Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
J Immunol. 2018 May 15;200(10):3372-3382. doi: 10.4049/jimmunol.1701284. Epub 2018 Apr 9.
Among HIV-infected individuals, long-term nonprogressor (LTNP) patients experience slow CD4 T cell decline and almost undetectable viral load for several years after primary acquisition of HIV. Type I IFN has been suggested to play a pathogenic role in HIV pathogenesis, and therefore diminished IFN responses may underlie the LTNP phenotype. In this study, we examined the presence and possible immunological role of multiple homozygous single-nucleotide polymorphisms in the stimulator of IFN genes (STING) encoding gene involved in IFN induction and T cell proliferation in HIV LTNP patients. We identified LTNPs through the Danish HIV Cohort and performed genetic analysis by Sanger sequencing, covering the R71H-G230A-R293Q (HAQ) single-nucleotide polymorphisms in This was followed by investigation of STING mRNA and protein accumulation as well as innate immune responses and proliferation following STING stimulation and infection with replication-competent HIV in human blood-derived cells. We identified G230A-R293Q/G230A-R293Q and HAQ/HAQ homozygous variants in 2 out of 11 LTNP patients. None of the 11 noncontrollers on antiretroviral treatment were homozygous for these variants. We found decreased innate immune responses to DNA and HIV as well as reduced STING-dependent inhibition of CD4 T cell proliferation, particularly in the HAQ/HAQ HIV LTNP patients, compared with the age- and gender-matched noncontrollers on antiretroviral treatment. These findings suggest that homozygous HAQ STING variants contribute to reduced inhibition of CD4 T cell proliferation and a reduced immune response toward DNA and HIV, which might result in reduced levels of constitutive IFN production. Consequently, the HAQ/HAQ genotype may contribute to the slower disease progression characteristic of LTNPs.
在 HIV 感染者中，长期非进展者（LTNP）患者在原发性 HIV 感染后数年经历 CD4 T 细胞缓慢下降和几乎无法检测到的病毒载量。I 型干扰素被认为在 HIV 发病机制中起致病作用，因此 IFN 反应减弱可能是 LTNP 表型的基础。在这项研究中，我们检查了 HIV LTNP 患者中参与 IFN 诱导和 T 细胞增殖的 IFN 基因刺激物（STING）编码基因中多个纯合单核苷酸多态性的存在和可能的免疫学作用。我们通过丹麦 HIV 队列识别出 LTNP，并通过 Sanger 测序进行遗传分析，涵盖了 STING 基因中的 R71H-G230A-R293Q（HAQ）单核苷酸多态性。随后，我们调查了 STING mRNA 和蛋白积累以及先天免疫反应，以及在人源性细胞中 STING 刺激和复制型 HIV 感染后的增殖。我们在 11 名 LTNP 患者中的 2 名中发现了 G230A-R293Q/G230A-R293Q 和 HAQ/HAQ 纯合 变体。在接受抗逆转录病毒治疗的 11 名非控制者中，没有一个是这些变体的纯合子。与接受抗逆转录病毒治疗的年龄和性别匹配的非控制者相比，我们发现对 DNA 和 HIV 的先天免疫反应降低，以及 STING 依赖性抑制 CD4 T 细胞增殖减少，特别是在 HAQ/HAQ HIV LTNP 患者中。这些发现表明，纯合的 HAQ STING 变体导致 CD4 T 细胞增殖抑制减少和对 DNA 和 HIV 的免疫反应降低，这可能导致组成型 IFN 产生水平降低。因此，HAQ/HAQ 基因型可能导致 LTNP 特征性的疾病进展缓慢。
