Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California USA.
UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, California, USA.
J Virol. 2018 Jul 31;92(16). doi: 10.1128/JVI.00617-18. Print 2018 Aug 15.
Although a high level of promiscuity for heterologous epitopes is believed to exist for cellular immunity, limited data explore this issue for human immunodeficiency virus type 1 (HIV-1)-specific CD8 T lymphocyte (CTL) responses. Here, we found an unexpected degree of heterologous cross-reactivity against HIV-1 epitopes, in addition to the targeted index epitope. Most CTL clones screened cross-reacted against other known HIV-1 epitopes of the same major histocompatibility complex type I (MHC-I) restriction, up to 40% of tested nonindex epitopes in some cases. The observed cross-reactivity was universally lower avidity than recognition of the index epitope when examined for several A02- and B57-restricted CTL clones, demonstrating that the high concentrations of exogenous epitope typically used for screening of CTL responses are prone to detect such cross-reactivity spuriously. In agreement with this, we found that these cross-reactive responses do not appear to mediate CTL activity against HIV-1-infected cells. Overall, our data indicate that low-level cross-reactivity is remarkably common for HIV-1-specific CTLs. The role of this phenomenon is unclear, but low-avidity interactions have been shown to foster homeostatic proliferation of memory T cells. This study raises two issues related to HIV-1-specific CTL responses. These are key immune responses that retard disease progression in infected persons that are highly relevant to immunotherapies and vaccines for HIV-1. First, we make the novel observation that these responses are promiscuous and that CTLs targeting one epitope may cross-recognize other, completely distinct epitopes in the virus. While these are low-avidity interactions that do not appear to contribute directly to the antiviral activity of CTLs, this raises interesting biologic implications regarding the purpose of the phenomenon, such as providing a stimulus for these responses to persist long term. Second, the data raise a technical caveat to detection of CTL responses against particular epitopes, suggesting that some methodologies may unintentionally detect cross-reactivity and overestimate responses against an epitope.
尽管人们认为细胞免疫中存在针对异源表位的高度混杂性，但针对人类免疫缺陷病毒 1 型 (HIV-1) 特异性 CD8 T 淋巴细胞 (CTL) 反应，仅有有限的数据对此进行了探讨。在此，我们发现了出乎意料的程度的针对 HIV-1 表位的异源交叉反应性，除了靶向的指标表位。筛选出的大多数 CTL 克隆除了针对相同主要组织相容性复合物 I 型 (MHC-I) 限制的其他已知 HIV-1 表位发生交叉反应，在某些情况下，高达 40%的测试非指标表位。当对几个 A02 和 B57 限制的 CTL 克隆进行检测时，观察到的交叉反应普遍比识别指标表位的亲和力低，这表明通常用于筛选 CTL 反应的高浓度外源性表位易于虚假地检测到这种交叉反应。一致的是，我们发现这些交叉反应性的应答似乎不会介导针对 HIV-1 感染细胞的 CTL 活性。总体而言，我们的数据表明，HIV-1 特异性 CTL 具有显著的低水平交叉反应性。这种现象的作用尚不清楚，但已经表明低亲和力相互作用可以促进记忆 T 细胞的稳态增殖。这项研究提出了与 HIV-1 特异性 CTL 反应相关的两个问题。这些是延迟感染个体疾病进展的关键免疫反应，与 HIV-1 的免疫疗法和疫苗密切相关。首先，我们做出了一个新的观察结果，即这些反应是混杂的，针对一个表位的 CTL 可能会交叉识别病毒中其他完全不同的表位。虽然这些是低亲和力的相互作用，不会直接导致 CTL 的抗病毒活性，但这引起了关于该现象目的的有趣生物学含义，例如为这些反应的长期持续提供刺激。其次，数据提出了检测针对特定表位的 CTL 反应的技术警告，表明一些方法可能无意中检测到交叉反应并高估了针对特定表位的反应。
