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Env-2dCD4 S60C复合物作为超级免疫原,可引发针对临床相关的1型人类免疫缺陷病毒(HIV-1)的强效、广泛中和抗体。

Env-2dCD4 S60C complexes act as super immunogens and elicit potent, broadly neutralizing antibodies against clinically relevant human immunodeficiency virus type 1 (HIV-1).

作者信息

Killick Mark A, Grant Michelle L, Cerutti Nichole M, Capovilla Alexio, Papathanasopoulos Maria A

机构信息

HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg 2193, South Africa.

HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg 2193, South Africa.

出版信息

Vaccine. 2015 Nov 17;33(46):6298-306. doi: 10.1016/j.vaccine.2015.09.056. Epub 2015 Oct 1.

Abstract

The ability to induce a broadly neutralizing antibody (bNAb) response following vaccination is regarded as a crucial aspect in developing an effective vaccine against human immunodeficiency virus type 1 (HIV-1). The bNAbs target the HIV-1 envelope glycoprotein (Env) which is exposed on the virus surface, thereby preventing cell entry. To date, conventional vaccine approaches such as the use of Env-based immunogens have been unsuccessful. We expressed, purified, characterized and evaluated the immunogenicity of several unique HIV-1 subtype C Env immunogens in small animals. Here we report that vaccine immunogens based on Env liganded to a two domain CD4 variant, 2dCD4(S60C) are capable of consistently eliciting potent, broadly neutralizing antibody responses in New Zealand white rabbits against a panel of clinically relevant HIV-1 pseudoviruses. This was irrespective of the Env protein subtype and context. Importantly, depletion of the anti-CD4 antibodies appeared to abrogate the neutralization activity in the rabbit sera. Taken together, this data suggests that the Env-2dCD4(S60C) complexes described here are "super" immunogens, and potentially immunofocus antibody responses to a unique epitope spanning the 2dCD4(60C). Recent data from the two available anti-CD4 monoclonal antibodies, Ibalizumab and CD4-Ig (and bispecific variants thereof) have highlighted that the use of these broad and potent entry inhibitors could circumvent the need for a conventional vaccine targeting HIV-1. Overall, the ability of the unique Env-2dCD4(S60C) complexes to elicit potent bNAb responses has not been described previously, reinforcing that further investigation for their utility in preventing and controlling HIV-1/SIV infection is warranted.

摘要

接种疫苗后诱导产生广泛中和抗体(bNAb)反应的能力被视为开发针对1型人类免疫缺陷病毒(HIV-1)的有效疫苗的关键方面。bNAb靶向暴露于病毒表面的HIV-1包膜糖蛋白(Env),从而阻止细胞进入。迄今为止,使用基于Env的免疫原等传统疫苗方法尚未成功。我们表达、纯化、表征并评估了几种独特的HIV-1 C亚型Env免疫原在小动物中的免疫原性。在此我们报告,基于与双结构域CD4变体2dCD4(S60C)结合的Env的疫苗免疫原能够在新西兰白兔中持续引发针对一组临床相关HIV-1假病毒的强效、广泛中和抗体反应。这与Env蛋白亚型和背景无关。重要的是,抗CD4抗体的耗竭似乎消除了兔血清中的中和活性。综上所述,这些数据表明此处描述的Env-2dCD4(S60C)复合物是“超级”免疫原,并可能使抗体反应聚焦于跨越2dCD4(60C)的独特表位。来自两种可用抗CD4单克隆抗体Ibalizumab和CD4-Ig(及其双特异性变体)的最新数据突出表明,使用这些广泛且强效的进入抑制剂可能无需针对HIV-1的传统疫苗。总体而言,独特的Env-2dCD4(S60C)复合物引发强效bNAb反应的能力此前尚未见报道,这进一步表明有必要对其在预防和控制HIV-1/SIV感染中的效用进行进一步研究。

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