Münch Jan, Ständker Ludger, Adermann Knut, Schulz Axel, Schindler Michael, Chinnadurai Raghavan, Pöhlmann Stefan, Chaipan Chawaree, Biet Thorsten, Peters Thomas, Meyer Bernd, Wilhelm Dennis, Lu Hong, Jing Weiguo, Jiang Shibo, Forssmann Wolf-Georg, Kirchhoff Frank
Institute of Virology, University of Ulm, 89081 Ulm, Germany.
Cell. 2007 Apr 20;129(2):263-75. doi: 10.1016/j.cell.2007.02.042.
A variety of molecules in human blood have been implicated in the inhibition of HIV-1. However, it remained elusive which circulating natural compounds are most effective in controlling viral replication in vivo. To identify natural HIV-1 inhibitors we screened a comprehensive peptide library generated from human hemofiltrate. The most potent fraction contained a 20-residue peptide, designated VIRUS-INHIBITORY PEPTIDE (VIRIP), corresponding to the C-proximal region of alpha1-antitrypsin, the most abundant circulating serine protease inhibitor. We found that VIRIP inhibits a wide variety of HIV-1 strains including those resistant to current antiretroviral drugs. Further analysis demonstrated that VIRIP blocks HIV-1 entry by interacting with the gp41 fusion peptide and showed that a few amino acid changes increase its antiretroviral potency by two orders of magnitude. Thus, as a highly specific natural inhibitor of the HIV-1 gp41 fusion peptide, VIRIP may lead to the development of another class of antiretroviral drugs.
人类血液中的多种分子被认为具有抑制HIV-1的作用。然而，哪种循环天然化合物在体内控制病毒复制最为有效仍不清楚。为了鉴定天然的HIV-1抑制剂，我们筛选了一个由人类血液滤过液生成的综合肽库。最有效的部分含有一种20个氨基酸残基的肽，命名为病毒抑制肽（VIRIP），它对应于α1-抗胰蛋白酶的C端区域，α1-抗胰蛋白酶是循环中最丰富的丝氨酸蛋白酶抑制剂。我们发现VIRIP能抑制多种HIV-1毒株，包括那些对当前抗逆转录病毒药物耐药的毒株。进一步分析表明，VIRIP通过与gp41融合肽相互作用来阻断HIV-1的进入，并且还表明少数氨基酸的改变可使其抗逆转录病毒效力提高两个数量级。因此，作为HIV-1 gp41融合肽的一种高度特异性天然抑制剂，VIRIP可能会促成另一类抗逆转录病毒药物的研发。
