How to Control HTLV-1-Associated Diseases: Preventing de Novo Cellular Infection Using Antiviral Therapy

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.

Regulation of Expression and Latency in BLV and HTLV

“…However, the effect is only transient in HAM/TSP patients [ 40 ], and may be related to temporal fluctuations in viral RNA and response to immune control mechanisms in these patients [ 250 , 251 , 252 ]. Improved therapies include VPA combinations with zidovudine (AZT) or cytokines (IFNα) [ 253 , 254 , 255 ].…”

Antiretroviral Therapy in HTLV-1 Infection: An Updated Overview

“…Accordingly, attention has been recently paid to a novel generation of NRTIs anti-HIV drugs, i.e., the acyclic nucleoside phosphonates (ANP). In particular, prodrugs of the already mentioned TFV, also named as PMPA [9-R-(2-phosphonomethoxypropyl)adenine], were investigated in a new model of HTLV-1 infection in vitro using as recipient cells LTR luciferase reporter Jurkat T-cells [25]. Interestingly the results showed that the RT inhibitors, acyclic nucleotide analogue of adenosine adefovir (or PMEA), and its pro drug, adefovir dipivoxil (or bis-POM-PMEA) were found to be more active than AZT in inhibiting HTLV-1 infection in vitro while the pro-drugs of PMPA, such as tenofovir disoproxil (bis-POC-PMPA), TDF and TAF (tenofovir alafenamide) had more effect than TFV.…”

Microbial Biofilms: Human T-cell Leukemia Virus Type 1 First in Line for Viral Biofilm but Far Behind Bacterial Biofilms

“…Adult T-cell leukemia (ATL) patients are mainly treated with drugs that target infected cells regardless of their ability to express the virus (Miyazato et al, 2016), while HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are treated with drugs reducing inflammation but not the proviral load (Futsch et al, 2017). Nevertheless, reducing the proviral load remains a promising strategy and screening of antivirals that target viral replication and viral dissemination are ongoing (Macchi et al, 2011;Pasquier et al, 2018;Barski et al, 2019).…”