HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models

Forlani, Greta; Shallak, Mariam; Accolla, Roberto S.; Romanelli, Maria Grazia

doi:10.3390/ijms22158001

Cited by 29 publications

(18 citation statements)

References 192 publications

(215 reference statements)

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“…To determine whether the distinct transformation tropism conferred by viral Env is at the level of entry or occurs later during infection, Kannian et al investigated preference for T-cell type in an immune competent New Zealand white (NZW) rabbit model of HTLV infection and persistence [43,81,[98][99][100][101][102][103]. Although they do not develop disease, rabbits inoculated with lethally irradiated HTLV-1 or HTLV-2 producer cells become persistently infected [43,99].…”

Section: Role Of Env In Htlv T-cell Transformation Tropismmentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Envelope Protein: Post-Entry Roles in Viral Pathogenesis

Maksimova

Panfil

2022

Viruses

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Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and fatal CD4+ T-cell malignancy, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic neurological disease. Disease progression in infected individuals is the result of HTLV-1-driven clonal expansion of CD4+ T-cells and is generally associated with the activities of the viral oncoproteins Tax and Hbz. A closely related virus, HTLV-2, exhibits similar genomic features and the capacity to transform T-cells, but is non-pathogenic. In vitro, HTLV-1 primarily immortalizes or transforms CD4+ T-cells, while HTLV-2 displays a transformation tropism for CD8+ T-cells. This distinct tropism is recapitulated in infected people. Through comparative studies, the genetic determinant for this divergent tropism of HTLV-1/2 has been mapped to the viral envelope (Env). In this review, we explore the emerging roles for Env beyond initial viral entry and examine current perspectives on its contributions to HTLV-1-mediated disease development.

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Section: Role Of Env In Htlv T-cell Transformation Tropismmentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Envelope Protein: Post-Entry Roles in Viral Pathogenesis

Maksimova

Panfil

2022

Viruses

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“…Histograms representing the distribution of log2FoldChange of 84 alternatively spliced cancer related genes in ATL-2 vs MOLT-4 (A) and in Jurkat-HBZ vs Jurkat (B). (1) Total ASE in ATL-2 vs MOLT-4 (2) Exon skipping events in ATL-2 vs MOLT-4 (3) Alternative acceptor site in ATL-2 vs MOLT-4 (4) Alternative donor site in ATL-2 vs MOLT-4 (5) Mutually exclusive exons in ATL-2 vs MOLT-4 (6) Multiple exons skipping in ATL-2 vs MOLT-4 (7) Total ASE in Jurkat-HBZ cells vs Jurkat cells (8) Exon skipping events in Jurkat-HBZ cells vs Jurkat cells (9) Alternative acceptor site in Jurkat-HBZ expressing cells vs Jurkat cells (10) Alternative donor site in Jurkat-HBZ cells vs Jurkat cells (11) Mutually exclusive exons in Jurkat-HBZ expressing cells vs Jurkat cells (12) Multiple exons skipping in Jurkat-HBZ cells vs Jurkat cells (13) GO-DAVID analysis of HBZ-induced ASEs (14) Exon ontology analysis of HBZ-induced ASEs SUPPLEMENTARY DATA SHEET 4 Common Genes that are differentially expressed and alternatively spliced in ATL-2 (1) and in Jurkat-HBZ cells (2). (3) Common alternative splicing genes between ATL-2 and Jurkat-HBZ cells.…”

Section: Supplementary Figurementioning

confidence: 99%

“…Two viral products, the Tax-1 transactivator and the HTLV-1 basic leucine zipper factor (HBZ) play an important role in the genesis and maintenance of the oncogenic process by disarranging basic mechanisms of cell activation ( 9 , 10 ). For example, Tax-1 constitutively activates NF-κB pathway and suppresses the DNA repair mechanism, thus favoring the accumulation of mutations essential for the establishment of the oncogenic phenotype ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing

