HIV-1 Vpu restricts Fc-mediated effector functions in vivo.
HIV-1 Vpu restricts Fc-mediated effector functions in vivo.
复制标题
DOI：
10.1016/j.celrep.2022.111624
复制
发表时间：
2022-11-08
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
非中和抗体（nnAb）可以通过抗体依赖性细胞毒性（ADCC）消除HIV-1感染的细胞，并在RV 144疫苗试验中被鉴定为保护相关物。Fc介导的nnAb的效应功能最近显示出使用vpu缺陷型病毒在体内改变HIV-1感染的过程。由于已知Vpu下调细胞表面CD 4，从而引发病毒包膜糖蛋白（Env）的构象变化，我们询问Vpu表达的缺乏是否与观察到的nnAbs活性有关。我们发现，恢复Vpu表达大大降低了感染细胞的nnAb识别，使它们对ADCC具有抗性。此外，在人源化小鼠中施用nnAb仅在感染vpu缺陷型病毒但不感染野生型病毒的动物中降低病毒载量。已知“打开”Env并暴露nnAb表位的CD 4模拟物施用使得野生型病毒对nnAb Fc效应子功能敏感。这项工作强调了Vpu介导的体液反应逃避的重要性。Prévost等人证明HIV-1辅助蛋白Vpu在体外和体内均保护受感染细胞免受Fc效应子功能的影响。此外，他们表明，非中和抗体（nnAb）不能改变HIV-1在人源化小鼠中的复制，除非使用小的CD 4模拟物来“打开”Env并使nnAb相互作用。
Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to “open” Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses. Prévost et al. demonstrate that the HIV-1 accessory protein Vpu protects infected cells from Fc-effector functions both in vitro and in vivo. Furthermore, they show that non-neutralizing antibodies (nnAb) fail to alter HIV-1 replication in humanized mice unless small CD4-mimetics are used to “open up” Env and enable nnAb interaction.
登录
查看更多内容
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Bournazos S;Gazumyan A;Seaman MS;Nussenzweig MC;Ravetch JV
通讯作者：
Ravetch JV
影响因子：
3.7
作者：
Corti D;Langedijk JP;Hinz A;Seaman MS;Vanzetta F;Fernandez-Rodriguez BM;Silacci C;Pinna D;Jarrossay D;Balla-Jhagjhoorsingh S;Willems B;Zekveld MJ;Dreja H;O'Sullivan E;Pade C;Orkin C;Jeffs SA;Montefiori DC;Davis D;Weissenhorn W;McKnight A;Heeney JL;Sallusto F;Sattentau QJ;Weiss RA;Lanzavecchia A
通讯作者：
Lanzavecchia A
影响因子：
5.4
作者：
Acharya, Priyamvada;Tolbert, William D.;Pazgier, Marzena
通讯作者：
Pazgier, Marzena
影响因子：
64.8
作者：
Caskey M;Klein F;Lorenzi JC;Seaman MS;West AP Jr;Buckley N;Kremer G;Nogueira L;Braunschweig M;Scheid JF;Horwitz JA;Shimeliovich I;Ben-Avraham S;Witmer-Pack M;Platten M;Lehmann C;Burke LA;Hawthorne T;Gorelick RJ;Walker BD;Keler T;Gulick RM;Fätkenheuer G;Schlesinger SJ;Nussenzweig MC
通讯作者：
Nussenzweig MC