Cellular Immunology Group, International Center for Genetic Engineering and Biotechnology, New Delhi, India.
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Autophagy. 2021 Feb;17(2):476-495. doi: 10.1080/15548627.2020.1725374. Epub 2020 Feb 20.
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 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 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 -infected PBMCs or PBMCs from treatment-naive HIV patients and also controlled mycobacterial survival within -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. AIDS: acquired immune deficiency syndrome; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; BafA1: bafilomycin A; 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: ; 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; ; 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.
HIV 感染者机会性细菌感染是导致与 HIV 相关死亡的重要原因。然而，HIV 介导的先天机制（如自噬）调节在促进机会性感染中的作用仍不清楚。在这里，我们表明，巨噬细胞中的 HIV 再激活或感染会抑制自噬，并有助于致病性和非致病性非结核分枝杆菌（NTM）菌株的存活。HIV 介导的吞噬作用通量受损促进了细菌的存活。海藻糖激活自噬可诱导吞噬作用通量，并在单感染或共感染期间杀死细胞内或 NTMs。我们阐述了海藻糖通过 PIKFYVE 激活，以 MCOLN1 依赖性方式导致 TFEB 核易位，从而诱导自噬。值得注意的是，海藻糖可显著降低感染 HIV 的 PBMC 或未经治疗的 HIV 患者 PBMC 中的 HIV-p24 水平，还可控制感染动物体内的分枝杆菌存活。总之，我们报告了机会性细菌病原体利用 HIV 介导的宿主先天免疫失调，并展示了一种有吸引力的 HIV 和相关合并症的治疗策略。AIDS：获得性免疫缺陷综合征；AMPK：AMP 激活的蛋白激酶；ATG5：自噬相关 5；BafA1：巴弗霉素 A；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：Förster 共振能量转移；GABARAP：γ-氨基丁酸受体相关蛋白；GAPDH：甘油醛 3-磷酸脱氢酶；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：雷帕霉素的机制靶标；mRFP：单体红色荧光蛋白；M6PR：甘露糖-6-磷酸受体；NAC：N-乙酰-L-半胱氨酸；NTM's：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 13-乙酸酯；PtdIns（3,5）P2：磷脂酰肌醇 3,5-二磷酸；ROS：活性氧物种；SQSTM1：自噬体相关蛋白 1；TFEB：转录因子 EB；MCOLN1/TRPML1：粘脂 1；PIP4P1/TMEM55B：人跨膜蛋白 55B；UVRAG：紫外线辐射抗性相关；VPS35：液泡蛋白分选相关蛋白 35；WDR45：WD 重复域 45；YCAM：黄变色龙。
