Quantification of HTLV-1 reverse transcriptase activity in ATL patients treated with zidovudine and interferon-α

Macchi, Beatrice; Balestrieri, Emanuela; Frezza, Caterina; Grelli, Sandro; Valletta, Elena; Marçais, Ambroise; Marino-Merlo, Francesca; Turpin, Jocelyn; Bangham, Charles R. M.; Hermine, Olivier; Mastino, Antonio; Bazarbachi, Ali

doi:10.1182/bloodadvances.2016001370

Cited by 25 publications

(22 citation statements)

References 22 publications

(25 reference statements)

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“… 37 Conversely, a recent report demonstrated that the combination AZT/IFN induced a significant inhibition of HTLV-I reverse transcription activity in responding ATL patients but not in resistant patients. 74 These results are in line with a direct antiviral effect, likely in the HTLV-1–infected nonmalignant cells, which may play a major role in the survival of ATL cells.…”

Section: Strategy Of Targeting Therapy: Preclinical Datasupporting

confidence: 72%

Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report

Cook

Fuji

Hermine

et al. 2019

JCO

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175

184

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Purpose Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches. Methods Reflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology—Human T-Lymphotropic Virus and Related Retroviruses—in Tokyo, Japan, March, 2017, to review evidence for current clinical practice and to update the consensus with a new focus on the subtype classification of cutaneous ATL, CNS lesions in aggressive ATL, management of elderly or transplantation-ineligible patients, and treatment strategies that incorporate up-front allogeneic hematopoietic stem-cell transplantation and novel agents. Results As a result of lower-quality clinical evidence, a best practice approach was adopted and consensus statements agreed on by coauthors (> 90% agreement). Conclusion This expert consensus highlights the need for additional clinical trials to develop novel standard therapies for the treatment of ATL

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Section: Strategy Of Targeting Therapy: Preclinical Datasupporting

confidence: 72%

Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report

Cook

Fuji

Hermine

et al. 2019

JCO

Self Cite

175

184

View full text Add to dashboard Cite

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“…Interestingly, moreover, the capacity of AZT to specifically inhibit retroviral gene expression in cells harboring the HK2 endogenous retrovirus has been reported, suggesting the possibility that the drug could actually affect retroviral mRNA transcription 46 . Our previous study has shown that in ATL patients who responded to therapy with AZT plus IFN, HTLV-1 RT activity was inhibited, while this did not occur in a nonresponder patient (ATL) 47 . This implies that AZT actually acts as HTLV-1 RT-inhibitor in vivo.…”

Section: Discussionmentioning

confidence: 94%

Inhibition of IκBα phosphorylation potentiates regulated cell death induced by azidothymidine in HTLV-1 infected cells

et al. 2020

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Adult T cell leukemia/lymphoma (ATL) can be susceptible, at least transiently, to treatments with azidothymidine (AZT) plus IFNα and/or arsenic trioxide. However, the real role of AZT in this effect is still unclear. In fact, while reverse transcriptase (RT) inhibition could explain reduction of clonal expansion and of renewal of HTLV-1 infected cells during ATL progression, this effect alone seems insufficient to justify the evident and prompt decrease of the pro-viral load in treated patients. We have previously demonstrated that AZT is endowed with an intrinsic pro-apoptotic potential towards both peripheral blood mononuclear cells from healthy donors or some tumor cell lines, but this cytotoxic potential cannot be fully achieved unless IκBα phosphorylation is inhibited. Since the constitutive activation of NFkappa B (NF-κB) appears a common biological basis of HTLV-1-infected cells, a pharmacological inhibition of IκBα phosphorylation seems a potential strategy for treating and preventing HTLV-1 related pathologies. In this study, we have demonstrated that a combination treatment with the IκBα phosphorylation inhibitor Bay 11-7085 and AZT induced increased levels of regulated cell death (RCD) by apoptosis compared to the single treatments in HTLV-1 infected cells of different origin. Importantly, levels of RCD were considerably higher in infected cells in comparison with the uninfected ones. Inhibition of NF-κB activation following the combined treatment was confirmed by analysis of both gel-shift and functional activity of the NF-κB complex proteins, p65/p52. Moreover, a transcriptional analysis revealed that the addition of Bay 11-7085 to AZT treatment in HTLV-1-infected cells modified their transcriptional profile, by inducing the upregulation of some pro-apoptotic genes together with the downregulation of some antiapoptotic genes. Our data suggest that addition of adequate concentrations of IκBα phosphorylation inhibitor to therapeutic regimens including AZT could be a promising strategy in ATL.

