AP-2 Adaptor Complex-Dependent Enhancement of HIV-1 Replication by Nef in the Absence of the Nef/AP-2 Targets SERINC5 and CD4.
AP-2 Adaptor Complex-Dependent Enhancement of HIV-1 Replication by Nef in the Absence of the Nef/AP-2 Targets SERINC5 and CD4.
复制标题
DOI：
10.1128/mbio.03382-22
复制
发表时间：
2023-02-28
期刊：
影响因子：
6.4
通讯作者：
Göttlinger H
中科院分区：
文献类型：
--
作者：
Olety B;Usami Y;Wu Y;Peters P;Göttlinger H
人类免疫缺陷病毒1型（HIV-1）Nef劫持网格蛋白接头复合物2（AP-2），下调病毒受体CD4和抗病毒多通道跨膜蛋白SERINC 3和SERINC 5，当掺入时抑制子代病毒粒子的感染性。在缺乏SERINC 3和SERINC 5的Jurkat Tag T淋巴细胞中，Nef不再是完全子代病毒感染性和有效病毒复制所需的。然而，在MOLT-3 T淋巴细胞中，HIV-1复制仍然高度依赖于Nef，即使在没有SERINC 3和SERINC 5的情况下。使用敲除（KO）方法，我们现在表明，Nef介导的增强HIV-1在MOLT-3细胞中的复制不依赖于Nef相互作用激酶LCK和PAK2。此外，Nef甚至在同时缺乏三个Nef/AP-2靶标SERINC 3、SERINC 5和CD 4的三重KO MOLT-3细胞中也显著增强了HIV-1的复制，并且用Nef抗性CD 4重建以允许HIV-1进入。然而，Nef突变体在三重KO细胞中促进HIV-1复制的能力与结合AP-2的能力严格相关。此外，敲除和重建实验证实了AP-2的参与。这些观察结果提出了MOLT-3细胞表达一种新的抗病毒因子的可能性，该因子以AP-2依赖的方式被Nef下调。
Human immunodeficiency virus type 1 (HIV-1) Nef hijacks the clathrin adaptor complex 2 (AP-2) to downregulate the viral receptor CD4 and the antiviral multipass transmembrane proteins SERINC3 and SERINC5, which inhibit the infectivity of progeny virions when incorporated. In Jurkat Tag T lymphoid cells lacking SERINC3 and SERINC5, Nef is no longer required for full progeny virus infectivity and for efficient viral replication. However, in MOLT-3 T lymphoid cells, HIV-1 replication remains highly dependent on Nef even in the absence of SERINC3 and SERINC5. Using a knockout (KO) approach, we now show that the Nef-mediated enhancement of HIV-1 replication in MOLT-3 cells does not depend on the Nef-interacting kinases LCK and PAK2. Furthermore, Nef substantially enhanced HIV-1 replication even in triple-KO MOLT-3 cells that simultaneously lacked the three Nef/AP-2 targets, SERINC3, SERINC5, and CD4, and were reconstituted with a Nef-resistant CD4 to permit HIV-1 entry. Nevertheless, the ability of Nef mutants to promote HIV-1 replication in the triple-KO cells correlated strictly with the ability to bind AP-2. In addition, knockdown and reconstitution experiments confirmed the involvement of AP-2. These observations raise the possibility that MOLT-3 cells express a novel antiviral factor that is downregulated by Nef in an AP-2-dependent manner.
登录
查看更多内容
影响因子：
5.3
作者：
Emert-Sedlak, Lori A.;Moukha-Chafiq, Omar;Shi, Haibin;Du, Shoucheng;Alvarado, John J.;Pathak, Vibha;Tanner, Samuel G.;Hunter, Robert N.;Nebane, Miranda;Chen, Li;Ilina, Tatiana, V;Ishima, Rieko;Zhang, Sixue;Kuzmichev, Yury, V;Wonderlich, Elizabeth R.;Schader, Susan M.;Augelli-Szafran, Corinne E.;Ptak, Roger G.;Smithgall, Thomas E.
通讯作者：
Smithgall, Thomas E.
影响因子：
3.3
作者：
Olivieri KC;Mukerji J;Gabuzda D
通讯作者：
Gabuzda D
影响因子：
3.7
作者：
Cheng, H;Hoxie, J;Parks, WP
通讯作者：
Parks, WP
影响因子：
5.4
作者：
Gondim, Marcos Vinicius;Wiltzer-Bach, Linda;Schindler, Michael
通讯作者：
Schindler, Michael
影响因子：
1.5
作者：
Jin, Yong-Jiu;Cai, Catherine Yi;Burakoff, Steven J.
通讯作者：
Burakoff, Steven J.