The CH1α domain of mucosal gp41 IgA contributes to antibody specificity and antiviral functions in HIV-1 highly exposed Sero-Negative individuals.
The CH1α domain of mucosal gp41 IgA contributes to antibody specificity and antiviral functions in HIV-1 highly exposed Sero-Negative individuals.
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DOI：
10.1371/journal.ppat.1009103
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发表时间：
2020-12
期刊：
影响因子：
6.7
通讯作者：
Bomsel M
中科院分区：
文献类型：
--
作者：
Khamassi M;Xu L;Rey J;Duchemin M;Bouceba T;Tuffery P;Tudor D;Bomsel M
抗体分子包括一个赋予抗原特异性和亲和力的可变域，不同于决定效应器功能的重链常数(CH)域。在这里，我们通过评估CH1gp41结构域对表位特异性和功能的独特影响来询问这一范式，使用来自α-1高暴露但持续血清阴性的两个粘膜gp41特异性FAB-IGAs(FABA)。这些HESN发展选择性亲和力成熟的HIV-1特异性黏膜IgA，靶向gp41病毒包膜，并可能提供保护，尽管机制尚不清楚。将Fabas同型转换为Fab-igs(FabGs)导致对HIV-1分支A、B和C gp41的亲和力降低10倍，同时减少了HIV-1交叉分支的中和。与FabGs不同，FabA构象表位选择性地以6-螺旋束和融合前构象交叉的形式映射在gp41上。最后，我们在Silico中设计了一个12个氨基酸的多肽，它概括了一个蚕豆构象表位，它抑制了蚕豆与gp41交叉支链的结合及其中和活性。总之，我们的结果表明，CH1的α结构域通过变构效应塑造抗体副表位，从而增强抗体的特异性和功能活性。此外，它们还阐明了这些HESN免疫球蛋白可能提供预防HIV-1性感染的机制。我们用反向疫苗学表征的IgA特异性表位可能有助于设计一种粘膜HIV-1疫苗。在HIV-1高暴露持续血清阴性个体(HESN)中，保护是一种多因素现象，在这种现象中，粘膜IgA而不是免疫球蛋白G起决定性的抗病毒作用。HESN IgA反应集中在HIV-1包膜gp41亚单位的保守区域，而在HIV-1感染者中观察到更广泛的免疫球蛋白和IgA反应。目前尚不清楚在HESN中如何只保护IgA，而不是免疫球蛋白。我们通过比较来源于HESN的粘膜gp41特异性Fab-IgA1(FABA)和配对Fab-IgG1(FabG)，探讨了每种同型的CH1结构域在抗原识别和功能中的作用。结果表明，CH1gp41和α结构域的结构差异影响了亲和力常数，蚕豆对A、B和C分支的gp41具有较高的亲和力。蚕豆对A、B和C分支γ感染的中和和从朗格罕向CD4+T细胞的转移是交叉的，并且高于相应的免疫球蛋白。因此，蚕豆和G识别gp41 A、B和C分支gp41晶体结构上的不同gp41表位。利用分子模拟，我们定义了一个与gp41 A、B和C分支gp41共有的三维表位相对应的多肽，该表位专用于其中一种蚕豆，它逆转了蚕豆的中和活性。总之，我们在这里展示了CH1结构域影响抗体副表位，进而影响其特异性和功能活性。在gp41上检索到的蚕豆跨分支表位可能在针对HIV-1的黏膜疫苗设计中有用。
The antibody molecule comprises a variable domain conferring antigen specificity and affinity distinct from the heavy chain constant (CH) domains dictating effector functions. We here interrogate this paradigm by evaluating the unique influence of the CH1α domain on epitope specificity and functions using two mucosal gp41-specific Fab-IgAs (FabA) derived from HIV-1 highly-exposed but persistently seronegative individuals (HESN). These HESN develop selectively affinity-matured HIV-1-specific mucosal IgA that target the gp41 viral envelope and might provide protection although by unclear mechanisms. Isotype-switching FabAs into Fab-IgGs (FabGs) results in a >10-fold loss in affinity for HIV-1 clade A, B, and C gp41, together with reduced neutralization of HIV-1 cross-clade. The FabA conformational epitopes map selectively on gp41 in 6-Helix bundle and pre-fusion conformations cross-clade, unlike FabGs. Finally, we designed in silico, a 12 amino-acid peptide recapitulating one FabA conformational epitope that inhibits the FabA binding to gp41 cross-clade and its neutralizing activity. Altogether, our results reveal that the CH1α domain shapes the antibody paratope through an allosteric effect, thereby strengthening the antibody specificity and functional activities. Further, they clarify the mechanisms by which these HESN IgAs might confer protection against HIV-1-sexual acquisition. The IgA-specific epitope we characterized by reverse vaccinology could help designing a mucosal HIV-1 vaccine. In HIV-1 highly exposed persistently seronegative individuals (HESN), protection is a multifactorial phenomenon whereby mucosal IgA, but not IgG, play a determinant anti-viral role. The HESN IgA response focuses on conserved regions of the HIV-1 envelope gp41 subunit, in contrast with the broader IgG and IgA response observed in HIV-1-infected individuals. How protective only IgA, but not IgG, develop in HESN remains unclear. We addressed the role of the CH1 domain of each isotype in antigen recognition and functions by comparing mucosal gp41 specific Fab-IgA1 (FabA) derived from HESN with paired Fab-IgG1 (FabG). We show that structural differences in the CH1α and γ domains impact affinity constants, FabA having higher affinity for gp41 derived from clade A, B and C. FabA neutralization of clade A, B and C HIV-1 infection and transfer from Langerhans to CD4+T cells were cross clade and higher than that observed with corresponding IgG. Accordingly, FabA and G recognize different gp41 epitopes on gp41 clade A, B and C gp41 crystal structures. Using molecular modeling, we defined a peptide corresponding to one 3-D epitope common to gp41 clade A, B and C gp41 specific for one of the FabA that reverses the FabA neutralizing activities. Altogether, we show here that the CH1 domain influences the antibody paratope and in turn its specificity and functional activities. The FabA cross-clade epitopes retrieved on gp41 could be useful in mucosal vaccine design against HIV-1.
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影响因子：
14.9
作者：
NCBI Resource Coordinators
通讯作者：
NCBI Resource Coordinators
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
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影响因子：
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作者：
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Connors M
影响因子：
1.6
作者：
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通讯作者：
Skerra, A
DOI：
10.1107/s0907444912048664
发表时间：
2013-03-01
影响因子：
2.2
作者：
Correa, Agustin;Trajtenberg, Felipe;Buschiazzo, Alejandro
通讯作者：
Buschiazzo, Alejandro