CAGE-seq reveals that HIV-1 latent infection does not trigger unique cellular responses in a Jurkat T cell model.

Autor: Matsui H; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Shirakawa K; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan kotash@kuhp.kyoto-u.ac.jp., Konishi Y; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.; Department of Hematology, Kansai Electric Power Medical Research Institute, Osaka, Japan., Hirabayashi S; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Sarca AD; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Fukuda H; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Nomura R; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Stanford E; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Horisawa Y; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Kazuma Y; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Matsumoto T; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Yamazaki H; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Murakawa Y; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.; Institute for the advanced study of human biology, Kyoto University, Kyoto, Japan.; Department of Medical Systems Genomics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.; The FIRC Institute of Molecular Oncology (IFOM), Milan, Italy., Battivelli E; Buck Institute for Research on Aging, Novato, CA, USA., Verdin E; Buck Institute for Research on Aging, Novato, CA, USA., Koyanagi Y; Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan., Takaori-Kondo A; From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Jazyk: angličtina
Zdroj: Journal of virology [J Virol] 2021 Mar 25; Vol. 95 (8). Date of Electronic Publication: 2021 Jan 27.
DOI: 10.1128/JVI.02394-20
Abstrakt: The cure for HIV-1 is currently stalled by our inability to specifically identify and target latently infected cells. HIV-1 viral RNA/DNA or viral proteins are recognized by cellular mechanisms and induce interferon responses in virus producing cells, but changes in latently infected cells remain unknown. HIV GKO contains a GFP reporter under the HIV-1 promoter and an mKO2 reporter under the internal EF1α promoter. This viral construct enables direct identification of HIV-1 both productively and latently infected cells. In this study we aim to identify specific cellular transcriptional responses triggered by HIV-1 entry and integration using Cap Analysis of Gene Expression (CAGE).We deep sequenced CAGE tags in uninfected, latently and productively infected cells and compared their differentially expressed transcription start site (TSS) profiles. Virus producing cells had differentially expressed TSSs related to T-cell activation and apoptosis when compared to uninfected cells or latently infected cells. Surprisingly, latently infected cells had only 33 differentially expressed TSSs compared to uninfected cells. Among these, SPP1 and APOE were down-regulated in latently infected cells. SPP1 or APOE knockdown in Jurkat T cells increased susceptibility to HIV GKO infection, suggesting that they have anti-viral properties. Components of the PI3K/mTOR pathway, MLST8, 4EBP and RPS6, were significant TSSs in productively infected cells, and S6K phosphorylation was increased compared to latently infected cells, suggesting that mTOR pathway activity plays a role in establishing the latent reservoir. These findings indicate that HIV-1 entry and integration do not trigger unique transcriptional responses when infection becomes latent. Importance: Latent HIV-1 infection is established as early as the first viral exposure and remains the most important barrier in obtaining the cure for HIV-1 infection. Here, we used CAGE to compare the transcriptional landscape of latently infected cells with that of non-infected or productively infected cells. We found that latently infected cells and non-infected cells show quite similar transcriptional profiles. Our data suggest that T-cells cannot recognize incoming viral components nor the integrated HIV-1 genome when infection remains latent. These findings should guide future research into widening our approaches to identify and target latent HIV-1 infected cells.
(Copyright © 2021 Matsui et al.)
Databáze: MEDLINE
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