Lack of viral escape and defective in vivo activation of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes in rapidly progressive infection
Lack of viral escape and defective in vivo activation of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes in rapidly progressive infection
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DOI：
10.1128/jvi.73.7.5509-5519.1999
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发表时间：
1999-07-01
影响因子：
5.4
通讯作者：
Walker, BD
中科院分区：
文献类型：
--
作者：
Hay, CM;Ruhl, DJ;Walker, BD
人类免疫缺陷病毒1型(HIV-1)在快速进行性感染过程中的特异性免疫反应尚未得到很好的定义。对一名表现为急性HIV-1感染、13个月后发展为艾滋病定义疾病、45个月后死亡的患者进行了详细的中和抗体、淋巴细胞增殖、体内激活和记忆细胞毒性T淋巴细胞(CTL)反应以及病毒序列变异的详细纵向分析。中和抗体反应始终很弱，甚至在病程早期也没有观察到HIV-1特异性淋巴细胞增殖反应。在病毒血症最初下降时，存在针对Env和POL表位的强大的体内激活的CTL，但很快就消失了。针对Env和Pol表位的记忆CTL在整个感染过程中都被检测到；然而，这些CTL在体内不被激活。尽管最初CTL反应很窄，但随着疾病的发展，新的表位并不是靶点。病毒测序显示，在两个靶向CTL表位内出现了变异；然而，免疫优势的Env表位内的病毒变异被CTL很好地识别，并且没有证据表明该表位内的病毒逃脱了免疫系统的检测。这些数据表明，在一名快速进展性疾病的患者中，有一种狭隘的静态CTL反应。我们还表明，在存在对自体表位的持久记忆CTL识别以及没有可检测到的逃避CTL反应的情况下，疾病进展可以发生，这与体内CTL激活的缺陷一致。
Human immunodeficiency virus type 1 (HIV-1)-specific immune responses over the course of rapidly progressive infection are not well defined. Detailed longitudinal analyses of neutralizing antibodies, lymphocyte proliferation, in vivo-activated and memory cytotoxic T-lymphocyte (CTL) responses, and viral sequence variation were performed on a patient who presented with acute HIV-1 infection, developed an AIDS-defining illness 13 months later, and died 45 months after presentation. Neutralizing-antibody responses remained weak throughout, and no HIV-1-specific lymphocyte proliferative responses were seen even early in the disease course. Strong in vivo-activated CTL directed against Env and Pol epitopes were present at the time of the initial drop in viremia but were quickly lost. Memory CTL against Env and Pol epitopes were detected throughout the course of infection; however, these CTL were not activated in vivo. Despite an initially narrow CTL response, new epitopes were not targeted as the disease progressed. Viral sequencing showed the emergence of variants within the two targeted CTL epitopes; however, viral variants within the immunodominant Env epitope were well recognized by CTL, and there was no evidence of viral escape from immune system detection within this epitope. These data demonstrate a narrowly directed, static CTL response in a patient with rapidly progressive disease. We also show that disease progression can occur in the presence of persistent memory CTL recognition of autologous epitopes and in the absence of detectable escape from CTL responses, consistent with an in vivo defect in activation of CTL.