Autophagy Deregulation in HIV-1-Infected Cells Increases Extracellular Vesicle Release and Contributes to TLR3 Activation
Catherine DeMarino,
Maria Cowen,
Anastasia Williams,
Pooja Khatkar,
Fardokht A. Abulwerdi,
Lisa Henderson,
Julia Denniss,
Michelle L. Pleet,
Delores R. Luttrell,
Iosif Vaisman,
Lance A. Liotta,
Joseph Steiner,
Stuart F. J. Le Grice,
Avindra Nath,
Fatah Kashanchi
Affiliations
Catherine DeMarino
Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA
Maria Cowen
Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA
Anastasia Williams
Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA
Pooja Khatkar
Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA
Fardokht A. Abulwerdi
Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702, USA
Lisa Henderson
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Julia Denniss
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Michelle L. Pleet
Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA
Delores R. Luttrell
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Iosif Vaisman
Laboratory for Structural Bioinformatics, School of Systems Biology, George Mason University, Manassas, VA 20110, USA
Lance A. Liotta
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
Joseph Steiner
Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Stuart F. J. Le Grice
Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702, USA
Avindra Nath
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Fatah Kashanchi
Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA
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.
