Autophagy Deregulation in HIV-1-Infected Cells Increases Extracellular Vesicle Release and Contributes to TLR3 Activation

• Published in: Viruses 2024-04, Vol.16 (4), p.643
• Main Authors: DeMarino, Catherine, Cowen, Maria, Williams, Anastasia, Khatkar, Pooja, Abulwerdi, Fardokht A, Henderson, Lisa, Denniss, Julia, Pleet, Michelle L, Luttrell, Delores R, Vaisman, Iosif, Liotta, Lance A, Steiner, Joseph, Le Grice, Stuart F J, Nath, Avindra, Kashanchi, Fatah
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Antibiotics; Antiretroviral drugs; Antiretroviral therapy; Autophagy; Autophagy (Cytology); Autophagy - drug effects; Care and treatment; Causes of; central nervous system (CNS); Cognition; combined antiretroviral therapy (cART); Complications and side effects; Cytokines; Darunavir; Development and progression; Emtricitabine; Ethylenediaminetetraacetic acid; Extracellular vesicles; Extracellular Vesicles - metabolism; Highly active antiretroviral therapy; HIV; HIV (Viruses); HIV Infections - drug therapy; HIV Infections - metabolism; HIV Infections - virology; HIV-1 - physiology; HIV-associated neurocognitive disorder (HAND); Human immunodeficiency virus; human immunodeficiency virus-1 (HIV-1); Humans; Immune system; Infection; Infections; Inflammation; Methods; Mitochondrial DNA; Morbidity; Myeloid cells; Nervous system diseases; Neurological complications; Neurological diseases; Neurophysiology; Packaging; Pathogenesis; Physiological aspects; Product introduction; Proteins; RNA; RNA polymerase; RNA, Viral - genetics; RNA, Viral - metabolism; TLR3; TLR3 protein; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism; Toll-like receptors; Viral infections
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v16040643

Human immunodeficiency virus type 1 (HIV-1) infection can result in HIV-associated neurocognitive disorder (HAND), a spectrum of disorders characterized by neurological impairment and chronic inflammation. Combined antiretroviral therapy (cART) has elicited a marked reduction in the number of individuals diagnosed with HAND. However, there is continual, low-level viral transcription due to the lack of a transcription inhibitor in cART regimens, which results in the accumulation of viral products within infected cells. To alleviate stress, infected cells can release accumulated products, such as TAR RNA, in extracellular vesicles (EVs), which can contribute to pathogenesis in neighboring cells. Here, we demonstrate that cART can contribute to autophagy deregulation in infected cells and increased EV release. The impact of EVs released from HIV-1 infected myeloid cells was found to contribute to CNS pathogenesis, potentially through EV-mediated TLR3 (Toll-like receptor 3) activation, suggesting the need for therapeutics to target this mechanism. Three HIV-1 TAR-binding compounds, 103FA, 111FA, and Ral HCl, were identified that recognize TAR RNA and reduce TLR activation. These data indicate that packaging of viral products into EVs, potentially exacerbated by antiretroviral therapeutics, may induce chronic inflammation of the CNS observed in cART-treated patients, and novel therapeutic strategies may be exploited to mitigate morbidity.