Inhibition of HTLV-1 Infection by HIV-1 First- and Second-Generation Integrase Strand Transfer Inhibitors.

Michał S Barski,Goedele N Maertens,Jordan J Minnell

doi:10.3389/fmicb.2019.01877

Abstract

More than 10 million people worldwide are infected with the retrovirus human T-cell lymphotropic virus type 1 (HTLV-1). Infection phenotypes can range from asymptomatic to severe adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy. HTLV-1, like human immunodeficiency virus type 1 (HIV-1), is a blood-borne pathogen and viral infection happens in a similar fashion, with the major mode of transmission through breastfeeding. There is a strong correlation between time of infection and disease development, with a higher incidence of ATLL in patients infected during childhood. There is no successful therapeutic or preventative regimen for HTLV-1. It is therefore essential to develop therapies to inhibit transmission or block the onset/development of HTLV-1 associated diseases. Recently, we have seen the overwhelming success of integrase strand transfer inhibitors (INSTIs) in the treatment of HIV-1. Previously, raltegravir was shown to inhibit HTLV-1 infection. Here, we tested FDA-approved and two Phase II HIV-1 INSTIs in vitro and in a cell-to-cell infection model and show that they are highly active in blocking HTLV-1 infection, with bictegravir (EC50 = 0.30 ± 0.17 nM) performing best overall. INSTIs, in particular bictegravir, are more potent in blocking HTLV-1 transmission than tenofovir disproxil fumarate (TDF), an RT inhibitor. Our data suggest that HIV-1 INSTIs could present a good clinical strategy in HTLV-1 management and justifies the inclusion of INSTIs in clinical trials.

Highlights

Human T-cell lymphotropic virus type 1 (HTLV-1) belongs to the delta-retrovirus genus and is the second most clinically relevant retrovirus after human immunodeficiency virus type 1 (HIV1)
Purification and further characterization of activity of full-length human T-cell lymphotropic virus type 1 (HTLV-1) IN, we have laid the groundwork for accurate assessment of its inhibition by a panel of selected integrase strand transfer inhibitors (INSTIs)
Previous study which first described the in vitro 3 -processing, strand transfer and disintegration activity of HTLV-1 IN using radiolabeled probes (Muller and Krausslich, 1999), the advantage of the integration assay employed here is that the biologically relevant concerted integration activity can be discerned from the aberrant half-site integration events and quantified separately

Summary

Introduction

Human T-cell lymphotropic virus type 1 (HTLV-1) belongs to the delta-retrovirus genus and is the second most clinically relevant retrovirus after human immunodeficiency virus type 1 (HIV1). Like HIV-1, HTLV-1 is a blood-borne pathogen and is transmitted horizontally by sexual intercourse, contact with infected blood, and vertically from mother to child during breastfeeding and labor. HTLV-1 is a highly potent oncogenic virus, despite the fact that pathology develops only in about 10% of carriers. The two main pathologies associated with infection are an aggressive form of blood cancer – adult T-cell leukaemia/lymphoma (ATLL) (Mahieux and Gessain, 2007) and a spectrum of neuromuscular disorders called HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (Matsuura et al, 2016). There is no therapeutic or preventative treatment for HTLV-1 and disease prognosis is very poor – for acute ATLL, where the median survival rate is about 2 months (Beltran et al, 2011).

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