Hammond S A, Bollinger R C, Stanhope P E, Quinn T C, Schwartz D, Clements M L, Siliciano R F
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
J Exp Med. 1992 Dec 1;176(6):1531-42. doi: 10.1084/jem.176.6.1531.
The lysis of infected host cells by virus-specific cytolytic T lymphocytes (CTL) is an important factor in host resistance to viral infection. An optimal vaccine against human immunodeficiency virus type 1 (HIV-1) would elicit virus-specific CTL as well as neutralizing antibodies. The induction by a vaccine of HIV-1-specific CD8+ CTL in humans has not been previously reported. In this study, CTL responses were evaluated in HIV-1-seronegative human volunteers participating in a phase I acquired immune deficiency syndrome (AIDS) vaccine trial involving a novel vaccine regimen. Volunteers received an initial immunization with a live recombinant vaccinia virus vector carrying the HIV-1 env gene and a subsequent boost with purified env protein. An exceptionally strong env-specific CTL response was detected in one of two vaccine recipients, while modest but significant env-specific CTL activity was present in the second vaccinee. Cloning of the responding CTL gave both CD4+ and CD8+ env-specific CTL clones, permitting a detailed comparison of critical functional properties of these two types of CTL. In particular, the potential antiviral effects of these CTL were evaluated in an in vitro system involving HIV-1 infection of cultures of normal autologous CD4+ lymphoblasts. At extremely low effector-to-target ratios, vaccine-induced CD8+ CTL clones lysed productively infected cells present within these cultures. When tested for lytic activity against target cells expressing the HIV-1 env gene, CD8+ CTL were 3-10-fold more active on a per cell basis than CD4+ CTL. However, when tested against autologous CD4+ lymphoblasts acutely infected with HIV-1, CD4+ clones lysed a much higher fraction of the target cell population than did CD8+ CTL. CD4+ CTL were shown to recognize not only the infected cells within these acutely infected cultures but also noninfected CD4+ T cells that had passively taken up gp120 shed from infected cells and/or free virions. These results were confirmed in studies in which CD4+ lymphoblasts were exposed to recombinant gp120 and used as targets for gp120-specific CD4+ and CD8+ CTL clones. gp120-pulsed, noninfected targets were lysed in an antigen-specific fashion by CD4+ but not CD8+ CTL clones. Taken together, these observations demonstrate that in an in vitro HIV-1 infection, sufficient amounts of gp120 antigen are produced and shed by infected cells to enable uptake by cells that are not yet infected, resulting in the lysis of these noninfected cells by gp120-specific, CD4+ CTL.(ABSTRACT TRUNCATED AT 400 WORDS)
病毒特异性细胞毒性T淋巴细胞（CTL）对受感染宿主细胞的裂解是宿主抵抗病毒感染的一个重要因素。一种针对1型人类免疫缺陷病毒（HIV-1）的理想疫苗应能引发病毒特异性CTL以及中和抗体。此前尚未有关于疫苗在人类中诱导HIV-1特异性CD8+CTL的报道。在本研究中，对参与一项涉及新型疫苗方案的I期获得性免疫缺陷综合征（AIDS）疫苗试验的HIV-1血清阴性人类志愿者的CTL反应进行了评估。志愿者首先用携带HIV-1 env基因的重组痘苗病毒活载体进行初次免疫，随后用纯化的env蛋白进行加强免疫。在两名疫苗接种者中的一名检测到了异常强烈的env特异性CTL反应，而另一名接种者中则存在适度但显著的env特异性CTL活性。对反应性CTL进行克隆得到了CD4+和CD8+ env特异性CTL克隆，从而能够详细比较这两种类型CTL的关键功能特性。特别是，在一个涉及HIV-1感染正常自体CD4+淋巴母细胞培养物的体外系统中评估了这些CTL的潜在抗病毒作用。在极低的效应细胞与靶细胞比例下，疫苗诱导的CD8+CTL克隆裂解了这些培养物中存在的高效感染细胞。当检测针对表达HIV-1 env基因的靶细胞的裂解活性时，CD8+CTL在每个细胞基础上的活性比CD4+CTL高3至10倍。然而，当针对急性感染HIV-1的自体CD4+淋巴母细胞进行检测时，CD4+克隆裂解的靶细胞群体比例比CD8+CTL高得多。已表明CD4+CTL不仅能识别这些急性感染培养物中的感染细胞，还能识别被动摄取了从感染细胞脱落的gp120和/或游离病毒粒子的未感染CD4+T细胞。在将CD4+淋巴母细胞暴露于重组gp120并用作gp120特异性CD4+和CD8+CTL克隆靶标的研究中证实了这些结果。gp120脉冲处理的未感染靶标以抗原特异性方式被CD4+而非CD8+CTL克隆裂解。综上所述，这些观察结果表明，在体外HIV-1感染中，感染细胞产生并释放了足够量的gp120抗原，使得尚未感染的细胞能够摄取，导致这些未感染细胞被gp120特异性CD4+CTL裂解。（摘要截短至400字）
