Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL.
Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL.
复制标题
具有抗 HIV-1 JRFL 中和活性的人 V3 特异性单克隆抗体 2424 的功能和结构表征。
DOI：
10.1128/jvi.01280-15
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发表时间：
2015
影响因子：
5.4
通讯作者：
Hioe,CatarinaE
中科院分区：
文献类型：
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作者：
Kumar,Rajnish;Pan,Ruimin;Upadhyay,Chitra;Mayr,Luzia;Cohen,Sandra;Wang,Xiao-Hong;Balasubramanian,Preetha;Nádas,Arthur;Seaman,MichaelS;Zolla-Pazner,Susan;Gorny,MiroslawK;Kong,Xiang-Peng;Hioe,CatarinaE
HIV-1 gp120 的 V3 区域对于病毒-辅助受体相互作用非常重要，并且具有高度免疫原性。尽管大多数抗V3抗体仅中和敏感的1级病毒，但存在对抵抗力更强的病毒有效的抗V3抗体，更好地了解这些抗体及其表位将有利于开发针对HIV的新型疫苗免疫原。 HIV-1 分离株 JRFL 及其神秘的 V3 对大多数 V3 特异性单克隆抗体 (MAb) 具有耐药性。然而，V3 MAb 2424 对 JRFL 实现了 100% 中和。 2424 由 IGHV3-53 和 IGLV2-28 基因编码，其他 V3 单克隆抗体很少使用这一配对。 2424 还具有独特的结合和中和特性。对甘露糖苷酶抑制剂产生的 2424 介导的 JRFL 中和的研究进一步表明，其中和活性不受病毒包膜的聚糖组成的影响。为了了解 2424 的独特活性，我们确定了 2424 Fab 与 JRFL V3 肽复合物的晶体结构，并表明 2424 表位位于 V3 冠 (307IHIGPGRAFYT319) 的尖端，主要与 HisP308、ProP313 和 ArgP315 相互作用。 2424 的结合模式与充分表征的 MAb 447-52D 类似，尽管 2424 更具有侧链依赖性。 2424 表位集中在 V3 的最顶端，远离附近的聚糖，有利于抗体的进入。这一特征将 2424 表位与其他 V3 冠表位区分开来，并表明 V3 的尖端是 HIV 疫苗免疫原的潜在靶点和整合位点。 重要性 HIV/AIDS 疫苗对于控制继续困扰全世界数百万人的 HIV 流行至关重要。然而，艾滋病毒疫苗的开发受到重大科学挑战的阻碍，其中之一是迄今为止评估的艾滋病毒候选疫苗无法引发有效且广泛中和的抗体的产生。 V3 环是病毒包膜糖蛋白上为数不多的可诱导中和抗体的免疫原性靶点之一，但在许多病毒中，V3 的某些部分无法被抗体识别。这项研究检测了一种 V3 特异性单克隆抗体，它可以完全中和 HIV-1 JRFL（一种对大多数 V3 抗体具有抗性的病毒分离株）。我们的数据表明，该抗体识别 V3 的最远端，该尖端不像 V3 的其他部分那样被遮挡。因此，2424的表位位于病毒的脆弱位点之一，可用于设计HIV疫苗免疫原。
The V3 region of HIV-1 gp120 is important for virus-coreceptor interaction and highly immunogenic. Although most anti-V3 antibodies neutralize only the sensitive tier 1 viruses, anti-V3 antibodies effective against the more resistant viruses exist, and a better understanding of these antibodies and their epitopes would be beneficial for the development of novel vaccine immunogens against HIV. The HIV-1 isolate JRFL with its cryptic V3 is resistant to most V3-specific monoclonal antibodies (MAbs). However, the V3 MAb 2424 achieves 100% neutralization against JRFL. 2424 is encoded by IGHV3-53 and IGLV2-28 genes, a pairing rarely used by the other V3 MAbs. 2424 also has distinct binding and neutralization profiles. Studies of 2424-mediated neutralization of JRFL produced with a mannosidase inhibitor further revealed that its neutralizing activity is unaffected by the glycan composition of the virus envelope. To understand the distinct activity of 2424, we determined the crystal structure of 2424 Fab in complex with a JRFL V3 peptide and showed that the 2424 epitope is located at the tip of the V3 crown (307IHIGPGRAFYT319), dominated by interactions with HisP308, ProP313, and ArgP315. The binding mode of 2424 is similar to that of the well-characterized MAb 447-52D, although 2424 is more side chain dependent. The 2424 epitope is focused on the very apex of V3, away from nearby glycans, facilitating antibody access. This feature distinguishes the 2424 epitope from the other V3 crown epitopes and indicates that the tip of V3 is a potential site to target and incorporate into HIV vaccine immunogens.IMPORTANCEHIV/AIDS vaccines are crucial for controlling the HIV epidemics that continue to afflict millions of people worldwide. However, HIV vaccine development has been hampered by significant scientific challenges, one of which is the inability of HIV vaccine candidates evaluated thus far to elicit production of potent and broadly neutralizing antibodies. The V3 loop is one of the few immunogenic targets on the virus envelope glycoprotein that can induce neutralizing antibodies, but in many viruses, parts of V3 are inaccessible for antibody recognition. This study examined a V3-specific monoclonal antibody that can completely neutralize HIV-1 JRFL, a virus isolate resistant to most V3 antibodies. Our data reveal that this antibody recognizes the most distal tip of V3, which is not as occluded as other parts of V3. Hence, the epitope of 2424 is in one of the vulnerable sites on the virus that may be exploited in designing HIV vaccine immunogens.