Berbamine promotes autophagy and GPX4 expression through inducing abundant ROS to restrict HIV-1 and Mtb coinfection in macrophages

Human immunodeficiency virus type 1 (HIV-1) and Mycobacterium tuberculosis (Mtb) co-infection poses a significant public health threat, characterized by a high mortality rate due to impaired host immune responses. In this study, we investigated the role of Autophagy, primarily using macrophage cell models co-infected with HIV-1 and Mtb. Our findings indicate that HIV-1 Infection or latency significantly suppresses Autophagy in macrophages, thereby creating a permissive environment for the survival and replication of intracellular Mtb. Co-infection experiments demonstrated that Mtb exacerbates the Autophagy suppression induced by HIV-1, further promoting Bacterial proliferation. Notably, pharmacological activation of Autophagy using berbamine (BBM), a natural compound, significantly reduced HIV-1 latency reactivation and decreased the intracellular Mtb burden. Colocalization of LC3 with the HIV-1 capsid protein p24 and Mtb was observed using a confocal microscope. Mechanistic investigations revealed that BBM-induced Autophagy is mediated by elevated levels of cytosolic Reactive Oxygen Species (ROS), which trigger autophagosome formation and lysosomal degradation. However, prolonged ROS elevation poses a risk of cellular damage; thus, BBM concurrently upregulates the antioxidant enzyme Glutathione Peroxidase 4 (GPX4) to alleviate oxidative stress and maintain redox homeostasis. These findings underscore Autophagy as a dual-function mechanism that restricts both viral persistence and Bacterial survival during co-infection. This study highlights the therapeutic potential of targeting the crosstalk between Autophagy and ROS to manage HIV-1-Mtb co-infection and suggests BBM as a promising candidate for further preclinical evaluation. These insights may inform the development of host-directed therapies aimed at improving clinical outcomes in co-infected patients.

mycobacterium tuberculosis; HIV-1; ROS; autophagy; berbamine.