Scala G, Chen X, Liu W, Telles J N, Cohen O J, Vaccarezza M, Igarashi T, Fauci A S
Laboratory of Immunoregulation, and Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Immunol. 1999 May 15;162(10):6155-61.
Efforts to develop a protective HIV-1 vaccine have been hindered by difficulties in identifying epitopes capable of inducing broad neutralizing Ab responses. In fact, the high mutation rate occurring in HIV-1 envelope proteins and the complex structure of gp120 as an oligomer associated with gp41 result in a high degree of antigenic polymorphism. To overcome these obstacles, we screened random peptide libraries using sera from HIV-infected subjects to identify antigenic and immunogenic mimics of HIV-1 epitopes. After extensive counterscreening with HIV-negative sera, we isolated peptides specifically recognized by Abs from HIV-1-infected individuals. These peptides behaved as antigenic mimics of linear or conformational HIV-1 epitopes generated in vivo in infected subjects. Consistent with these findings, sera of simian HIV-infected monkeys also recognized the HIV-specific epitopes. The selected peptides were immunogenic in mice, where they elicited HIV-specific Abs that effectively neutralized HIV-1 isolates. These results demonstrate that pools of HIV-1 mimotopes can be selected from combinatorial peptide libraries by taking advantage of the HIV-specific Ab repertoire induced by the natural infection.
开发一种保护性HIV-1疫苗的努力一直受到阻碍，原因在于难以鉴定能够诱导广泛中和抗体反应的表位。事实上，HIV-1包膜蛋白中出现的高突变率以及作为与gp41相关联的寡聚体的gp120的复杂结构，导致了高度的抗原多态性。为了克服这些障碍，我们使用来自HIV感染受试者的血清筛选随机肽库，以鉴定HIV-1表位的抗原性和免疫原性模拟物。在用HIV阴性血清进行广泛的反向筛选后，我们分离出了被HIV-1感染个体的抗体特异性识别的肽。这些肽表现为感染受试者体内产生的线性或构象性HIV-1表位的抗原模拟物。与这些发现一致，感染猿猴HIV的猴子的血清也识别HIV特异性表位。所选肽在小鼠中具有免疫原性，在小鼠体内它们引发了能有效中和HIV-1分离株的HIV特异性抗体。这些结果表明，利用自然感染诱导的HIV特异性抗体库，可以从组合肽库中选择HIV-1模拟表位库。
