Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for Adult T-Cell Leukemia/Lymphoma (ATLL) and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1 infects CD4+ T-cells via cell-to-cell transmission requiring reorganization of the cytoskeleton and expression of the viral transactivator and oncoprotein Tax. Viruses spread at the virological synapse (VS), a virus-induced specialized cell-cell contact, by polarized budding into synaptic clefts, and by cell surface transfer of viral biofilms (VBs). Since little is known about Tax’s role in formation of the VB, we asked which component of the VB is regulated by Tax and important for HTLV-1 transmission. Collagens are not only structural proteins of the extracellular matrix and basal membrane but also represent an important component of the VB. Here, we report that among the collagens known to be present in VBs, COL4 is specifically upregulated in the presence of HTLV-1 infection. Further, we found that transient expression of Tax is sufficient to induce COL4A1 and COL4A2 transcripts in Jurkat and CCRF-CEM T-cells, while robust induction of COL4 protein requires continuous Tax expression as shown in Tax-transformed T-cell lines. Repression of Tax led to a significant reduction of COL4A1/A2 transcripts and COL4 protein. Mechanistically, luciferase-based promoter studies indicate that Tax activates the COL4A2 and, to a less extent, the COL4A1 promoter. Imaging showing partial co-localization of COL4 with the viral Gag protein in VBs at the VS and transfer of COL4 and Gag to target cells suggests a role of COL4 in VB formation. Strikingly, in chronically infected C91-PL cells, knockout of COL4A2 impaired Gag transfer between infected T-cells and acceptor T-cells, while release of virus-like particles was unaffected. Taken together, we identified COL4 (COL4A1, COL4A2) as a component of the VB and a novel cellular target of Tax with COL4A2 appearing to impact virus transmission. Thus, this study is the first to provide a link between Tax’s activity and VB formation by hijacking COL4 protein functions.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) is a highly oncogenic retrovirus causing Adult T-cell Leukemia/Lymphoma (ATLL) or inflammatory diseases in up to 10% of infected individuals (Tagaya and Gallo, 2017)
We report that among the collagens known to be present in viral biofilms (VBs), COL4 is upregulated in the presence of HTLV-1 infection and Tax is sufficient to induce COL4A1 and COL4A2 transcripts, while robust induction of COL4 protein requires continuous Tax expression
Several cellular factors have been identified to account for the formation of VB (Pais-Correia et al, 2010), but only little is known about the involvement of HTLV-1/Tax in regulating expression of these cellular components of the VB (Tarasevich et al, 2015)
Summary
Human T-cell leukemia virus type 1 (HTLV-1) is a highly oncogenic retrovirus causing Adult T-cell Leukemia/Lymphoma (ATLL) or inflammatory diseases in up to 10% of infected individuals (Tagaya and Gallo, 2017). At least 5– 10 million people are infected with this yet neglected human retrovirus, it is estimated that there is a much higher number of unknown cases since statistics on HTLV-1 prevalence are lacking for several densely populated regions (Gessain and Cassar, 2012). Since up to 90% of infected patients stay lifelong asymptomatic and blood donors are not screened for HTLV-1 infection in most countries, asymptomatic carriers are mainly unaware of their infection and may pass the infection to other people (Caswell et al, 2019). Recent work suggests that infection of hematopoietic stem cells contributes to spread of HTLV-1 in vivo (Furuta et al, 2017)
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