veillette, Maxime;Finzi, Andres
通讯作者：
Finzi, Andres
影响因子：
56.9
作者：
Bauer, S;Groh, V;Spies, T
通讯作者：
Spies, T
影响因子：
6.7
作者：
Alpert MD;Harvey JD;Lauer WA;Reeves RK;Piatak M Jr;Carville A;Mansfield KG;Lifson JD;Li W;Desrosiers RC;Johnson RP;Evans DT
通讯作者：
Evans DT