Department of Biochemistry and Virology, National Institute for Research in Reproductive Health, Indian Council of Medical Research, J. M. Street, Parel, Mumbai, 400012, India.
Department of Medicine, Grant Medical College & Sir J. J. group of Hospitals, Mumbai, 400008, India.
BMC Infect Dis. 2019 Feb 11;19(1):135. doi: 10.1186/s12879-019-3743-7.
HIV-2 infection is characterised by a longer asymptomatic phase and slower AIDS progression than HIV-1 infection. Identifying unique immune signatures associated with HIV-2 pathogenesis may thus provide therapeutically useful insight into the management of HIV infection. This study examined the dynamics of the CD4T cell compartment, critical in disease progression, focussing on chronic HIV-2 and HIV-1 infected individuals at various stages of disease progression.
A total of 111 participants including untreated and treated HIV infected individuals and seronegative individuals were enrolled in this study. The relative proportion of CD4T cell subsets, expressing CD25 (IL-2Rα) and CD127 (IL-7R), in HIV infected individuals and seronegative controls were assessed by multiparametric flow cytometry. Additionally, levels of immune activation and cytotoxic T lymphocytes in both the CD4T and CD8T cell compartments was evaluated.
Both treated and untreated, HIV-1 and HIV-2 infected individuals showed apparent dysregulation in CD4 T cell subset frequency that was associated with disease progression. Furthermore, longitudinal sampling from a group of HIV-1 infected individuals on virologically effective ART showed no significant change in dysregulated CD4T cell subset frequency. For both ART naïve and receiving groups associations with disease progression were strongest and significant with CD4 T cell subset frequency compared to per cell expression of IL-2Rα and IL-7Rα. In untreated HIV-2 infected individuals, T cell activation was lower compared to ART naïve HIV-1 infected individuals and higher than seronegative individuals. Also, the level of Granzyme-B expressing circulating T cells was higher in both ART-naïve HIV-1 and HIV-2 infected individuals compared to seronegative controls.
Dysregulation of IL-2 and IL-7 homeostasis persists in CD4T cell subsets irrespective of presence or absence of viremia or antiretroviral therapy in HIV infection. Furthermore, we report for the first time on levels of circulating Granzyme-B expressing CD4T and CD8T cells in chronic HIV-2 infection. Lower immune activation in these individuals indicates that persistent immune activation driven CD4T cell depletion, as observed in untreated HIV-1 infected individuals, may not be as severe and provides evidence for a disparate pathogenesis mechanism. Our work also supports novel immunomodulatory therapeutic strategies for both HIV-1 and HIV-2 infection.
与 HIV-1 感染相比，HIV-2 感染的无症状期更长，艾滋病进展更缓慢。因此，鉴定与 HIV-2 发病机制相关的独特免疫特征，可能为 HIV 感染的治疗提供有用的见解。本研究检测了 CD4T 细胞群的动态变化，CD4T 细胞群在疾病进展中起关键作用，重点研究了处于不同疾病进展阶段的慢性 HIV-2 和 HIV-1 感染者。
本研究共纳入 111 名参与者，包括未经治疗和接受治疗的 HIV 感染者以及血清阴性者。通过多参数流式细胞术评估了 HIV 感染者和血清阴性对照者中表达 CD25（IL-2Rα）和 CD127（IL-7R）的 CD4T 细胞亚群的相对比例。此外，还评估了 CD4T 和 CD8T 细胞群中的免疫激活和细胞毒性 T 淋巴细胞水平。
未经治疗和接受治疗的 HIV-1 和 HIV-2 感染者的 CD4T 细胞亚群频率均出现明显失调，这种失调与疾病进展有关。此外，对一组接受病毒学有效抗逆转录病毒治疗（ART）的 HIV-1 感染者进行纵向采样显示，失调的 CD4T 细胞亚群频率无显著变化。对于未接受 ART 治疗的组和接受 ART 治疗的组，与疾病进展的相关性最强且最显著的是 CD4T 细胞亚群频率，而不是 CD25（IL-2Rα）和 CD127（IL-7Rα）的每个细胞的表达。与未经治疗的 HIV-1 感染者相比，未经治疗的 HIV-2 感染者的 T 细胞活化水平较低，而高于血清阴性者。此外，在未经治疗的 HIV-2 感染者中，循环表达颗粒酶 B 的 T 细胞水平高于血清阴性对照组和未经治疗的 HIV-1 感染者。
在 HIV 感染中，无论是否存在病毒血症或抗逆转录病毒治疗，IL-2 和 IL-7 稳态的失调都持续存在于 CD4T 细胞亚群中。此外，我们首次报告了慢性 HIV-2 感染中循环表达颗粒酶 B 的 CD4T 和 CD8T 细胞的水平。这些个体的免疫激活水平较低，表明未治疗的 HIV-1 感染者中观察到的持续免疫激活驱动的 CD4T 细胞耗竭可能不那么严重，并为不同的发病机制提供了证据。我们的工作还支持针对 HIV-1 和 HIV-2 感染的新型免疫调节治疗策略。
