MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV(162P3) in cynomolgus macaques.
MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV(162P3) in cynomolgus macaques.
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DOI：
10.1371/journal.ppat.1003071
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Martin L
中科院分区：
文献类型：
--
作者：
Dereuddre-Bosquet N;Morellato-Castillo L;Brouwers J;Augustijns P;Bouchemal K;Ponchel G;Ramos OH;Herrera C;Stefanidou M;Shattock R;Heyndrickx L;Vanham G;Kessler P;Le Grand R;Martin L
作为对有效疫苗的补充，开发强效抗艾滋病毒杀微生物剂仍然是一个重要的优先事项。我们之前已经证明，miniCD 4 M48 U1是一种存在于27个氨基酸稳定支架上的sCD 4功能模拟物，在细胞模型中以亚纳摩尔浓度抑制广泛的HIV-1分离株。在这里，我们报告说，M48 U1有效地抑制人类宫颈和结直肠组织的粘膜外植体中的HIV-1Ba-L。在性成熟雌性食蟹猴中评估miniCD 4凝胶制剂的药代动力学和药效学后，在SHIV 162 P3粘膜激发的非人灵长类动物（NHP）模型中评价了M48 U1的体内疗效。在12只雌性动物中，一半接受羟乙基纤维素基凝胶（对照）处理，另一半接受含有3 mg/g M48 U1的相同凝胶，阴道途径激发前1小时使用10 AID 50的SHIV 162 P3。所有对照动物均感染105-106病毒RNA（vRNA）拷贝/mL的峰值血浆病毒载量。在用miniCD 4处理的动物中，如通过qRT-PCR检测血浆中的vRNA、qPCR检测PBMC和淋巴结细胞中的病毒DNA所评估的，6只动物中有5只完全免于感染。该组中唯一感染的动物具有延迟一周的病毒血症高峰。这些结果表明，M48 U1 miniCD 4在体内作为一种有效的进入抑制剂发挥作用，这可能被认为是杀微生物剂的发展。本报告描述了CD 4肽模拟物对人粘膜外植体的HIV感染的保护作用，以及当用于杀微生物剂凝胶中时，对食蟹猴中SHIV攻击的保护作用。有证据表明，我们的“miniprotein工程”策略，这对应于通过将其结合位点转移到一个小的支架蛋白上，然后通过广泛的优化，这种miniprotein导致一个有前途的临床前抗逆转录病毒活性的gp 120/CD 4相互作用的情况下，活性肽的结合蛋白。用0.3% miniCD 4凝胶预处理的6只动物中有5只完全免受SHIV 162 P3阴道攻击。总的来说，我们证明了如此小的CD 4模拟肽可以代表一种针对性传播艾滋病毒的强大预防剂，验证了微型蛋白质界面设计直至发现潜在新药。
In complement to an effective vaccine, development of potent anti-HIV microbicides remains an important priority. We have previously shown that the miniCD4 M48U1, a functional mimetic of sCD4 presented on a 27 amino-acid stable scaffold, inhibits a broad range of HIV-1 isolates at sub-nanomolar concentrations in cellular models. Here, we report that M48U1 inhibits efficiently HIV-1Ba-L in human mucosal explants of cervical and colorectal tissues. In vivo efficacy of M48U1 was evaluated in nonhuman primate (NHP) model of mucosal challenge with SHIV162P3 after assessing pharmacokinetics and pharmacodynamics of a miniCD4 gel formulation in sexually matured female cynomolgus macaques. Among 12 females, half were treated with hydroxyethylcellulose-based gel (control), the other half received the same gel containing 3 mg/g of M48U1, one hour before vaginal route challenge with 10 AID50 of SHIV162P3. All control animals were infected with a peak plasma viral load of 105–106 viral RNA (vRNA) copies per mL. In animals treated with miniCD4, 5 out of 6 were fully protected from acquisition of infection, as assessed by qRT-PCR for vRNA detection in plasma, qPCR for viral DNA detection in PBMC and lymph node cells. The only infected animal in this group had a delayed peak of viremia of one week. These results demonstrate that M48U1 miniCD4 acts in vivo as a potent entry inhibitor, which may be considered in microbicide developments. This report describes the protective effect of a CD4 peptide mimetic against HIV infection on human mucosal explants and further on, when used in a microbicide gel, against a SHIV challenge in cynomolgus macaques. Evidence is given that our “miniprotein engineering” strategy, which corresponds to miniaturizing a binding protein by transferring its binding site onto a small scaffold protein, followed by an extensive optimization of this miniprotein led to an active peptide with promising pre-clinical antiretroviral activity in the case of the gp120/CD4 interaction. Five out of six animals, pre-treated with a 0.3% miniCD4 gel were fully protected from SHIV162P3 vaginal challenge. On the whole, we demonstrated that such a small CD4 mimetic peptide could represent a powerful preventive agent against sexual HIV transmission, validating miniaturized protein interface design up to the discovery of potential new drugs.
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影响因子：
3.3
作者：
Grupping, Katrijn;Selhorst, Philippe;Arien, Kevin K.
通讯作者：
Arien, Kevin K.
影响因子：
3.8
作者：
Bourry, Olivier;Brochard, Patricia;Le Grand, Roger
通讯作者：
Le Grand, Roger
影响因子：
3.3
作者：
Mannioui A;Bourry O;Sellier P;Delache B;Brochard P;Andrieu T;Vaslin B;Karlsson I;Roques P;Le Grand R
通讯作者：
Le Grand R
影响因子：
4.8
作者：
Martin, Gregoire;Burke, Brian;Martin, Loic
通讯作者：
Martin, Loic
DOI：
10.1073/pnas.96.23.13091
发表时间：
1999-11-09
影响因子：
11.1
作者：
Vita, C;Drakopoulou, E;Gluckman, JC
通讯作者：
Gluckman, JC