Department of Genetics, Federal University of Pernambuco - UFPE, Recife, Pernambuco, Brazil; Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco - UFPE, Recife, Pernambuco, Brazil.
Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco - UFPE, Recife, Pernambuco, Brazil.
Infect Genet Evol. 2019 Nov;75:103997. doi: 10.1016/j.meegid.2019.103997. Epub 2019 Aug 8.
Pyroptosis has been reported to be critical in human immunodeficiency virus type 1 (HIV-1) pathogenesis and acquired immunodeficiency syndrome (AIDS) progression. Even after achieving viral suppression to undetectable levels during antiretroviral therapy (ART), exacerbated CD4+ T-cell death by pyroptosis has been suggested as one of the main causes of immunological non-response. Thus, variants in genes of pyroptosis pathway were studied in individuals with poor CD4+ T-cell reconstitution under antiretroviral therapy against HIV-1.
248 virologically suppressed ART-treated patients, 126 immunological non-responders (INR) and 122 immunological responders (IR) were recruited. Genotyping was performed using TaqMan probe-based realtime PCR platform. Genotype-guided flow cytometry analysis with general and recent thymic emigrant (RTE) CD4+ T-cells in pyroptosis was performed based on associated polymorphisms.
Both IL18 rs187238 G allele and GG genotype were associated as protection factors against poor CD4+ T-cell recovery (OR = 0.22; 95%CI = 0.50-0.77; P = .010 and OR = 0.58; 95%CI = 0.36-0.93; P = .022, respectively). It was demonstrated a statistical association between IL18 rs187238 genotypes of ART-treated patients and death by Caspase-1 levels (P = .020). The GG genotype showed lower pyroptotic RTE CD4+ T-lymphocytes levels in the ART-treated groups comparing with CC (P = .029) and CG (P = .018) genotypes, suggesting that the G allele presence may be related to a lower IL-18 production and thus reduced dead CD4+ T-cells levels by Caspase-1.
We observed that IL18 G variant allele and genotype were associated with a better immunological response, which may influence on immunological recovery of HIV-positive patients receiving antiretroviral therapy, and low Caspase-1 activity levels was observed on GG genotype when compared CC genotypes.
细胞焦亡已被报道在人类免疫缺陷病毒 1 型（HIV-1）发病机制和获得性免疫缺陷综合征（AIDS）进展中起关键作用。即使在抗逆转录病毒治疗（ART）期间将病毒抑制到无法检测的水平，细胞焦亡导致的 CD4+T 细胞死亡加剧也被认为是免疫无应答的主要原因之一。因此，研究人员在接受抗 HIV-1 的 ART 治疗的个体中研究了细胞焦亡途径基因的变异。
共招募了 248 名病毒学抑制的 ART 治疗患者，其中 126 名免疫无应答者（INR）和 122 名免疫应答者（IR）。使用 TaqMan 探针实时 PCR 平台进行基因分型。根据相关多态性，对细胞焦亡中的总和近期胸腺迁出（RTE）CD4+T 细胞进行基于基因型指导的流式细胞术分析。
IL18 rs187238 G 等位基因和 GG 基因型均与 CD4+T 细胞恢复不良的保护因素相关（OR=0.22；95%CI=0.50-0.77；P=0.010 和 OR=0.58；95%CI=0.36-0.93；P=0.022）。结果表明，ART 治疗患者的 IL18 rs187238 基因型与 Caspase-1 水平的死亡之间存在统计学关联（P=0.020）。与 CC（P=0.029）和 CG（P=0.018）基因型相比，GG 基因型的 ART 治疗组的细胞焦亡 RTE CD4+T 淋巴细胞水平较低，表明 G 等位基因的存在可能与 IL-18 产生减少有关，从而降低 Caspase-1 导致的 CD4+T 细胞死亡。
我们观察到，IL18 G 变异等位基因和基因型与更好的免疫反应相关，这可能影响接受抗逆转录病毒治疗的 HIV 阳性患者的免疫恢复，并且与 CC 基因型相比，GG 基因型的 Caspase-1 活性水平较低。
