Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein
Open accessAbstract
Chronic immune activation is a major complication of antiretroviral therapy (ART) for HIV infection and can cause a devastating immune reconstitution inflammatory syndrome (IRIS) in the brain. The mechanism of T-cell activation in this population is not well understood. We found HIV-Tat protein and IL-17–expressing mononuclear cells in the brain of an individual with IRIS. Tat was also present in the CSF of individuals virologically controlled on ART. Hence we examined if Tat protein could directly activate T cells. Tat transcriptionally dysregulated 94 genes and induced secretion of 11 cytokines particularly activation of IL-17 signaling pathways supporting the development of a proinflammatory state. Tat increased IL-17 transcription and secretion in T cells. Tat entered the T cells rapidly by clathrin-mediated endocytosis and localized to both the cytoplasm and the nucleus. Tat activated T cells through a nonclassical pathway dependent upon vascular endothelial growth factor receptor-2 and downstream secondary signaling pathways but independent of the T-cell receptor. However, Tat stimulation of T cells did not induce T-cell proliferation but increased viral infectivity. This study demonstrates Tat’s role as a virulence factor, by driving T-cell activation and contributing to IRIS pathophysiology. This supports the necessity of an anti-Tat therapy in conjunction with ART and identifies multiple targetable pathways to prevent Tat-mediated T-cell activation.
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Pathogenic viral proteins including Tat are present in the cerebrospinal fluid of HIV-1-positive patients receiving HAART.
“pathogenic viral proteins including transactivator of transcription (Tat) are present in the cerebrospinal fluid of HIV-1-positive patients receiving HAART”
From RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection (2014) · cites this paper as [6]
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RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection
Hu, W., Kaminski, R., Yang, F., Zhang, Y., Cosentino, L., Li, F., Luo, B., Alvarez-Carbonell, D., Garcia-Mesa, Y., Karn, J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1405186111 · Cited by 527 · see citing works
- Authors
- Johnson, T. P., Patel, K., Johnson, K. R., Maric, D., Calabresi, P. A., Hasbun, R., & Nath, A.
- Affiliations
- National Institutes of Health (US)
- Johns Hopkins University (US)
- The University of Texas Health Science Center at Houston (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-07-29
- Volume
- 110
- Issue
- 33
- Pages
- 13588-13593
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3746932
- OpenAlex
- W2084251620
- Cited by
- 265
- References
- 40
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 20 · 2023: 14 · 2022: 20 · 2021: 28 · 2020: 27 · 2019: 24 · 2018: 17 · 2017: 19 · 2016: 22 · 2015: 21 · 2014: 19 · 2013: 5
- FWCI
- 10.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS039253, R01NS056884, F31NS063855)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Keywords
- HIV-1 Tat protein, IL-17, T cell activation, immune reconstitution inflammatory syndrome, chronic immune activation, antiretroviral therapy, clathrin-mediated endocytosis, VEGFR2 signaling, viral virulence factors, cerebrospinal fluid, T cell proliferation, viral infectivity
- MeSH terms
- Brain, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Leukocytes, Mononuclear, Lymphocyte Activation, T-Lymphocytes, Immunoblotting, Signal Transduction, HIV Infections, Gene Expression Regulation, Viral, Interleukin-17, Virulence Factors, Anti-Retroviral Agents, Microarray Analysis, Immune Reconstitution Inflammatory Syndrome, tat Gene Products, Human Immunodeficiency Virus
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