Localization, quantification and interaction with host factors of endogenous HTLV-1 HBZ protein in infected cells and ATL

Raval, Goutham; Bidoia, Carlo; Forlani, Greta; Tosi, Giovanna; Gessain, Antoine; Accolla, Roberto S.

doi:10.1186/s12977-015-0186-0

Cited by 34 publications

(69 citation statements)

References 39 publications

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“…As shown in previous reports, GFP-HBZ was observed in speckle-like structures in the nuclear compartment ( Fig. 4A) (58,59). BRG1 localized in the nucleus in distinct foci ( Fig.…”

Section: Resultssupporting

confidence: 86%

“…While BRG1 has a euchromatin nucleoplasmic distribution with several prominent foci that localize in the nucleolus (60,61), HBZ is a predominately nucleus-localizing protein with a speckled pattern associated with heterochromatin (15,55,58). Using immunofluorescence (IF) studies, we observed that BRG1 expression changes the localization pattern of HBZ.…”

Section: Discussionmentioning

confidence: 93%

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Novel Interactions between the Human T-Cell Leukemia Virus Type 1 Antisense Protein HBZ and the SWI/SNF Chromatin Remodeling Family: Implications for Viral Life Cycle

Alasiri

Hall

et al. 2019

J Virol

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The human T-cell leukemia virus type 1 (HTLV-1) regulatory proteins Tax and HBZ play indispensable roles in regulating viral and cellular gene expression. BRG1, the ATPase subunit of the SWI/SNF chromatin remodeling complex, has been demonstrated to be essential not only for Tax transactivation but also for viral replication. We sought to investigate the physical interaction between HBZ and BRG1 and to determine the effect of these interactions on Tax-mediated long terminal repeat (LTR) activation. We reveal that HTLV-1 cell lines and adult T-cell leukemia (ATL) cells harbor high levels of BRG1. Using glutathione S-transferase (GST) pulldown and coimmunoprecipitation assays, we have demonstrated physical interactions between BRG1 and HBZ and characterized the protein domains involved. Moreover, we have identified the PBAF signature subunits BAF200 and BAF180 as novel interaction partners of HBZ, suggesting that the PBAF complex may be required for HTLV-1 transcriptional repression by HBZ. Additionally, we found that BRG1 expression translocates HBZ into distinct nuclear foci. We show that HBZ substantially represses HTLV-1 LTR activation by Tax/BRG1. Interestingly, we found that Tax stabilizes the expression of exogenous and endogenous BRG1 and that HBZ reverses this effect. Finally, using a chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) assay, we illustrate that HBZ facilitates the downregulation of HTLV-1 transcription by deregulating the recruitment of SWI/SNF complexes to the promoter. Overall, we conclude that SWI/SNF complexes, in addition to other cellular transcription factors, are involved in HBZmediated suppression of HTLV-1 viral gene expression. IMPORTANCE The pathogenic potential of HTLV-1 is linked to the indispensable multifaceted functions of the viral regulatory proteins Tax and HBZ, encoded by the sense and antisense viral transcripts, respectively. The interaction between Tax and the SWI/SNF family of chromatin remodeling complexes has been associated with HTLV-1 transcriptional activation. To date, the relationship between the SWI/SNF chromatin remodeling family and HBZ, the only viral protein that is consistently expressed in infected cells and ATL cells, has not been elucidated. Here, we have characterized the biological significance of the SWI/SNF family in regard to viral transcriptional repression by HBZ. This is important because it provides a better understanding of the function and role of HBZ in downregulating viral transcription and, hence, its contribution to viral latency and persistence in vivo, a process that may ultimately lead to the development of ATL.

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“…As shown in previous reports, GFP-HBZ was observed in speckle-like structures in the nuclear compartment ( Fig. 4A) (58,59). BRG1 localized in the nucleus in distinct foci ( Fig.…”

Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 93%

Novel Interactions between the Human T-Cell Leukemia Virus Type 1 Antisense Protein HBZ and the SWI/SNF Chromatin Remodeling Family: Implications for Viral Life Cycle

Alasiri

Hall

et al. 2019

J Virol

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“…Moreover, the cellular immune response has been implicated in the control of HTLV-1 infection as well as in the development of related inflammatory alterations in patients [26] . The cellular immune response involves CD4 + T cells differentiating towards the Th1, Th2 and Th17 lineages, producing a variety of proinflammatory cytokines, chemokines, adhesion molecules and proinflammatory enzymes, which contribute to chronic inflammatory conditions and include reactive oxygen species (ROS), tumour necrosis factor alpha (TNFα), interleukins (IL1, 6, 8 and 18), nuclear factor-kappa B (NF-κB), hypoxia-inducible factor (HIF), IFNγ, and cyclooxygenase (COX) [27,28] . Moreover, contributions of different HTLV-1 oncogenic pathways related to viral proteins have been recently described recently [29] .…”

