Identification of Near-Pan-neutralizing Antibodies against HIV-1 by Deconvolution of Plasma Humoral Responses.
Identification of Near-Pan-neutralizing Antibodies against HIV-1 by Deconvolution of Plasma Humoral Responses.
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DOI：
10.1016/j.cell.2018.03.061
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发表时间：
2018-06-14
期刊：
影响因子：
64.5
通讯作者：
DeVico AL
中科院分区：
文献类型：
--
作者：
Sajadi MM;Dashti A;Rikhtegaran Tehrani Z;Tolbert WD;Seaman MS;Ouyang X;Gohain N;Pazgier M;Kim D;Cavet G;Yared J;Redfield RR;Lewis GK;DeVico AL
从记忆 B 细胞中分离出的抗 HIV-1 包膜广泛中和单克隆抗体 (bNAb) 可能无法完全代表血浆中测量的 HIV-1 中和特征。因此，我们鉴定了直接从两个“精英中和者”血浆中提取的近泛中和抗体。使用蛋白质组学对循环抗 gp120 多克隆抗体进行解卷积，以指导骨髓浆细胞的谱系分析。在这两名受试者中，抗 CD4 结合位点 (CD4bs) 抗体的单一谱系解释了血浆中和活性。重要的是，这些谱系的成员有效中和了多层 117 种假病毒组的 89-100%，与循环抗体的特异性和广度密切匹配。对一种单克隆 N49P7 的 X 射线晶体学分析表明，它具有绕过 CD4bs Phe43 空腔的独特能力，同时深入到 gp120 内部结构域第 3 层高度保守的残基，这可能解释了其极端的效力和广度。对血浆抗 HIV-1 bNAb 的进一步直接分析应该为开发基于抗体的抗病毒药物和疫苗提供新的见解。 HIV 中和抗体通过识别病毒 gp120 糖蛋白的高度保守且难以接近的区域，实现了接近泛中和的活性。
Anti-HIV-1 envelope broadly neutralizing monoclonal antibodies (bNAbs) isolated from memory B-cells may not fully represent HIV-1 neutralizing profiles measured in plasma. Accordingly, we characterized near pan-neutralizing antibodies extracted directly from the plasma of two “elite neutralizers.” Circulating anti-gp120 polyclonal antibodies were deconvoluted using proteomics to guide lineage analysis of bone marrow plasma cells. In both subjects, a single lineage of anti-CD4-binding site (CD4bs) antibodies explained the plasma neutralizing activity. Importantly, members of these lineages potently neutralized 89–100% of a multi-tier 117 pseudovirus panel, closely matching the specificity and breadth of the circulating antibodies. X-ray crystallographic analysis of one monoclonal, N49P7, suggested a unique ability to bypass the CD4bs Phe43 cavity, while reaching deep into highly conserved residues of Layer 3 of the gp120 inner domain, likely explaining its extreme potency and breadth. Further direct analyses of plasma anti-HIV-1 bNAbs should provide new insights for developing antibody-based antiviral agents and vaccines. An HIV-neutralizing antibody achieves near pan-neutralizing activity through recognition of a highly conserved, difficult to access region of the viral gp120 glycoprotein.
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DOI：
10.1073/pnas.1217609110
发表时间：
2013-01-02
影响因子：
11.1
作者：
Guan, Yongjun;Pazgier, Marzena;Lewis, George K.
通讯作者：
Lewis, George K.
影响因子：
5.4
作者：
Lynch, Rebecca M.;Wong, Patrick;Mascola, John R.
通讯作者：
Mascola, John R.
影响因子：
64.5
作者：
de Taeye SW;Ozorowski G;Torrents de la Peña A;Guttman M;Julien JP;van den Kerkhof TL;Burger JA;Pritchard LK;Pugach P;Yasmeen A;Crampton J;Hu J;Bontjer I;Torres JL;Arendt H;DeStefano J;Koff WC;Schuitemaker H;Eggink D;Berkhout B;Dean H;LaBranche C;Crotty S;Crispin M;Montefiori DC;Klasse PJ;Lee KK;Moore JP;Wilson IA;Ward AB;Sanders RW
通讯作者：
Sanders RW
影响因子：
32.4
作者：
Halliley JL;Tipton CM;Liesveld J;Rosenberg AF;Darce J;Gregoretti IV;Popova L;Kaminiski D;Fucile CF;Albizua I;Kyu S;Chiang KY;Bradley KT;Burack R;Slifka M;Hammarlund E;Wu H;Zhao L;Walsh EE;Falsey AR;Randall TD;Cheung WC;Sanz I;Lee FE
通讯作者：
Lee FE
DOI：
10.1126/science.1213782
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Diskin R;Scheid JF;Marcovecchio PM;West AP Jr;Klein F;Gao H;Gnanapragasam PN;Abadir A;Seaman MS;Nussenzweig MC;Bjorkman PJ
通讯作者：
Bjorkman PJ