A multi-omics approach reveals specific oncogenic and inflammatory potential of viral oncoproteins Tax from neglected HTLV-1b and -1c genotypes

Over the recent years, reports of very high prevalences of Human T-cell Leukemia Virus (HTLV) type 1 genotype c infection in remote aboriginal populations in Central Australia have sparked a renewed interest in the genetic variability of this human oncogenic retrovirus. While clinical and epidemiological studies suggest that HTLV-1 genotypes might be associated with varying risks of pathological manifestations, molecular comparisons of the viral determinants among genotypes remain scarce. In this study, we provide the first comprehensive comparative analysis of the major oncoprotein Tax1 from genotypes a (Japanese), b (African) and c (Australo-Melanesia). Using unbiased analysis of image cytometry data from Tax1-expressing Jurkat T-cells, combined with proximity labelling, we first show that Tax1 variants exhibit distinct subcellular localization in T-cells. Indeed, in contrast to Tax1a that assembles a NF-κB-activating signalosome associated with the Golgi apparatus, Tax1c variants lack any significant association with this cell compartment. Surprisingly however, Tax1c does not show any general defect in NF-κB activation compared to Tax1a and Tax1b. Nevertheless, transcriptomics analysis combined with pathway inference indicate that the quality of the NF-κB signature induced by Tax1c differs from that of Tax1a, and that the transcriptional landscape of Tax1c-expressing cells is biased towards T-cell activation and inflammation, an observation that is consistent with the kinome profiling of Tax1c-expressing cells. Analysis of Tax1b-induced transcriptional reprogramming revealed that it closely parallels that of Tax1a, but with a higher magnitude. In addition, distinct modulation of cell cycle-related kinase activity by Tax1b compared to Tax1a was correlated with a specific modulation of the cell cycle. Consistently, functional cell transformation assays demonstrated that Tax1b presents a higher oncogenic potential compared to Tax1a, while Tax1c harbours a decreased transforming activity. Altogether, we provide evidence of functional divergence among Tax1 from different genotypes that may have pathophysiological and clinical implications.