Host genetic determinants of HTLV-1 infection outcomes

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Human T-cell lymphotropic virus type 1 (HTLV-1) is a persistent human retrovirus associated with severe outcomes, most notably adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Despite lifelong infection, only a minority of carriers develop clinical disease, highlighting a decisive role for host genetic background in shaping viral control, immune activation, and pathogenic progression. This mini-review synthesizes evidence demonstrating how inherited host genetic variation and acquired somatic alterations influence HTLV infection outcomes. Polymorphisms in HLA class I and II genes critically modulate antigen presentation and cytotoxic or helper T-cell responses, thereby regulating proviral load and immune-mediated tissue damage. Variants in cytokine, chemokine, and innate restriction factor genes, including IL28B, IL8, TRIM5α, and APOBEC family members, further influence viral persistence and inflammatory risk. In parallel, accumulating somatic mutations in TP53, CCR4, JAK/STAT components, NOTCH1, and epigenetic regulators such as TET2 and KMT2D drive clonal expansion, genomic instability, and malignant transformation in ATLL. Together, these data support a continuum model in which inherited host genetics condition viral persistence and immune pressure, while acquired genetic and epigenetic lesions determine disease phenotype and severity. Integrating host genomics with viral genetics and clonal evolution analyses will be essential for developing predictive biomarkers and personalized therapeutic strategies for HTLV-associated diseases.