Sequence variability of the K1 gene in Kaposi's sarcoma-associated herpesvirus and its role in pathogenesis

Infectious pathogens account for approximately 13% of all human cancers globally, with oncogenic viruses constituting the majority. Among them, Kaposi's sarcoma-associated herpesvirus (KSHV), a gammaherpesvirus, remains a persistent public health concern. Although KSHV is endemic in sub-Saharan Africa, where it drives high rates of pediatric and endemic Kaposi's sarcoma (KS), AIDS-related KS remains a significant burden among immunocompromised individuals, especially in areas with limited access to long-term antiretroviral therapy. Additionally, KSHV is etiologically linked to primary effusion lymphoma and multicentric Castleman disease, both increasingly observed in transplant recipients and individuals undergoing long-term immunosuppressive therapy. Despite decades of research, no approved vaccine or curative treatment is currently available. Among the KSHV-encoded proteins, the K1 oncoprotein, encoded by the first open reading frame of the viral genome, exhibits exceptional sequence diversity and plays a critical role in viral pathogenesis. K1 activates key host signaling pathways involved in angiogenesis, cellular transformation, and survival. Importantly, genetic variation within K1, particularly in its variable regions, forms the basis for classifying KSHV into distinct genotypes that show different geographic distributions and may have divergent pathogenic potentials. In this review, we provide an updated overview of functions of K1, highlight genotype-specific oncogenic mechanisms, and examine how K1 sequence diversity may shape viral evolution, host interactions, and clinical outcomes.