Untangling the causes of geographical disparities in the clinical outcome of HTLV-1 infection: a critical perspective on the contribution of viral genetic diversity.

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is the etiological agent of two major diseases, adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), as well as various other inflammatory manifestations. The prevalence of HTLV-1 infection varies greatly from region to region, and available epidemiological data support the notion that even among regions of similarly high prevalence of HTLV-1 infection, such as Japan, South America, or Central Australia, the incidence of each associated disease may vary drastically. Here, we critically review evidence supporting a high incidence of ATLL in Japan, in contrast to a high incidence of HAM/TSP in South America, and a low incidence of both diseases in Central Australia, where other HTLV-1 inflammatory diseases are common. We further aim to explore these singularities through the lens of HTLV-1 genetic diversity. Different genetic clades are geographically restricted, such as HTLV-1a-Jpn and HTLV-1a-TC in Japan, HTLV-1a-TC in South America, HTLV-1a-TC and HTLV-1b in Africa, and HTLV-1c in Australo-Melanesia. We analyze potential correlations between HTLV-1 genotypes and disease outcomes while also discussing the interaction with other genetic or environmental factors that may contribute to these differences (e.g., host genetic background, age of infection, routes of transmission, or environmental factors). This perspective raises important questions about the unique properties of the different HTLV-1 genotypes and how they may reshape our understanding of HTLV-1 pathophysiology on both molecular and epidemiological levels.