Enhancing HIV-1 Neutralization by Increasing the Local Concentration of Membrane-Proximal External Region-Directed Broadly Neutralizing Antibodies.
Enhancing HIV-1 Neutralization by Increasing the Local Concentration of Membrane-Proximal External Region-Directed Broadly Neutralizing Antibodies.
复制标题
DOI：
10.1128/jvi.01647-22
复制
发表时间：
2023-01-31
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
--
作者：
针对人类免疫缺陷病毒1型（HIV-1）包膜（Env）gp 41组分的膜近端外部区域（MPER）的广泛中和抗体（bNAb）的特征在于长的疏水性重链互补决定区3s（HCDR 3s），其与MPER和一些病毒膜脂质相互作用以实现局部浓度增加。在这里，我们表明，通过与高亲和力Fc受体FcγRI结合，增加细胞表面的MPER定向bNAb的局部浓度，以类似于先前报道的观察结果的方式增强了它们阻止病毒进入的能力，其中MPER bNAb的脂质结合活性增加了它们在病毒表面膜上的浓度。然而，MPR导向的bNAb 10 E8与FcγRI的结合消除了N-七肽重复序列（NHR）靶向抗体D5_AR和NHR靶向小分子恩夫韦肽（T20）的中和协同作用，这可能是由于FcγRI-10 E8-MPER复合物中NHR的可及性降低。综上所述，我们的结果表明，脂质结合活性和Fcγ RI介导的增强作用共同作用，通过增加病毒融合位点附近的局部浓度来提高MPR定向bNAb的效力。因此，脂质结合可能不是MPER靶向bNAb有效中和的严格要求，因为替代方法可以实现局部浓度的类似增加，同时避免与免疫宿主耐受性相关的潜在责任。三聚体糖蛋白Env是HIV-1表面表达的唯一病毒蛋白，是广泛中和抗体的靶点，也是大多数疫苗开发工作的重点。靶向Env的膜近端外部区域（MPER）的广泛中和抗体显示脂质结合特征，并且调节这种相互作用影响中和。在本研究中，我们检测了具有不同病毒膜结合和宿主Fcγ RI结合能力的MPR靶向抗体10 E8变体的中和效力。我们的研究结果表明，与脂质和FcγRI的结合通过将抗体集中在病毒融合位点来提高MPR定向抗体的中和效力。因此，脂质结合可能不是靶向MPER的广泛中和抗体唯一需要的，因为增加局部浓度的替代方法可以实现类似的效力改善。
Broadly neutralizing antibodies (bNAbs) against the membrane-proximal external region (MPER) of the gp41 component of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) are characterized by long, hydrophobic, heavy chain complementarity-determining region 3s (HCDR3s) that interact with the MPER and some viral membrane lipids to achieve increased local concentrations. Here, we show that increasing the local concentration of MPER-directed bNAbs at the cell surface via binding to the high-affinity Fc receptor FcγRI potentiates their ability to prevent viral entry in a manner analogous to the previously reported observation wherein the lipid-binding activity of MPER bNAbs increases their concentration at the viral surface membrane. However, binding of MPER-directed bNAb 10E8 to FcγRI abolishes the neutralization synergy that is seen with the N-heptad repeat (NHR)-targeting antibody D5_AR and NHR-targeting small molecule enfuvirtide (T20), possibly due to decreased accessibility of the NHR in the FcγRI-10E8-MPER complex. Taken together, our results suggest that lipid-binding activity and FcγRI-mediated potentiation function in concert to improve the potency of MPER-directed bNAbs by increasing their local concentration near the site of viral fusion. Therefore, lipid binding may not be a strict requirement for potent neutralization by MPER-targeting bNAbs, as alternative methods can achieve similar increases in local concentrations while avoiding potential liabilities associated with immunologic host tolerance. IMPORTANCE The trimeric glycoprotein Env, the only viral protein expressed on the surface of HIV-1, is the target of broadly neutralizing antibodies and the focus of most vaccine development efforts. Broadly neutralizing antibodies targeting the membrane proximal external region (MPER) of Env show lipid-binding characteristics, and modulating this interaction affects neutralization. In this study, we tested the neutralization potencies of variants of the MPER-targeting antibody 10E8 with different viral-membrane-binding and host FcγRI-binding capabilities. Our results suggest that binding to both lipid and FcγRI improves the neutralization potency of MPER-directed antibodies by concentrating the antibodies at sites of viral fusion. As such, lipid binding may not be uniquely required for MPER-targeting broadly neutralizing antibodies, as alternative methods to increase local concentration can achieve similar improvements in potency.
登录
查看更多内容
影响因子：
4.8
作者：
Champagne, Kelly;Shishido, Akira;Root, Michael J.
通讯作者：
Root, Michael J.
DOI：
10.1073/pnas.1807259115
发表时间：
2018-09-18
影响因子：
11.1
作者：
Fu, Qingshan;Shaik, Md Munan;Chou, James J.
通讯作者：
Chou, James J.
影响因子：
5.4
作者：
Donius LR;Cheng Y;Choi J;Sun ZY;Hanson M;Zhang M;Gierahn TM;Marquez S;Uduman M;Kleinstein SH;Irvine D;Love JC;Reinherz EL;Kim M
通讯作者：
Kim M
影响因子：
2.6
作者：
Foucquier, Julie;Guedj, Mickael
通讯作者：
Guedj, Mickael
影响因子：
6.7
作者：
Verkoczy L;Kelsoe G;Haynes BF
通讯作者：
Haynes BF