Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China.
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, P.R. China.
Nat Commun. 2024 Aug 13;15(1):6961. doi: 10.1038/s41467-024-51414-6.
Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4's potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab's efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.
尽管抗逆转录病毒疗法 (ART) 在抑制 HIV-1 复制方面取得了进展，但现有的抗病毒药物存在局限性，包括终身用药、频繁给药、副作用和病毒耐药性，因此需要新的 HIV-1 治疗方法。CD4 是 HIV-1 进入的关键因素，由于中和和细胞毒性问题，给药物开发带来了挑战。然而，伊伐布雷定是唯一批准用于 HIV-1 治疗的 CD4 特异性抗体，这重新激发了人们探索替代抗 HIV 靶点的兴趣，强调了 CD4 在有效药物开发方面的潜在价值。在这里，我们研究了抗 CD4 纳米抗体，特别是来自 CD4 免疫羊驼的 Nb457。Nb457 对 HIV-1 具有高活性和广谱活性，超过了伊伐布雷定的疗效。引人注目的是，工程化的三聚体 Nb457 纳米抗体可完全抑制活 HIV-1，优于伊伐布雷定和母体 Nb457。结构分析揭示了 Nb457 诱导的 CD4 构象变化，阻止了病毒进入。值得注意的是，Nb457 在人源化雌性小鼠模型中显示出治疗效果。我们的研究结果表明，抗 CD4 纳米抗体是有前途的 HIV-1 治疗药物，可能对推进针对这一全球健康挑战的临床治疗具有重要意义。
