Abstract
Five to ten million individuals are infected by Human T-cell Leukemia Virus type 1 (HTLV-1). HTLV-1 is transmitted through prolonged breast-feeding, by sexual contacts and by transmission of infected T lymphocytes through blood transfusion. One to ten percent of infected carriers will develop a severe HTLV-1-associated disease: Adult-T-cell leukemia/lymphoma (ATLL), or a neurological disorder named Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). In vivo, HTLV-1 is mostly detected in CD4+ T-cells, and to a lesser extent in CD8+ T cells and dendritic cells. There is a strong correlation between HTLV-1 proviral load (PVL) and clinical status of infected individuals. Thus, reducing PVL could be part of a strategy to prevent or treat HTLV-1-associated diseases among carriers. Treatment of ATLL patients using conventional chemotherapy has very limited benefit. Some chronic and acute ATLL patients are, however, efficiently treated with a combination of interferon α and zidovudine (IFN-α/AZT), to which arsenic trioxide is added in some cases. On the other hand, no efficient treatment for TSP/HAM patients has been described yet. It is therefore crucial to develop therapies that could either prevent the occurrence of HTLV-1-associated diseases or at least block the evolution of the disease in the early stages. In vivo, reverse transcriptase (RT) activity is low in infected cells, which is correlated with a clonal mode of viral replication. This renders infected cells resistant to nucleoside RT inhibitors such as AZT. However, histone deacetylase inhibitors (HDACi) associated to AZT efficiently induces viral expression and prevent de novo cellular infection. In asymptomatic STLV-1 infected non-human primates, HDACi/AZT combination allows a strong decrease in the PVL. Unfortunately, rebound in the PVL occurs when the treatment is stopped, highlighting the need for better antiviral compounds. Here, we review previously used strategies targeting HTLV-1 replication. We also tested a series of HIV-1 RT inhibitors in an in vitro anti-HTLV-1 screen, and report that bis-POM-PMEA (adefovir dipivoxil) and bis-POC-PMPA (tenofovir disoproxil) are much more efficient compared to AZT to decrease HTLV-1 cell-to-cell transmission in vitro. Our results suggest that revisiting already established antiviral drugs is an interesting approach to discover new anti-HTLV-1 drugs.
Highlights
Five to ten million individuals are infected worldwide by the oncogenic Human T-cell Leukemia Virus type 1 (HTLV-1) (Gessain and Cassar, 2012)
We report for the first time that bis-POM-PMEA and bis-POCPMPA are much more efficient compared to AZT to decrease HTLV-1 cell-to-cell transmission in vitro
High-throughput screening efforts against HIV-1 followed by structure-based drug design have allowed the discovery of several drugs that are more potent than AZT and related nucleoside analogs, and are still ongoing (Taylor et al, 2016)
Summary
Five to ten million individuals are infected worldwide by the oncogenic Human T-cell Leukemia Virus type 1 (HTLV-1) (Gessain and Cassar, 2012). This retrovirus is mainly present in Japan, Sub-Saharan Africa, the Caribbean region and Brazil. HTLV-1 is mostly detected in CD4+ T-lymphocytes, and to a lesser extent CD8+ T-cells and dendritic cells in vivo. In vitro, human monocyte-derived dendritic cells are more susceptible to HTLV-1 infection than autologous CD4+ T-cells (Alais et al, 2015). It infects CD8+ T-cells and dendritic cells in the early phase of infection, HTLV-1 does not transform CD8+ T-cells (Rahman et al, 2010; Valeri et al, 2010; Kannian et al, 2013). A biomarker that would predict which carrier will develop an HTLV-1-associated pathology has not been described so far
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