Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), affecting approximately one third of the world’s population. Development of an adequate immune response will determine disease progression or progress to chronic infection. Risk of developing TB among human immunodeficiency virus (HIV)-coinfected patients (HIV-TB) is 20–30 times higher than those without HIV infection, and a synergistic interplay between these two pathogens accelerates the decline in immunological functions. TB treatment in HIV-TB coinfected persons is challenging and it has a prolonged duration, mainly due to the immune system failure to provide an adequate support for the therapy. Therefore, we aimed to study the role of the hormone 7-oxo-dehydroepiandrosterone (7-OD) as a modulator of anti-tuberculosis immune responses in the context of HIV-TB coinfection. A cross-sectional study was conducted among HIV-TB patients and healthy donors (HD). We characterized the ex vivo phenotype of CD4 + T cells and also evaluated in vitro antigen-specific responses by Mtb stimulation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of 7-OD. We assessed lymphoproliferative activity, cytokine production and master transcription factor profiles. Our results show that HIV-TB patients were not able to generate successful anti-tubercular responses in vitro compared to HD, as reduced IFN-γ/IL-10 and IFN-γ/IL-17A ratios were observed. Interestingly, treatment with 7-OD enhanced Th1 responses by increasing Mtb-induced proliferation and the production of IFN-γ and TNF-α over IL-10 levels. Additionally, in vitro Mtb stimulation augmented the frequency of cells with a regulatory phenotype, while 7-OD reduced the proportion of these subsets and induced an increase in CD4 + T-bet+ (Th1) subpopulation, which is associated with clinical data linked to an improved disease outcome. We conclude that 7-OD modifies the cytokine balance and the phenotype of CD4 + T cells towards a more favorable profile for mycobacteria control. These results provide new data to delineate novel treatment approaches as co-adjuvant for the treatment of TB.

中文翻译：

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7-oxo-DHEA 增强 HIV-TB 共感染期间受损的结核分枝杆菌特异性 T 细胞反应

结核分枝杆菌 (Mtb) 是结核病 (TB) 的病原体，影响着世界约三分之一的人口。充分的免疫反应的发展将决定疾病的进展或进展为慢性感染。人类免疫缺陷病毒（HIV）合并感染患者（HIV-TB）患结核病的风险比未感染HIV的患者高20-30倍，并且这两种病原体之间的协同相互作用加速了免疫功能的下降。HIV-TB 合并感染者的结核病治疗具有挑战性，且持续时间较长，主要是由于免疫系统未能为治疗提供足够的支持。因此，我们的目的是研究激素 7-氧代-脱氢表雄酮 (7-OD) 在 HIV-TB 合并感染情况下作为抗结核免疫反应调节剂的作用。在 HIV-TB 患者和健康捐赠者 (HD) 中进行了一项横断面研究。我们表征了 CD4 + T 细胞的离体表型，并在存在或不存在 7-OD 的情况下通过 Mtb 刺激外周血单核细胞 (PBMC) 评估了体外抗原特异性反应。我们评估了淋巴增殖活性、细胞因子产生和主转录因子谱。我们的结果表明，与 HD 患者相比，HIV-TB 患者无法在体外产生成功的抗结核反应，因为观察到 IFN-γ/IL-10 和 IFN-γ/IL-17A 比率降低。有趣的是，7-OD 治疗通过增加 Mtb 诱导的增殖以及超过 IL-10 水平的 IFN-γ 和 TNF-α 的产生来增强 Th1 反应。此外，体外 Mtb 刺激增加了具有调节表型的细胞的频率，而 7-OD 降低了这些亚群的比例，并诱导 CD4 + T-bet+ (Th1) 亚群的增加，这与与改善疾病结果。我们得出的结论是，7-OD 可以改变细胞因子平衡和 CD4 + T 细胞的表型，以达到更有利的分枝杆菌控制效果。这些结果提供了新的数据来描述作为结核病辅助治疗的新治疗方法。