Susceptibility of Human T Cell Leukemia Virus Type 1 to Reverse‐Transcriptase Inhibitors: Evidence for Resistance to Lamivudine

Garcı́a-Lerma, J. Gerardo; Nidtha, Soumya; Heneine, Walid

doi:10.1086/322785

Cited by 34 publications

(25 citation statements)

References 16 publications

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“…Of the few compounds that have actually been tested, IFN, AZT, some anti-HIV RT nucleoside analogues, and TFV were found by us and other authors to be active toward HTLV-1 infection in vitro (2,15,17,24). Conversely, at least two studies have shown that a nucleoside analogue, such as lamivudine, known for its ability to control HIV infection, was not as effective toward HTLV-1 infection in vitro, probably due to some natural resistance (12,40). Similarly, none of the inhibitors designed to act against the HIV-1 proteinases was able to efficiently inhibit Gag processing in HTLV-1-infected cells (31).…”

Section: Discussionmentioning

confidence: 90%

Effect of Phosphonated Carbocyclic 2′-Oxa-3′-Aza-Nucleoside on Human T-Cell Leukemia Virus Type 1 Infection In Vitro

Balestrieri¹,

Matteucci

Ascolani

et al. 2008

Antimicrob Agents Chemother

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The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is an oncogenic retrovirus endemic in certain areas of the world including Japan and North and South America, where about 5% of the estimated 20 million HTLV-1-infected people develop HTLV-1-associated diseases (10,11,43), such as adult T-cell leukemia (ATL), human myelopathy/tropical spastic paraparesis (/TSP), or other minor inflammatory diseases. A number of studies have shown that HTLV-1 infects different types of cells (e.g., lymphocytes, monocytes, and fibroblasts) but preferentially T lymphocytes with a CD4 ϩ phenotype, which become immortalized following infection (26). In HTLV-1 infection viremia is essentially a "cytoviremia," since the virus is cell associated. In fact, cell-free virions are rarely infectious, and spreading of the virus in vivo does not require the extracellular release of viral particles. The spread of the virus within an individual host is most commonly recognized as being through the mitotic pathway, in which cell divisions and clonal expansion of infected cells ensure a constant level of viral load. However, recently it has been highlighted that the HTLV-1 viral load in vivo is also sustained by cell-tocell contact, involving intercellular viral spread. In particular, this "horizontal" spread allows the transfer of HTLV-1 infectious viral particles across the cell-cell junction by the generation of "virological synapses" between infected and uninfected cells (19,21). Transmission of HTLV-1 via cell-to-cell contact involves both integrin (3) and cytoskeleton proteins and participation of Env protein-cell receptor interactions (37). Either way, efficient transmission of HTLV-1 to noninfected cells implies reverse transcriptase (RT) dependency.In recent years, a number of strategies for therapeutic intervention have been pursued in the treatment of ATL or TSP, based on conventional chemotherapy or innovative approaches. However, until now, limited advances have been achieved in improving the therapy for HTLV-1-associated diseases. Therefore, symptomatic HTLV-1-infected patients still have inadequate treatment options with poor prognoses. Among the novel approaches for treating HTLV-1-related diseases, the use of topoisomerase 1 or 2 inhibitors in a pilot phase II study in refractory ATL did not provide satisfactory results (41). Similarly, treatments with the nucleoside analogue 2Ј deoxycoformycin (39) or inhibitors of AMP synthesis resulted in a limited response in ATL patients (42). Interestingly, studies based on a different strategy of chemotherapeutic intervention showed that ATL patients transiently responded to combined therapy with the nucleoside reverse transcriptase inhibitor (NRTI) azidothymidine (AZT) and interferon (IFN) (15) and that AZT treatment was beneficial to TSP patients (33), giving more encouraging results. In addition, a transient response to therapy with the NRTI lamivudine alone (38) or in combination with AZT (25) has been reported for human myelopathy/TSP. Moreover, IFN-␣ has been shown to have some ...

