Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies.
Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies.
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DOI：
10.1016/j.chom.2014.08.006
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发表时间：
2014-09-10
影响因子：
30.3
通讯作者：
Haynes BF
中科院分区：
文献类型：
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作者：
Kepler TB;Liao HX;Alam SM;Bhaskarabhatla R;Zhang R;Yandava C;Stewart S;Anasti K;Kelsoe G;Parks R;Lloyd KE;Stolarchuk C;Pritchett J;Solomon E;Friberg E;Morris L;Karim SS;Cohen MS;Walter E;Moody MA;Wu X;Altae-Tran HR;Georgiev IS;Kwong PD;Boyd SD;Fire AZ;Mascola JR;Haynes BF
诱导HIV-1广谱中和抗体（bnAb）是HIV-1疫苗开发的目标，但由于bnAb的不寻常特性，包括高体细胞超突变（SHM）频率和框内插入和缺失（indels），仍然具有挑战性。在这里，我们检查了HIV-1 bnAb内indel的倾向和功能要求。HIV-1感染者和未感染者的免疫球蛋白（IG）VHDJH基因的高通量测序显示，在HIV-1感染者中插入缺失频率升高，没有独特的属性归因于bnAb产生的个体。这种增加的indel发生仅取决于SHM点突变的频率。插入缺失编码区通常邻近抗原结合位点。此外，HIV-1 CD 4结合位点bnAb克隆谱系的重建揭示了bnAb活性需要大的化合物VHDJH插入缺失。因此，疫苗开发应集中于设计靶向持续激活bnAb谱系的方案，以实现所需的SHM和插入缺失事件。
Induction of HIV-1 broad neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development but has remained challenging partially due to unusual traits of bnAbs, including high somatic hypermutation (SHM) frequencies and in-frame insertions and deletions (indels). Here we examined the propensity and functional requirement for indels within HIV-1 bnAbs. High-throughput sequencing of the immunoglobulin (Ig) VHDJH genes in HIV-1 infected and uninfected individuals revealed that the indel frequency was elevated among HIV-1-infected subjects, with no unique properties attributable to bnAb-producing individuals. This increased indel occurrence depended only on the frequency of SHM point-mutations. Indel-encoded regions were generally proximal to antigen binding sites. Additionally, reconstruction of a HIV-1 CD4-binding site bnAb clonal lineage revealed that a large compound VHDJH indel was required for bnAb activity. Thus, vaccine development should focus on designing regimens targeted at sustained activation of bnAb lineages to achieve the required SHM and indel events.
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影响因子：
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作者：
Kepler TB
通讯作者：
Kepler TB
DOI：
10.1097/qad.0000000000000106
发表时间：
2014-01-14
期刊：
AIDS (London, England)
影响因子：
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作者：
Hraber P;Seaman MS;Bailer RT;Mascola JR;Montefiori DC;Korber BT
通讯作者：
Korber BT
影响因子：
56.9
作者：
Haynes, BF;Fleming, J;Alam, SM
通讯作者：
Alam, SM
DOI：
10.1126/science.1213256
发表时间：
2011-11-25
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Pejchal R;Doores KJ;Walker LM;Khayat R;Huang PS;Wang SK;Stanfield RL;Julien JP;Ramos A;Crispin M;Depetris R;Katpally U;Marozsan A;Cupo A;Maloveste S;Liu Y;McBride R;Ito Y;Sanders RW;Ogohara C;Paulson JC;Feizi T;Scanlan CN;Wong CH;Moore JP;Olson WC;Ward AB;Poignard P;Schief WR;Burton DR;Wilson IA
通讯作者：
Wilson IA
影响因子：
46.9
作者：
通讯作者：
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