The viral and host genomic landscape of human T-cell leukemia virus type I in Peru

Background: The human T-cell leukemia virus type 1 (HTLV-1) is a neglected oncogenic retrovirus responsible for adult T-cell leukemia/lymphoma (ATLL) and autoimmune diseases that disproportionately affects marginalized populations worldwide. Peru reports the highest global ATLL incidence, yet comprehensive genomic studies remain limited. We aimed to characterize the virological, immunological, and host genetic landscape of HTLV-1 infection to identify population-specific high-risk features. Methods: We conducted a prospective cohort study (2017–2018) of 67 HTLV-1-infected individuals from Lima, Peru, using an integrated high-throughput genomic approach. This included whole-genome HTLV-1 sequencing, targeted ultra-deep sequencing of 280 hematological malignancy-associated genes, high-resolution HLA typing, GATK-based variant calling, and comprehensive clinical follow-up over 7 years. Phylogenomic analyses were performed using maximum likelihood and Bayesian approaches. Results: The cohort exhibited exceptionally high-risk characteristics with a median proviral load (PVL) of 4.5 ± 3.8, and 13.4% cumulative crude mortality over 7 years. Phylogenomic analysis revealed 96.8% of isolates belonged to the Transcontinental subtype, with most clustering in a newly identified Andean-Amazonian subgroup. HLA-I analysis demonstrated unique population-specific allele distributions with significantly reduced evolutionary divergence compared to Japanese cohorts (HLA-HED: 5.34 vs. 6.87, p = 0.0002), potentially differences in mechanisms of viral immune control. Ultra-deep sequencing identified early clonal hematopoiesis with prevalent mutations in cancer-associated genes including KMT2D (55%), NOTCH1 (49%), and TP53 (27%). Mutation burden correlated significantly with proviral load (r = 0.34, p = 0.003), and longitudinal analysis revealed progressive genomic instability with more than two-fold increase in mutations over 3 years (7.25 vs. 19.5 mutations per patient, p = 0.01). High PVL (> 4%) was the only independent predictor of crude mortality (OR: 1.07; 95% CI: 1.01–1.15; p = 0.033). Contrary to previous reports, Strongyloides coinfection was not associated with disease progression. Conclusions: This first comprehensive genomic characterization of HTLV-1 in South America reveals population-specific viral evolution, reduced HLA diversity, and evidence of early oncogenic transformation events. The exceptionally high proviral loads and unique mutational landscape provide novel insights into HTLV-1 pathogenesis and support the development of population-tailored risk stratification approaches. These findings emphasize the urgent need for expanded genomic surveillance and targeted interventions in underrepresented populations bearing disproportionate HTLV-1 burden.