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Section: Discussionmentioning

confidence: 90%

Effect of Phosphonated Carbocyclic 2′-Oxa-3′-Aza-Nucleoside on Human T-Cell Leukemia Virus Type 1 Infection In Vitro

Balestrieri¹,

Matteucci

Ascolani

et al. 2008

Antimicrob Agents Chemother

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“…We next explored biochemically the impact of variable dATP levels on the ability of TFV-DP to inhibit reverse transcription of a heteropolymeric RNA template in an in vitro assay (9,10). A 5 M concentration of TFV-DP inhibited WT SHIV SF162P3 RT when the concentration of dATP was also 5 M (a 1:1 ratio).…”

Section: Resultsmentioning

confidence: 99%

Natural Substrate Concentrations Can Modulate the Prophylactic Efficacy of Nucleotide HIV Reverse Transcriptase Inhibitors

Garcı́a-Lerma

Aung

Cong

et al. 2011

J Virol

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Preexposure prophylaxis (PrEP) with antiretroviral drugs is a novel human immunodeficiency virus (HIV) prevention strategy. It is generally thought that high systemic and mucosal drug levels are sufficient for protection. We investigated whether GS7340, a next-generation tenofovir (TFV) prodrug that effectively delivers tenofovir diphosphate (TFV-DP) to lymphoid cells and tissues, could protect macaques against repeated weekly rectal simian-human immunodeficiency virus (SHIV) exposures. Macaques received prophylactic GS7340 treatment 3 days prior to each virus exposure. At 3 days postdosing, TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) were about 50-fold higher than those seen with TFV disoproxil fumarate (TDF), and they remained above 1,000 fmol/10 6 cells for as long as 7 days. TFV-DP accumulated in lymphoid and rectal tissues, with concentrations at 3 days exceeding 500 fmol/10 6 mononuclear cells. Despite high mucosal and systemic TFV levels, GS7340 was not protective. Since TFV-DP blocks reverse transcription by competing with the natural dATP substrate, we measured dATP contents in peripheral lymphocytes, lymphoid tissue, and rectal mononuclear cells. Compared to those in circulating lymphocytes and lymphoid tissue, rectal lymphocytes had 100-fold higher dATP concentrations and dATP/TFV-DP ratios, likely reflecting the activated status of the cells and suggesting that TFV-DP may be less active at the rectal mucosa. Our results identify dATP/TFV-DP ratios as a possible correlate of protection by TFV and suggest that natural substrate concentrations at the mucosa will likely modulate the prophylactic efficacy of nucleotide reverse transcriptase inhibitors.The human immunodeficiency virus (HIV)/AIDS pandemic remains one of our greatest public health challenges. Globally, an estimated 33.2 million people were living with HIV infection or AIDS in 2007. In that year, the annual incidence of new infections was an estimated 2.7 million, and there were an estimated 2.0 million HIV-related deaths (20). The ongoing high incidence of HIV infection and the incomplete coverage of basic HIV prevention tools underscore the need for new, highly effective biomedical HIV interventions to complement existing prevention strategies.Oral administration of antiretroviral drugs prior to and during HIV exposure (preexposure prophylaxis [PrEP]) is a novel intervention to protect high-risk HIV-1-negative people from becoming infected (3, 12, 15). Drug candidates for oral PrEP have been selected from drugs currently approved for treatment of HIV-1-infected individuals. Among the drugs available, the well-established potency and tolerability of tenofovir disoproxil fumarate (TDF), the approved oral prodrug of the nucleotide analog tenofovir (TFV), makes it an attractive candidate for PrEP. A recently concluded human trial with a daily combination of TDF and emtricitabine (FTC) (Truvada) for HIV-seronegative men or transgender women who have sex with men has shown a 44% reduction in the incidence of HIV-1, giving ...

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“…70 For example, in patients with HTLV-1-associated myelopathy (HAM), reduction of HTLV-1 viral DNA load was reported during treatment with the reverse transcriptase inhibitor lamivudine, 71 and HTLV-1 replication was inhibited by the nucleoside reverse-transcriptase inhibitors tenofovir, abacavir, lamivudine, zalcitabine, stavudine, zidovudine and didanosine. 72,73 Another report described the successful treatment of a patient with ATL using zidovudine, lamivudine and IFN-a. 74 Thus, antiretroviral treatment appears to be a promising strategy for the treatment of ATL as a viral infectious disease, but further studies are required in order to elucidate the mechanisms of the anti-ATL effects.…”

Section: New Chemical Anti-tumor Agents 1) Antiretroviral 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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Susceptibility of Human T Cell Leukemia Virus Type 1 to Reverse‐Transcriptase Inhibitors: Evidence for Resistance to Lamivudine

Cited by 34 publications

References 16 publications

Effect of Phosphonated Carbocyclic 2′-Oxa-3′-Aza-Nucleoside on Human T-Cell Leukemia Virus Type 1 Infection In Vitro

Effect of Phosphonated Carbocyclic 2′-Oxa-3′-Aza-Nucleoside on Human T-Cell Leukemia Virus Type 1 Infection In Vitro

Natural Substrate Concentrations Can Modulate the Prophylactic Efficacy of Nucleotide HIV Reverse Transcriptase Inhibitors

Treatment of Adult T-cell Leukemia

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