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“…Previous studies of gene expression in individual cells have shown that both allelic expression (42) and transcriptional bursting (43,44) are mechanisms that control gene expression in mammalian cells. The control of gene transcription in latent human T cell leukemia virus type 1 (HTLV-1) infection has shown that retroviral gene expression occurs by a process of burst expression (45). For clonally expanded cells infected with HTLV-1, latency is determined by a balance between the burst expression of Tax and the low-level, persistent expression of HTLV-1 basic leucine zipper factor (HBZ) (45).…”

Section: Discussionmentioning

confidence: 99%

“…The control of gene transcription in latent human T cell leukemia virus type 1 (HTLV-1) infection has shown that retroviral gene expression occurs by a process of burst expression (45). For clonally expanded cells infected with HTLV-1, latency is determined by a balance between the burst expression of Tax and the low-level, persistent expression of HTLV-1 basic leucine zipper factor (HBZ) (45). During reactivation of latent HIV infection, levels of HIV expression depend on both the frequency of bursting and the burst size (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

The Pathway To Establishing HIV Latency Is Critical to How Latency Is Maintained and Reversed

Rezaei

Chang

Rhodes

et al. 2018

J Virol

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HIV infection requires lifelong antiretroviral therapy because of the persistence of latently infected CD4 T cells. The induction of virus expression from latently infected cells occurs following T cell receptor (TCR) activation, but not all latently infected cells respond to TCR stimulation. We compared two models of latently infected cells using an enhanced green fluorescent protein (EGFP) reporter virus to infect CCL19-treated resting CD4 (rCD4) T cells (preactivation latency) or activated CD4 T cells that returned to a resting state (postactivation latency). We isolated latently infected cells by sorting for EGFP-negative (EGFP) cells after infection. These cells were cultured with antivirals and stimulated with anti-CD3/anti-CD28, mitogens, and latency-reversing agents (LRAs) and cocultured with monocytes and anti-CD3. Spontaneous EGFP expression was more frequent in postactivation than in preactivation latency. Stimulation of latently infected cells with monocytes/anti-CD3 resulted in an increase in EGFP expression compared to that for unstimulated controls using the preactivation latency model but led to a reduction in EGFP expression in the postactivation latency model. The reduced EGFP expression was not associated with reductions in the levels of viral DNA or T cell proliferation but depended on direct contact between monocytes and T cells. Monocytes added to the postactivation latency model during the establishment of latency reduced spontaneous virus expression, suggesting that monocyte-T cell interactions at an early time point postinfection can maintain HIV latency. This direct comparison of pre- and postactivation latency suggests that effective strategies needed to reverse latency will depend on how latency is established. One strategy being evaluated to eliminate latently infected cells that persist in HIV-infected individuals on antiretroviral therapy (ART) is to activate HIV expression or production with the goal of inducing virus-mediated cytolysis or immune-mediated clearance of infected cells. The gold standard for the activation of latent virus is T cell receptor stimulation with anti-CD3/anti-CD28. However, this stimulus activates only a small proportion of latently infected cells. We show clear differences in the responses of latently infected cells to activating stimuli based on how latent infection is established, an observation that may potentially explain the persistence of noninduced intact proviruses in HIV-infected individuals on ART.

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Quantification of HTLV-1 reverse transcriptase activity in ATL patients treated with zidovudine and interferon-α

Abstract: Key Points• The therapeutic efficacy of the AZT and IFN combination in ATL presumably reflects the inhibition of RT-related functions.• HTLV-1-RT activity from short-term cultured PBMCs may represent a predictive correlate of clinical response to AZT/IFN in ATL patients.

Cited by 25 publications

References 22 publications

Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report

Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report

Inhibition of IκBα phosphorylation potentiates regulated cell death induced by azidothymidine in HTLV-1 infected cells

The Pathway To Establishing HIV Latency Is Critical to How Latency Is Maintained and Reversed

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