Ancient Ancestry of KFDV and AHFV Revealed by Complete Genome Analyses of Viruses Isolated from Ticks and Mammalian Hosts

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Abstract
Alkhurma hemorrhagic fever virus (AHFV) and Kyasanur forest disease virus (KFDV) cause significant human disease and mortality in Saudi Arabia and India, respectively. Despite their distinct geographic ranges, AHFV and KFDV share a remarkably high sequence identity. Given its emergence decades after KFDV, AHFV has since been considered a variant of KFDV and thought to have arisen from an introduction of KFDV to Saudi Arabia from India. To gain a better understanding of the evolutionary history of AHFV and KFDV, we analyzed the full length genomes of 16 AHFV and 3 KFDV isolates. Viral genomes were sequenced and compared to two AHFV sequences available in GenBank. Sequence analyses revealed higher genetic diversity within AHFVs isolated from ticks than human AHFV isolates. A Bayesian coalescent phylogenetic analysis demonstrated an ancient divergence of AHFV and KFDV of approximately 700 years ago. The high sequence diversity within tick populations and the presence of competent tick vectors in the surrounding regions, coupled with the recent identification of AHFV in Egypt, indicate possible viral range expansion or a larger geographic range than previously thought. The divergence of AHFV from KFDV nearly 700 years ago suggests other AHFV/KFDV-like viruses might exist in the regions between Saudi Arabia and India. Given the human morbidity and mortality associated with these viruses, these results emphasize the importance of more focused study of these significant public health threats. Alkhurma hemorrhagic fever (AHF) and Kyasanur Forest disease (KFD) viruses both cause serious and sometimes fatal human disease in their respective ranges, Saudi Arabia and India. AHFV was first identified in the mid-1990s and due to its strong genetic similarity to KFDV it has since been considered the result of a recent introduction of KFDV into Saudi Arabia. To gain a better understanding of the evolutionary history of AHFV and KFDV, we sequenced the full-length genomes of 3 KFDV and 16 AHFV. Sequence analyses show a greater genetic diversity within AHFV than previously thought, particularly within the tick population. The phylogeny constructed with these 19 full-length sequences and two AHFV sequences from GenBank indicates AHFV diverged from KFDV almost 700 years ago. Given the presence of competent tick vectors in the regions between and surrounding Saudi Arabia and India and the recent identification of AHFV in Egypt, these results suggest a broader geographic range of AHFV and KFDV, and raise the possibility of other AHFV/KFDV–like viruses circulating in these regions.

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