The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1α, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant-N-acetyl cysteine (NAC)-or with inhibitors of host factors-galectins and Hsp90-attenuated HIV-1 reactivation by M. tuberculosis -specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies.IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.

中文翻译：

---

结核分枝杆菌通过外来体介导的细胞氧化还原电位和生物能学的重置来重新激活HIV-1。

结核分枝杆菌与人类免疫缺陷病毒1（HIV-1）之间的协同作用会干扰治疗并促进两种人类病原体的发病机理。结核分枝杆菌加剧HIV-1感染的基本机制尚不清楚。在这里，我们表明由结核分枝杆菌感染的巨噬细胞分泌的外泌体，包括耐药性临床菌株，通过诱导氧化应激而重新激活了HIV-1。从机制上讲，结核分枝杆菌特异的外泌体重新调整了线粒体和非线粒体的耗氧率（OCR），并调节了介导氧化应激反应，炎症和HIV-1反式激活的宿主基因的表达。蛋白质组学分析显示，已知多种宿主因子（例如，HIF-1α，半乳糖凝集素和Hsp90）的富集可促进M-1中HIV-1的活化。结核特异性外来体。用已知的抗氧化剂-N-乙酰半胱氨酸（NAC）-或宿主因子抑制剂-半乳糖凝集素和Hsp90减弱了结核分枝杆菌特异性外泌体对HIV-1的活化作用。我们的发现揭示了理解HIV-M的氧化还原和生物能学基础的新范例。结核病合并感染，这将有助于设计有效的治疗策略。重要事项在全球范围内，艾滋病病毒（HIV-1）和结核分枝杆菌（结核病[TB]的致病原）合并感染的个体在这两种疾病的临床管理中均构成主要障碍。疾病。这个问题的核心是两种人类病原体之间明显的协同作用。一方面，由HIV-1诱导的艾滋病患者结核病再激活机制已得到很好的表征。另一方面，尽管临床发现清楚地表明结核病是HIV-1活化和相关死亡率的危险因素，但结核分枝杆菌加剧HIV-1复制和感染的基本机制仍知之甚少。我们研究的意义在于确定氧化还原和能量代谢等基本机制在催化HIV-M中的作用。结核协同作用。量化结核分枝杆菌在刺激HIV-1中影响的氧化还原和呼吸参数将大大增强我们对HIV-M的了解。结核病合并感染，从而对生物医学研究界产生更广泛的影响，并创造新的转化机会。结核病加剧了HIV-1的复制，感染的特征仍然很差。我们研究的意义在于确定氧化还原和能量代谢等基本机制在催化HIV-M中的作用。结核协同作用。量化结核分枝杆菌在刺激HIV-1中影响的氧化还原和呼吸参数将大大增强我们对HIV-M的了解。结核病合并感染，从而对生物医学研究界产生更广泛的影响，并创造新的转化机会。结核病加剧了HIV-1的复制，感染的特征仍然很差。我们研究的意义在于确定氧化还原和能量代谢等基本机制在催化HIV-M中的作用。结核协同作用。量化结核分枝杆菌在刺激HIV-1中影响的氧化还原和呼吸参数将大大增强我们对HIV-M的了解。结核病合并感染，从而对生物医学研究界产生更广泛的影响，并创造新的转化机会。结核病在刺激HIV-1方面将大大增进我们对HIV-M的了解。结核病合并感染，从而对生物医学研究界产生更广泛的影响，并创造新的转化机会。结核病在刺激HIV-1方面将大大增进我们对HIV-M的了解。结核病合并感染，从而对生物医学研究界产生更广泛的影响，并创造新的转化机会。