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PLoS One. 2017 Jun 22;12(6):e0179882. doi: 10.1371/journal.pone.0179882. eCollection 2017.

HIV-Tat regulates macrophage gene expression in the context of neuroAIDS.

Author information

1
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
2
Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
3
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

Abstract

Despite the success of cART, greater than 50% of HIV infected people develop cognitive and motor deficits termed HIV-associated neurocognitive disorders (HAND). Macrophages are the major cell type infected in the CNS. Unlike for T cells, the virus does not kill macrophages and these long-lived cells may become HIV reservoirs in the brain. They produce cytokines/chemokines and viral proteins that promote inflammation and neuronal damage, playing a key role in HIV neuropathogenesis. HIV Tat is the transactivator of transcription that is essential for replication and transcriptional regulation of the virus and is the first protein to be produced after HIV infection. Even with successful cART, Tat is produced by infected cells. In this study we examined the role of the HIV Tat protein in the regulation of gene expression in human macrophages. Using THP-1 cells, a human monocyte/macrophage cell line, and their infection with lentivirus, we generated stable cell lines that express Tat-Flag. We performed ChIP-seq analysis of these cells and found 66 association sites of Tat in promoter or coding regions. Among these are C5, CRLF2/TSLPR, BDNF, and APBA1/Mint1, genes associated with inflammation/damage. We confirmed the association of Tat with these sequences by ChIP assay and expression of these genes in our THP-1 cell lines by qRT-PCR. We found that HIV Tat increased expression of C5, APBA1, and BDNF, and decreased CRLF2. The K50A Tat-mutation dysregulated expression of these genes without affecting the binding of the Tat complex to their gene sequences. Our data suggest that HIV Tat, produced by macrophage HIV reservoirs in the brain despite successful cART, contributes to neuropathogenesis in HIV-infected people.

PMID:
28640909
PMCID:
PMC5481010
DOI:
10.1371/journal.pone.0179882
[Indexed for MEDLINE]
Free PMC Article

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