Zidovudine and interferon-α treatment induces a high response rate and reduces HTLV-1 proviral load and VEGF plasma levels in patients with adult T-cell leukemia from North East Iran

Kchour, Ghada; Makhoul, Nadine J.; Mahmoudi, Mahmoud; Kooshyar, Mohammad Mahdi; Shirdel, Abbas; Rastin, Maryam; Rafatpanah, Houshang; Tarhini, Mahdi; Zalloua, Pierre; Hermine, Olivier; Farid, Reza; Bazarbachi, Ali

doi:10.1080/10428190601071717

Cited by 37 publications

(22 citation statements)

References 24 publications

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“…Treatment with a combination of azidothymidine and interferon-␣ can decrease the proviral load in patients with ATLL, perhaps by inhibiting cellular proliferation or angiogenesis. 36,37 The long-term stability of the UIS populations suggests that the majority of these clones were generated by viral dissemination during the early phase of infection. This conclusion is consistent with previous evidence from studies of adult seroconverters 38 and animal models.…”

Section: Discussionmentioning

confidence: 99%

The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clones

Gillet

Malani

Melamed

et al. 2011

Blood

271

467

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Human T-lymphotropic virus type 1 (HTLV-1) persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1-associated diseases. Yet the reasons for the variation within and between persons in the abundance of HTLV-1-infected clones remain unknown. We devised a highthroughput protocol to map the genomic location and quantify the abundance of > 91 000 unique insertion sites of the provirus from 61 HTLV-1 ؉ persons and > 2100 sites from in vitro infection. We show that a typical HTLV-1-infected host carries between 500 and 5000 unique insertion sites. We demonstrate that negative selection dominates during chronic infection, favoring establishment of proviruses integrated in transcriptionally silenced DNA: this selection is significantly stronger in asymptomatic carriers. We define a parameter, the oligoclonality index, to quantify clonality. The high proviral load characteristic of HTLV-1- IntroductionHuman T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATLL), HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP), uveitis, and infective dermatitis. It is estimated that 15 to 20 million persons live with HTLV-1 infection worldwide. A small proportion (up to 7%, depending on the area) of HTLV-1-infected persons develop disease, whereas the majority remain asymptomatic carriers (ACs). Infection occurs via breastfeeding, transfusion of infected cellular blood products, or sexual intercourse. Symptoms appear after a long period (years or decades) of clinical latency. 1 The HTLV-1 proviral load (PVL) remains stable within each infected person and correlates with the outcome of infection. However, the PVL varies widely among infected people, even within a particular diagnostic group. [2][3][4] The sequence of HTLV-1 is also stable within a person, 5,6 indicating that the PVL is maintained in vivo mainly by mitosis of infected cells during the chronic phase of the infection. This interpretation is supported by the observation that individual clones of infected cells can persist in patients for several years. 7-9 Thus, it has been hypothesized that infectious transmission of HTLV-1 is important early in infection across the virologic synapse, 10 whereas mitotic replication is responsible for maintaining proviral load once a persistent infection has been established and reached an equilibrium with the immune response. 11 In approximately 5% of infected people, persistent clonal proliferation culminates in malignant transformation in the disease ATLL. 7,8 The leukemic clones carry generally one (complete or defective) provirus per cell. [12][13][14] There has been a longstanding debate on the question of whether HTLV-1 is latent or persistently expressed in vivo. Persistent expression is strongly suggested by the extensive evidence that the strong, chronically activated cytotoxic T lymphocyte (CTL) response to HTLV-1 limits the proviral load and reduces the risk of HAM/TSP. 11 Furthermore, there is both experimental evidence 15 and th...

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Section: Discussionmentioning

confidence: 99%

The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clones

Gillet

Malani

Melamed

et al. 2011

Blood

271

467

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“…166 Treatment with IFN/AZT reduced plasma levels of vascular endothelial growth factor (VEGF). 167 Although the efficacy of bevacizumab, an anti-VEGF mAb, in the treatment of NHL, is under evaluation, 168 anti-angiogenic therapy of ATL might be potentially interesting.…”

Section: ) Anti-angiogenic Therapymentioning

confidence: 99%

Treatment of Adult T-cell Leukemia

Uozumi

2010

J Clin Exp Hematopathol

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Adult T-cell Leukemia (ATL) is an aggressive malignant disease of CD4 + T-cells associated with human T-cell leukemia virus type I (HTLV-I). Prognosis of ATL patients is directly correlated to the subtype of ATL. Treatment of the aggressive forms (acute and lymphoma types) of ATL remains inadequate, as most ATL patients receive conventional chemotherapy without stem cell rescue. At present, LSG15 is the standard chemotherapy for the treatment of aggressive ATL, but the efficacy of LSG15 in most patients is transient. To prolong median survival time, additional therapies for maintenance of complete response (CR) are needed after achieving CR by induction chemotherapy. Improved outcome after allogeneic stem cell transplantation (allo-SCT), despite a high incidence of graft-versus-host disease, has been reported. Thus, allogeneic bone marrow transplantation and allogeneic peripheral blood SCT may have great potential for eradication of HTLV-1 and cure of ATL. Recently, reduced-intensity conditioning stem cell transplantation was also reported to be effective for ATL. Although several issues, including selection criteria for patients and sources of stem cells remain to be resolved, allo-SCT may be considered as a treatment option for patients with aggressive ATL. To evaluate whether allo-SCT is more effective than the standard chemotherapy (LSG15) for aggressive ATL, an upfront phase II clinical trial of JCOG-LSG is now being planned. Novel innovative targeted strategies, such as antiretroviral therapy, arsenic trioxide, nuclear factor-kB inhibitors, proteasome inhibitors, histone deacetylase inhibitors, several monoclonal antibodies including anti-CC chemokine receptor 4, anti-folate, purine nucleotide phosphorylase inhibitor, mTOR (mammalian target of rapamycin) inhibitor, bendamustine, small molecule Bcl-2 inhibitors and Tax-targeted immunotherapy, should be promptly studied in order to develop curative treatments for ATL in the near future. 〔J Clin Exp Hematopathol 50(1) : 9-25, 2010〕

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“…In view of the very poor outcome of the latter despite intensive therapeutic efforts, a better understanding of the molecular basis of the disease and novel therapeutic approaches are urgently needed. While some promising results have been reported in ATLL using a combination therapy of AZT and IFNa [13][14][15], these studies do not offer detailed insights into the underlying molecular mechanisms of response to therapy. Alizadeh's study [8] that reports molecular profiling results of ATLL cells investigated before and after combination therapy with AZT and IFNa sheds some light on this issue.…”

Section: Institute Of Pathology University Of Wü Rzburg Germanymentioning

confidence: 95%

Gene expression signatures of adult T-cell leukemia: is treatment response prediction on the horizon?

Hartmann

Rosenwald

2010

Leukemia & Lymphoma

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Zidovudine and interferon-α treatment induces a high response rate and reduces HTLV-1 proviral load and VEGF plasma levels in patients with adult T-cell leukemia from North East Iran

Cited by 37 publications

References 24 publications

The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clones

The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clones

Treatment of Adult T-cell Leukemia

Gene expression signatures of adult T-cell leukemia: is treatment response prediction on the horizon?

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