HTLV-1 persistence and leukemogenesis: A game of hide-and-seek with the host immune system

Tan, Benjy J.Y.; Sugata, Kenji; Ono, Masahiro; Satou, Yorifumi

doi:10.3389/fimmu.2022.991928

Cited by 6 publications

(5 citation statements)

References 131 publications

(155 reference statements)

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“…Alterations in immune responses are associated with HTLV-1 infection and contribute to disease development [ 10 , 27 , 28 , 71 , 72 , 73 , 74 ]. While CD4 cells are the primary target of HTLV-1, the virus is also found in CD8, monocytes, macrophages, and dendritic cells from infected individuals [ 75 , 76 , 77 , 78 , 79 , 80 ].…”

Section: Discussionmentioning

confidence: 99%

“…Immune dysregulation is a common feature in HTLV-1 infection [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], and although there is a strong innate and adaptive response to the virus, it results in a lifelong persistent infection of primarily T lymphocytes [ 21 , 22 , 23 , 24 , 25 , 26 ]. This is likely linked to the ability of the virus to counteract host responses [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells

Gutowska,

Sarkis,

Rahman

et al. 2024

Pathogens

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The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1WT (wild type) and HTLV-1p12KO (Orf-1 knockout) infectivity, but seroconversion to either virus is not sustained over time, suggesting a progressive decrease in virus expression. These results raise the hypotheses that either HTLV-1 persistence depends on a monocyte reservoir or monocyte depletion provides a transient immune evasion benefit. To test these hypotheses, we simultaneously depleted NK cells, CD8+ T cells, and monocytes (triple depletion) prior to exposure to HTLV-1WT or HTLV-1p12KO. Remarkably, triple depletion resulted in exacerbation of infection by both viruses and complete rescue of HTLV-1p12KO infectivity. Following triple depletion, we observed rapid and sustained seroconversion, high titers of antibodies against HTLV-1 p24Gag, and frequent detection of viral DNA in the blood and tissues of all animals when compared with depletion of only CD8+ and NK cells, or monocytes alone. The infection of macaques with HTLV-1WT or HTLV-1p12KO was associated with higher plasma levels of IL-10 after 21 weeks, while IL-6, IFN-γ, IL-18, and IL-1β were only elevated in animals infected with HTLV-1WT. The repeat depletion of monocytes, NK, and CD8+ cells seven months following the first exposure to HTLV-1 did not further exacerbate viral replication. These results underscore the contribution of monocytes in orchestrating anti-viral immunity. Indeed, the absence of orf-1 expression was fully compensated by the simultaneous depletion of CD8+ T cells, NK cells, and monocytes, underlining the primary role of orf-1 in hijacking host immunity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells

Gutowska,

Sarkis,

Rahman

et al. 2024

Pathogens

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“…Another recent large cohort study from Brazil similarly found HIV and HCV coinfection to be independent predictors of mortality in PLHTLV (HR 15.1, 95% CI 5.5–41.3) ( Marcusso et al, 2019 ). This has been hypothesized to be due to the impaired cellular immune responses in HTLV-1-infected T-cells mediated by HTLV-1 bZIP factor (HBZ) induced expression of co-inhibitory molecules (such as PD-1, CTLA-4, and TIGIT) and production of inhibitory cytokines like interleukin-10 (IL-10), leading to ineffective resolutions of infections ( Kozako et al, 2009 ; Sawada et al, 2017 ; Higuchi et al, 2020 ; Tan et al, 2022 ). Interestingly, the immunomodulating effects of HTLV-2 infection are less well understood, with recent studies of HIV/HTLV-2 co-infection suggesting that HTLV-2 may exert a protective effect on survival and slowing rate of disease progression to AIDS, although these results are mixed ( Giacomo et al, 1995 ; Hershow et al, 1996 ; Castro-Sansores et al, 2006 ; Bassani et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and outcomes of infection with human T-lymphotropic virus in a non-endemic area: a single institution study

