Opportunistic bacterial infections amongst HIV-infected individuals contribute significantly to HIV-associated mortality. The role of HIV-mediated modulation of innate mechanisms like autophagy in promoting opportunistic infections, however, remains obscure. Here we show, HIV reactivation in or infection of macrophages inhibits autophagy and helps the survival of pathogenic Mycobacterium tuberculosis (Mtb) and nonpathogenic non-tuberculous mycobacterial strains (NTMs). The HIV-mediated impairment of xenophagy flux facilitated bacterial survival. Activation of autophagy by trehalose could induce xenophagy flux and kill intracellular Mtb or NTMs either during single or co-infections. Trehalose, we delineate, activates PIKFYVE leading to TFEB nuclear translocation in MCOLN1-dependent manner to induce autophagy. Remarkably, trehalose significantly reduced HIV-p24 levels in ex-vivo-infected PBMCs or PBMCs from treatment-naive HIV patients and also controlled mycobacterial survival within Mtb-infected animals. To conclude, we report leveraging of HIV-mediated perturbed host innate-immunity by opportunistic bacterial pathogens and show an attractive therapeutic strategy for HIV and associated co-morbidities.Abbreviations: AIDS: acquired immune deficiency syndrome; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; BafA1: bafilomycin A1; CFU: colony forming unit; CTSD: cathepsin D; CD63: CD63 molecule; EGFP: enhanced green fluorescent protein; FRET: Förster resonance energy transfer; GABARAP: gamma-aminobutyric acid receptor-associated protein; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GLUT: glucose transporter; HIV: human immunodeficiency virus; hMDMs: human monocyte derived macrophages; IL2: interleukin 2; LAMP1: lysosomal-associated membrane protein 1; LC3B-II: lipidated microtubule-associated proteins 1A/1B light chain 3B; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin; mRFP: monomeric red fluorescent protein; M6PR: mannose-6-phosphate receptor; NAC: N- acetyl- L -cysteine; NTM's: non-tuberculous mycobacteria; PBMC: Peripheral Blood Mononuclear cells; PIKFYVE: phosphoinositide kinase; FYVE-Type Zinc Finger; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; PtdIns(3,5)P2: Phosphatidylinositol 3,5-bisphosphate; ptfLC3: pEGFP-mRFP-LC3; ROS: reactive oxygen species; SQSTM1: sequestosome1; TFEB: transcription factor EB; MCOLN1/TRPML1: mucolipin 1; PIP4P1/TMEM55B: Human trans-membrane Protein 55B; UVRAG: UV Radiation Resistance Associate; VPS35: vacuolar protein sorting associated protein 35; WDR45: WD repeat domain 45; YCAM: Yellow Chameleon.

中文翻译：

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海藻糖通过逆转 HIV 介导的自噬阻滞来限制 HIV 共感染期间的机会性分枝杆菌存活。

HIV 感染者中的机会性细菌感染显着增加了 HIV 相关死亡率。然而，HIV 介导的自噬等先天机制调节在促进机会性感染中的作用仍然不清楚。在这里我们显示，巨噬细胞中的 HIV 再激活或感染会抑制自噬，并有助于致病性结核分枝杆菌 (Mtb) 和非致病性非结核分枝杆菌菌株 (NTM) 的存活。HIV 介导的异食通量受损促进了细菌的存活。海藻糖对自噬的激活可以在单次感染或合并感染期间诱导异体吞噬通量并杀死细胞内 Mtb 或 NTM。我们描述了海藻糖激活 PIKFYVE，导致 TFEB 核易位，以 MCOLN1 依赖性方式诱导自噬。值得注意的是，海藻糖显着降低了体外感染的 PBMC 或来自未经治疗的 HIV 患者的 PBMC 中的 HIV-p24 水平，并且还控制了 Mtb 感染动物中分枝杆菌的存活率。总之，我们报告了机会性细菌病原体对 HIV 介导的扰动宿主先天免疫的利用，并展示了一种针对 HIV 和相关合并症的有吸引力的治疗策略。AMPK：AMP 活化蛋白激酶；ATG5：自噬相关5；BafA1：巴弗洛霉素A1；CFU：菌落形成单位；CTSD：组织蛋白酶 D；CD63：CD63分子；EGFP：增强型绿色荧光蛋白；FRET：福斯特共振能量转移；GABARAP：γ-氨基丁酸受体相关蛋白；GAPDH：3-磷酸甘油醛脱氢酶；GLUT：葡萄糖转运蛋白；HIV：人类免疫缺陷病毒；hMDMs：人单核细胞衍生的巨噬细胞；IL2：白细胞介素2；LAMP1：溶酶体相关膜蛋白 1；LC3B-II：脂化微管相关蛋白 1A/1B 轻链 3B；Mtb：结核分枝杆菌；MTOR：雷帕霉素的机制靶点；mRFP：单体红色荧光蛋白；M6PR：6-磷酸甘露糖受体；NAC：N-乙酰基-L-半胱氨酸；NTM：非结核分枝杆菌；PBMC：外周血单核细胞；PIKFYVE：磷酸肌醇激酶；FYVE-型锌指；PHA：植物血凝素；PMA：佛波醇 12-肉豆蔻酸酯 13-乙酸酯；PtdIns(3,5)P2：磷脂酰肌醇 3,5-二磷酸；ptfLC3：pEGFP-mRFP-LC3；ROS：活性氧；SQSTM1：sequestosome1；TFEB：转录因子EB；MCOLN1/TRPML1：粘蛋白 1；PIP4P1/TMEM55B：人跨膜蛋白 55B；UVRAG：抗紫外线辐射协会；VPS35：液泡蛋白分选相关蛋白35；WDR45：WD 重复域 45；YCAM：黄色变色龙。