Section: Clinical Implications Of Hcv/htlv-1/2 Co-infectionmentioning

confidence: 99%

Hepatitis C virus/human T lymphotropic virus 1/2 co-infection: Regional burden and virological outcomes in people who inject drugs

Castro¹,

Roger²

2016

WJV

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This review analyses current data concerning co-infection with hepatitis C virus (HCV) and human T lymphotropic virus (HTLV)-1/2 in people who inject drugs (PWID), with a particular focus on disease burden and global implications for virological outcome. In addition, the available treatment options for HTLV-1/2 are summarized and the ongoing and likely future research challenges are discussed. The data in this review was obtained from 34 articles on HCV/HTLV-1/2 co-infection in PWID retrieved from the PubMed literature database and published between 1997 and 2015. Despite unavailable estimates of the burden of HCV/HTLV-1/2 co-infection in general, the epidemiologic constellation of HTLV-1/2 shows high incidence in PWID with history of migration, incarceration, and other blood-borne infectious diseases such as HCV or human immunodeficiency virus. The most recent research data strongly suggest that HTLV-1 co-infection can influence HCV viral load, HCV sustained virological response to α-interferon treatment, and HCV-related liver disease progression. In short, outcome of HCV infection is worse in the context of HTLV-1 co-infection, yet more studies are needed to gain accurate estimations of the burden of HCV/HTLV-1/2 co-infections. Moreover, in the current era of new direct-acting antiviral treatments for HCV and proven HTLV-1/2 treatment options, prospective clinical and treatment studies should be carried out, with particular focus on the PWID patient population, with the aim of improving virological outcomes.

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“…The HBZ protein level is also of great interest because the CD8 + T cell response against HBZ is a significant determinant of the HTLV-1 proviral load [25], the main correlate of the risk of HAM and ATL [1]. A previous study from others estimated, by western blotting, that the abundance of endogenous HBZ protein is 17 molecules per cell in an ATL case [26]. However, this study did not report HBZ protein expression in nonmalignant cells, or its variance in a polyclonal population.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

Miura

Dey

Singh

et al. 2019

Preprint

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20The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-21 strand transcription is usually silent at a given time in each cell. However, cellular stress responses 22 trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-23 molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral 24 blood mononuclear cells (PBMCs) isolated from HTLV-1 + individuals. The abundance of the HTLV-1 sense 25 and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. 26We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-27 rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked 28 between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity 29 was similar in polyclonal HTLV-1 + PBMCs (with tens of thousands of distinct provirus insertion sites), and 30 in samples with a single dominant HTLV-1 + clone. A stochastic simulation model was developed to 31 estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject 32 with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand 33 activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription 34 was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an 35 average rate of ~0.1 molecules per hour per HTLV-1 + cell; however, between 20% and 70% of HTLV-1-36 infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. 37 HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which 38 initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable 39 throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and 40 occurs in short, self-terminating bursts. 41 3 Author summary 42 Human retroviruses such as HIV-1 and HTLV-1 (human T cell leukemia virus) can establish a latent 43 infection in the host cell. However, these viruses need to be able to produce viral genome to propagate 44 in a new host. HTLV-1-infected cells are transmitted through breastfeeding, blood transfusion and sexual 45 contact, and HTLV-1 restores transcription once the infected cells are drawn from infected individuals. 46We measured the kinetics of the HTLV-1 transcriptional reactivation in blood cells isolated from HTLV-1 + 47 individuals by single-molecule RNA FISH. Viral transcripts were visualised as diffraction-limited spots and 48 their abundance was quantified at one-hour intervals. The onset of the virus transcription peaked after 49 one to three hours of incubation. In each cell, a short period of slow HTLV-1 transcription was followed 50 by a phase of rapid transcription. Computer simu...

show abstract

Localization, quantification and interaction with host factors of endogenous HTLV-1 HBZ protein in infected cells and ATL

Cited by 34 publications

References 39 publications

Novel Interactions between the Human T-Cell Leukemia Virus Type 1 Antisense Protein HBZ and the SWI/SNF Chromatin Remodeling Family: Implications for Viral Life Cycle

Novel Interactions between the Human T-Cell Leukemia Virus Type 1 Antisense Protein HBZ and the SWI/SNF Chromatin Remodeling Family: Implications for Viral Life Cycle

Hepatitis C virus/human T lymphotropic virus 1/2 co-infection: Regional burden and virological outcomes in people who inject drugs

Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

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