Reconstructing the viral histories of human, simian and prosimian immunodeficiency viruses across multiple evolutionary timescales.

The evolutionary history of simian and prosimian immunodeficiency viruses (SIVs and pSIVs) remains difficult to resolve, because divergence-time estimates from standard clock analyses using contemporary sequences conflict with palaeovirological and biogeographical evidence. One proposed explanation is that inferred substitution rates decline with increasing timescale, a pattern known as the time-dependent rate phenomenon. Here, we apply the Prisoner of War model, which maps genetic divergence to time under a mechanistic model of time-dependent rate decay, to reconstruct the evolutionary history of primate lentiviruses. Using non-recombinant genomic regions from 436 human immunodeficiency virus (HIV), SIV and pSIV sequences, we estimate that the most recent common ancestor of extant SIVs dates to approximately 1 million years ago. The lineages giving rise to HIV-1 and HIV-2 (SIVcpz and SIVsmm) have circulated in their respective hosts for tens to hundreds of thousands of years, suggesting prolonged pre-pandemic human exposure. The divergence between the lineages leading to extant SIV and Malagasy pSIV is dated to 17-51 million years ago, consistent with ancient lentiviral transfer via over-water dispersal and/or non-primate vectors. Our analysis reconciles divergence-time estimates of primate lentiviruses across recent (HIV), intermediate (Bioko Island SIVs) and ancient (pSIV) timescales under an explicit model of time-dependent rate decay, enabling inferences not possible from any single timescale alone. It also highlights the sensitivity of deep viral dating to modelling assumptions, recombination and locus-specific evolutionary histories. This model-based framework provides new insights into primate lentivirus origins, virus-host associations and zoonotic risk.