AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges

摘要

Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC_(80)) ＞ 5 μg ml~(-1)), suggesting that high concentrations of these antibodies would be necessary to achieve general protection. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5 -mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC_(50)) ＜ 0.05 μg ml~(-1)). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HFV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17-77 μg ml~(-1) of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.%这项研究介绍了新的一类强效HIV-1侵入抑制剂，它们能够通过一个基因疗法载体来输送，可以成为传统HIV-1疫苗的有效替代药物。为了进入细胞，HIV-1首先要与其细胞受体CD4结合，然后再与共受体CCR5或CXCR4结合。这一新的侵入抑制剂由融合到一个模仿硫代肽的CCR5上的免疫粘附素CD4-Ig组成。这种融合体(被称为eCD4-Ig)会"贪婪地"结合HIV-1的Env蛋白，不可逆转地使其失活。Michael Farzan及同事发现，这种抑制剂的药效和作用范围都极大，能100%地中和一组对中和有抵抗力的多样化HIV-1。当利用一种"腺相关病毒"将这种抑制剂送入猕猴体内时，它能面对用病毒进行的多种挑战对猕猴提供保护。