et al. 2023

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IntroductionUnderstanding of human T-lymphotropic virus (HTLV) remains largely based on epidemiologic and clinical data from endemic areas. Globalization has resulted in migration of persons living with HTLV (PLHTLV) from endemic to non-endemic areas, and a rise of HTLV infection in the United States. Yet, due to the historical rarity of this disease, affected patients are often under- and mis-diagnosed. Thus, we sought to characterize the epidemiology, clinical features, comorbidities, and survival of HTLV-1- or HTLV-2-positive individuals identified in a non-endemic area.MethodsOur study was a single institution, retrospective case–control analysis of HTLV-1 or HTLV-2 patients between 1998 and 2020. We utilized two HTLV-negative controls, matched for age, sex, and ethnicity, for each HTLV-positive case. We evaluated associations between HTLV infection and several hematologic, neurologic, infectious, and rheumatologic covariates. Finally, clinical factors predictive of overall survival (OS) were assessed.ResultsWe identified 38 cases of HTLV infection, of whom 23 were HTLV-1 and 15 were HTLV-2 positive. The majority (~54%) of patients in our control group received HTLV testing for transplant evaluation, compared to ~24% of HTLV-seropositive patients. Co-morbidities associated with HTLV, hepatitis C seropositivity were higher in HTLV-seropositive patients compared to controls (OR 10.7, 95% CI = 3.2–59.0, p < 0.001). Hepatitis C and HTLV co-infection resulted in decreased OS, compared to no infection, hepatitis C infection alone, or HTLV infection alone. Patients with any cancer diagnosis and HTLV infection had worse OS compared to patients with cancer or HTLV alone. HTLV-1 positive patients had lower median OS compared to HTLV-2 patients (47.7 months vs. 77.4 months). In univariate analysis, the hazard for 1-year all-cause mortality was increased among patients with HTLV-seropositivity, adult T-cell leukemia, acute myelogenous leukemia, and hepatitis C infection. When corrected, multivariate analysis showed that HTLV seropositivity was no longer associated with 1 year all-cause mortality; however association with AML and hepatitis C infection remained significant.ConclusionHTLV-seropositivity was not associated with increased 1 year mortality in multivariate analysis. However, our study is limited by our small patient sample size, as well as the biased patient control population due to selection factors for HTLV testing.

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“…The retrovirus Human T-cell Leukemia Virus type 1 (HTLV-1) primarily infects T lymphocytes, leading to a range of diseases, including adult T-cell leukemia/lymphoma (ATLL) and various inflammatory diseases ( 1 ). HTLV-1 replication initially involves cell-to-cell transmission followed by clonal expansion of infected cells which is responsible for the persistence of the virus and associated diseases ( 2 ). One of the key viral proteins involved in HTLV-1 infection is the oncoprotein Tax that has been first described as a transcriptional activator interacting with a variety of host cell proteins, including the NF-κB family of transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Gene-to-gene coordinated regulation of transcription and alternative splicing by 3D chromatin remodeling upon NF-κB activation

Marie,

Bazire,

Ladet

et al. 2024

Nucleic Acids Research

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The NF-κB protein p65/RelA plays a pivotal role in coordinating gene expression in response to diverse stimuli, including viral infections. At the chromatin level, p65/RelA regulates gene transcription and alternative splicing through promoter enrichment and genomic exon occupancy, respectively. The intricate ways in which p65/RelA simultaneously governs these functions across various genes remain to be fully elucidated. In this study, we employed the HTLV-1 Tax oncoprotein, a potent activator of NF-κB, to investigate its influence on the three-dimensional organization of the genome, a key factor in gene regulation. We discovered that Tax restructures the 3D genomic landscape, bringing together genes based on their regulation and splicing patterns. Notably, we found that the Tax-induced gene–gene contact between the two master genes NFKBIA and RELA is associated with their respective changes in gene expression and alternative splicing. Through dCas9-mediated approaches, we demonstrated that NFKBIA–RELA interaction is required for alternative splicing regulation and is caused by an intragenic enrichment of p65/RelA on RELA. Our findings shed light on new regulatory mechanisms upon HTLV-1 Tax and underscore the integral role of p65/RelA in coordinated regulation of NF-κB-responsive genes at both transcriptional and splicing levels in the context of the 3D genome.

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HTLV-1 persistence and leukemogenesis: A game of hide-and-seek with the host immune system

Cited by 6 publications

References 131 publications

Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells

Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells

Clinical characteristics and outcomes of infection with human T-lymphotropic virus in a non-endemic area: a single institution study

Gene-to-gene coordinated regulation of transcription and alternative splicing by 3D chromatin remodeling upon NF-κB activation

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