Isolation of an HIV-1 neutralizing peptide mimicking the CXCR4 and CCR5 surface from the heavy-chain complementary determining region 3 repertoire of a viremic controller
Isolation of an HIV-1 neutralizing peptide mimicking the CXCR4 and CCR5 surface from the heavy-chain complementary determining region 3 repertoire of a viremic controller
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DOI：
10.1097/qad.0000000000000925
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发表时间：
2016-01-28
期刊：
影响因子：
3.8
通讯作者：
Deroo, Sabrina
中科院分区：
文献类型：
--
作者：
Chevigne, Andy;Delhalle, Sylvie;Deroo, Sabrina
目的：最近发现的中和抗体能够防止病毒反弹，再次强调了体液免疫反应控制HIV-1感染的兴趣。在这项研究中，我们从病毒血症控制者的重链互补决定区3（HCDR 3）库中鉴定HIV-1抑制序列。设计和方法：在丝状噬菌体上展示病毒血症控制者的IgM和IgG衍生的HCDR 3库，该病毒血症控制者具有血浆中和活性，其特征是感染超过20年，CD 4（+）T细胞计数稳定，以鉴定HCDR 3库衍生的抑制HIV-1进入的肽。结果：针对重组gp 120筛选噬菌体文库导致鉴定HCDR 3衍生肽序列（LRTV-1）显示出抗X4和R5病毒的抗病毒特性。LRTV-1与gp 120的相互作用在CD 4结合后增强，序列比较显示LRTV-1与C-X-C趋化因子受体4型（CXCR 4）的第二胞外环（11/23）和C-C趋化因子受体5型（CCR 5）的N-末端（7/23）之间具有同源性。丙氨酸扫描实验确定了不同的集群的残基与病毒envelope protein.Conclusions相互作用的关键：LRTV-1肽是迄今为止最小的人HCDR 3的库衍生肽通过噬菌体展示抑制HIV进入R5和X4病毒。该肽识别对辅助受体结合至关重要的CD 4依赖性gp 120表位，并模拟CXCR 4和CCR 5的表面。我们的数据强调了人类HCDR 3免疫库作为HIV治疗的小生物活性肽来源的潜力。
Objectives:The recent identification of neutralizing antibodies able to prevent viral rebound reemphasized the interest in humoral immune responses to control HIV-1 infection. In this study, we characterized HIV-1-inhibiting sequences from heavy-chain complementary determining region 3 (HCDR3) repertoires of a viremic controller.Design and methods:IgM and IgG-derived HCDR3 repertoires of a viremic controller presenting plasma-neutralizing activity and characterized by over 20 years of infection with a stable CD4(+) T-cell count were displayed on filamentous phage to identify HCDR3 repertoire-derived peptides inhibiting HIV-1 entry.Results:Screening of phage libraries against recombinant gp120 led to the identification of an HCDR3-derived peptide sequence (LRTV-1) displaying antiviral properties against both X4 and R5 viruses. The interaction of LRTV-1 with gp120 was enhanced upon CD4 binding and sequence comparison revealed homology between LRTV-1 and the second extracellular loop of C-X-C chemokine receptor type 4 (CXCR4) (11/23) and the N-terminus of C-C chemokine receptor type 5 (CCR5) (7/23). Alanine scanning experiments identified different clusters of residues critical for interaction with the viral envelope protein.Conclusions:LRTV-1 peptide is to date the smallest human HCDR3 repertoire-derived peptide identified by phage display inhibiting HIV entry of R5 and X4 viruses. This peptide recognizes a CD4-dependent gp120 epitope critical for coreceptor binding and mimics the surface of CXCR4 and CCR5. Our data emphasize the potential of human HCDR3 immune repertoires as sources of small biologically active peptides for HIV cure.