Tang Shengquan, Lu Yanqiu, Sun Feng, Qin Yuanyuan, Harypursat Vijay, Deng Renni, Zhang Gong, Chen Yaokai, Wang Tong
The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China; Department of Infectious Diseases, Chongqing Public Health Medical Center, 109 Baoyu Road, Shapingba District, Chongqing 400036, China.
Department of Infectious Diseases, Chongqing Public Health Medical Center, 109 Baoyu Road, Shapingba District, Chongqing 400036, China.
J Infect. 2024 May;88(5):106151. doi: 10.1016/j.jinf.2024.106151. Epub 2024 Apr 4.
Immunological non-responders (INRs) among people living with HIV have inherently higher mortality and morbidity rates. The underlying immunological mechanisms whereby failure of immune reconstitution occurs in INRs require elucidation.
HIV-1 DNA and HIV-1 cell-associated RNA (CA-HIV RNA) quantifications were conducted via RT-qPCR. Transcriptome sequencing (RNA-seq), bioinformatics, and biological verifications were performed to discern the crosstalk between host and viral factors. Flow cytometry was employed to analyze cellular activation, proliferation, and death.
HIV-1 DNA and CA-HIV RNA levels were observed to be significantly higher in INRs compared to immunological responders (IRs). Evaluation of CD4/CD8 ratios showed a significantly negative correlation with HIV-1 DNA in IRs, but not in INRs. Bioinformatics analyses and biological verifications showed IRF7/INF-α regulated antiviral response was intensified in INRs. PBMCs of INRs expressed significantly more HIV integrase-mRNA (p31) than IRs. Resting (CD4CD69 T-cells) and activated (CD4CD69 T-cells) HIV-1 reservoir harboring cells were significantly higher in INRs, with the co-occurrence of significantly higher cellular proliferation and cell death in CD4 T-cells of INRs.
In INRs, the systematic crosstalk between the HIV-1 reservoir and host cells tends to maintain a persistent antiviral response-associated inflammatory environment, which drives aberrant cellular activation, proliferation, and death of CD4 T-cells.
HIV感染者中的免疫无应答者（INR）的死亡率和发病率本质上更高。INR中发生免疫重建失败的潜在免疫机制需要阐明。
通过逆转录定量聚合酶链反应（RT-qPCR）对HIV-1 DNA和HIV-1细胞相关RNA（CA-HIV RNA）进行定量。进行转录组测序（RNA-seq）、生物信息学分析和生物学验证，以识别宿主和病毒因素之间的相互作用。采用流式细胞术分析细胞活化、增殖和死亡情况。
与免疫应答者（IR）相比，观察到INR中的HIV-1 DNA和CA-HIV RNA水平显著更高。CD4/CD8比值评估显示，IR中的该比值与HIV-1 DNA呈显著负相关，而INR中则不然。生物信息学分析和生物学验证表明，INR中干扰素调节因子7/干扰素-α调节的抗病毒反应增强。INR的外周血单个核细胞（PBMC）表达的HIV整合酶mRNA（p31）明显多于IR。INR中携带HIV-1储存库的静止（CD4CD69 T细胞）和活化（CD4CD69 T细胞）细胞显著更多，且INR的CD4 T细胞中同时出现显著更高的细胞增殖和细胞死亡。
在INR中，HIV-1储存库与宿主细胞之间的系统性相互作用倾向于维持一种与持续抗病毒反应相关的炎症环境，这会导致CD4 T细胞异常活化、增殖和死亡。
