AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.
The University of Hong Kong AIDS Institute Shenzhen Research Laboratory, Guangdong Key Laboratory of Emerging Infectious Diseases and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen, Guangdong Province, People's Republic of China.
J Clin Invest. 2018 Jun 1;128(6):2239-2251. doi: 10.1172/JCI96764. Epub 2018 Apr 23.
The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral therapy (cART). Here, we investigate the potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving 2 single-chain variable fragment (scFv) binding domains of each parental bnAb, a single gene-encoded tandem bs-bnAb, BiIA-SG, displayed substantially improved breadth and potency. BiIA-SG neutralized all 124 HIV-1-pseudotyped viruses tested, including global subtypes/recombinant forms, transmitted/founder viruses, variants not susceptible to parental bnAbs and to many other bnAbs with an average IC50 value of 0.073 μg/ml (range < 0.001-1.03 μg/ml). In humanized mice, an injection of BiIA-SG conferred sterile protection when administered prior to challenges with diverse live HIV-1 stains. Moreover, whereas BiIA-SG delayed viral rebound in a short-term therapeutic setting when combined with cART, a single injection of adeno-associated virus-transferred (AAV-transferred) BiIA-SG gene resulted dose-dependently in prolonged in vivo expression of BiIA-SG, which was associated with complete viremia control and subsequent elimination of infected cells in humanized mice. These results warrant the clinical development of BiIA-SG as a promising bs-bnAb-based biomedical intervention for the prevention and treatment of HIV-1 infection.
HIV-1 治愈方法的发现仍然是一个医学挑战，因为在停止联合抗逆转录病毒疗法 (cART) 后，病毒会迅速反弹。在这里，我们研究了工程串联双特异性广谱中和抗体 (bs-bnAb) 作为 HIV-1 预防和治疗干预的创新产品的潜力。我们发现，通过保留每个亲本 bnAb 的 2 个单链可变片段 (scFv) 结合结构域，单个基因编码的串联 bs-bnAb，BiIA-SG，显示出显著提高的广度和效力。BiIA-SG 中和了所有 124 种经过 HIV-1 假型化的病毒，包括全球亚型/重组形式、传播/原始病毒、对亲本 bnAbs 以及许多其他 bnAbs 不敏感的变体，平均 IC50 值为 0.073 μg/ml（范围 <0.001-1.03 μg/ml）。在人源化小鼠中，在接受多种活 HIV-1 毒株挑战之前注射 BiIA-SG 可提供无菌保护。此外，虽然 BiIA-SG 与 cART 联合使用时在短期治疗中延迟了病毒反弹，但单次注射腺相关病毒转移 (AAV 转移) 的 BiIA-SG 基因会导致 BiIA-SG 在体内表达的时间延长，这与完全控制病毒血症和随后在人源化小鼠中消除感染细胞有关。这些结果证明了 BiIA-SG 作为一种有前途的基于 bs-bnAb 的生物医学干预措施，用于预防和治疗 HIV-1 感染的临床开发。