et al. 2022

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Adult T-cell leukemia/lymphoma (ATL) is a T-cell lymphoproliferative neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). Two viral proteins, Tax-1 and HBZ play important roles in HTLV-1 infectivity and in HTLV-1-associated pathologies by altering key pathways of cell homeostasis. However, the molecular mechanisms through which the two viral proteins, particularly HBZ, induce and/or sustain the oncogenic process are still largely elusive. Previous results suggested that HBZ interaction with nuclear factors may alter cell cycle and cell proliferation. To have a more complete picture of the HBZ interactions, we investigated in detail the endogenous HBZ interactome in leukemic cells by immunoprecipitating the HBZ-interacting complexes of ATL-2 leukemic cells, followed by tandem mass spectrometry analyses. RNA seq analysis was performed to decipher the differential gene expression and splicing modifications related to HTLV-1. Here we compared ATL-2 with MOLT-4, a non HTLV-1 derived leukemic T cell line and further compared with HBZ-induced modifications in an isogenic system composed by Jurkat T cells and stably HBZ transfected Jurkat derivatives. The endogenous HBZ interactome of ATL-2 cells identified 249 interactors covering three main clusters corresponding to protein families mainly involved in mRNA splicing, nonsense-mediated RNA decay (NMD) and JAK-STAT signaling pathway. Here we analyzed in detail the cluster involved in RNA splicing. RNAseq analysis showed that HBZ specifically altered the transcription of many genes, including crucial oncogenes, by affecting different splicing events. Consistently, the two RNA helicases, members of the RNA splicing family, DDX5 and its paralog DDX17, recently shown to be involved in alternative splicing of cellular genes after NF-κB activation by HTLV-1 Tax-1, interacted and partially co-localized with HBZ. For the first time, a complete picture of the endogenous HBZ interactome was elucidated. The wide interaction of HBZ with molecules involved in RNA splicing and the subsequent transcriptome alteration strongly suggests an unprecedented complex role of the viral oncogene in the establishment of the leukemic state.

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“…Both HTLV-1 and HTLV-2 survive through a persistent clonal expansion of infected cells; however, unlike HTLV-1, HTLV-2 exhibits a predominant transformation of the CD8+ T cell subset, which harbors the majority of HTLV-2 proviral load [ 19 ]. Cellular immortalization in vivo, as well as viral pathogenesis, are primarily mediated by Tax-1 and Tax-2 transactivating proteins, whose effects on the cellular pathways are divergent [ 20 , 21 , 22 , 23 , 24 ]. Although Tax-1 and Tax-2 show an amino acid similarity of 85%, Tax-2 differs in recruiting host co-activators to enhance LTR transcription and signal transduction compared with Tax-1 [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

A Panel of Eight miRNAs Is Deregulated in HTLV-2 Infected PBMCs and BJABGu Cell Line

Pilotti

Cannata²,

Magnani

et al. 2022

IJMS

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Despite human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 being retroviruses closely related at a genomic level, HTLV-2 differs from HTLV-1 in terms of pathogenicity in both single infection and coinfection contexts. Moreover, the HTLV-2 association with clinical outcomes is still debated and several mechanisms underlying HTLV-2 infection remain unexplored as well. Cellular miRNAs are key factors in the post-transcriptional regulation of gene expression and they are known to be potential targets for several pathogens to control the host microenvironment and, in particular, escape immune responses. Here, we identified a HTLV-2-related signature of eight miRNAs (miR-125a-3p, miR-381-3p, miR-502-5p, miR-708-5p, miR-548d-5p, miR-548c-5p, miR-1-3p, and miR-511-5p) in both HTLV-2 infected PBMC and BJABGu cell lines. Altered miRNA expression patterns were correlated with the impairment of Th cell differentiation and signaling pathways driven by cytokines and transcriptional factors such as the Runt-related transcription factor (RUNX) family members. Specifically, we demonstrated that the RUNX2 protein was significantly more expressed in the presence of Tax-2 compared with Tax-1 in an in vitro cell model. To the best of our knowledge, these data represent the first contribution to elucidating the HTLV-2 mediated alteration of host cell miRNA profiles that may impact on HTLV-2 replication and persistent infection.

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HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models

Cited by 29 publications

References 192 publications

Human T-Cell Leukemia Virus Type 1 Envelope Protein: Post-Entry Roles in Viral Pathogenesis

Human T-Cell Leukemia Virus Type 1 Envelope Protein: Post-Entry Roles in Viral Pathogenesis

The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing

A Panel of Eight miRNAs Is Deregulated in HTLV-2 Infected PBMCs and BJABGu Cell Line

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