Ferrari G, Humphrey W, McElrath M J, Excler J L, Duliege A M, Clements M L, Corey L C, Bolognesi D P, Weinhold K J
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1396-401. doi: 10.1073/pnas.94.4.1396.
A fundamental goal of current strategies to develop an efficacious vaccine for AIDS is the elicitation of broadly reactive cytotoxic T lymphocyte (CTL) reactivities capable of destroying virally infected targets. Recent application of recombinant canarypox ALVAC/HIV-1 vectors as vaccine immunogens in HIV-1,-noninfected volunteers has produced CTL responses in a significant number of vaccinees. Using a newly developed targeting strategy, we examined the capacity of vaccine-induced CTL to lyse autologous targets infected with a diverse group of viral isolates. CTL derived from recipients of a canarypox ALVAC/HIV-1 gp160 (MN) vaccine were found capable of lysing autologous CD4+ lymphoblasts infected with the prototypic LAI strain of HIV-1. When tested against autologous targets infected with primary HIV-1 isolates representing genetically diverse viral clades, CTL from ALVAC/gp160 recipients showed both a broad pattern of cytolysis in which viruses from all clades tested were recognized as well as a highly restricted pattern in which no primary isolates, including clade B, were lysed. Differences in the HLA haplotypes of the volunteers immunized with the envelope vector might be a major determinant of the relative breadth of their CTL response. In contrast to ALVAC/gp160 vaccinees, recipients of the ALVAC/HIV-1 immunogen containing envelope as well as gag and protease genes consistently had CTL reactivities effective against a spectrum of primary isolate-infected targets. These studies demonstrate for the first time that clade B-based canarypox vaccines can elicit broad CTL reactivities capable of recognizing viruses belonging to genetically diverse HIV-1 clades. The results also reinforce the impact of viral core elements in the vaccine as well as the pattern of major histocompatibility complex class I allelic expression by the vaccine recipient in determining the relative breadth of the cellular response.
当前开发艾滋病有效疫苗策略的一个基本目标是引发具有广泛反应性的细胞毒性T淋巴细胞（CTL）反应，这种反应能够破坏病毒感染的靶细胞。重组金丝雀痘病毒ALVAC/HIV-1载体最近作为疫苗免疫原应用于未感染HIV-1的志愿者，在大量接种疫苗者中产生了CTL反应。我们采用一种新开发的靶向策略，检测了疫苗诱导的CTL裂解感染多种病毒分离株的自体靶细胞的能力。发现来自接种金丝雀痘病毒ALVAC/HIV-1 gp160（MN）疫苗的受者的CTL能够裂解感染HIV-1原型LAI株的自体CD4+淋巴母细胞。当检测针对感染代表基因多样化病毒分支的原发性HIV-1分离株的自体靶细胞时，来自ALVAC/gp160受者的CTL既表现出广泛的细胞溶解模式，即所有测试分支的病毒都能被识别，也表现出高度受限的模式，即包括B分支在内的原发性分离株均未被裂解。用包膜载体免疫的志愿者的HLA单倍型差异可能是其CTL反应相对广度的主要决定因素。与ALVAC/gp160疫苗接种者不同，接种包含包膜以及gag和蛋白酶基因的ALVAC/HIV-1免疫原的受者始终具有针对一系列原发性分离株感染靶细胞的有效CTL反应。这些研究首次证明，基于B分支的金丝雀痘疫苗能够引发广泛的CTL反应，能够识别属于基因多样化HIV-1分支的病毒。结果还强化了疫苗中病毒核心元件以及疫苗接种者主要组织相容性复合体I类等位基因表达模式在决定细胞反应相对广度方面的影响。
