Human cytomegalovirus (HCMV) infects most of the population worldwide, persisting
throughout the host's life in a latent state with periodic episodes of reactivation. While
typically asymptomatic, HCMV can cause fatal disease among congenitally infected infants
and immunocompromised patients. These clinical issues are compounded by the emergence of
antiviral resistance and the absence of an effective vaccine, the development of which is
likely complicated by the numerous immune evasins encoded by HCMV to counter the host's
adaptive immune responses, a feature that facilitates frequent super-infections.
Understanding the evolutionary dynamics of HCMV is essential for the development of
effective new drugs and vaccines. By comparing viral genomes from uncultivated or
low-passaged clinical samples of diverse origins, we observe evidence of frequent
homologous recombination events, both recent and ancient, and no structure of HCMV genetic
diversity at the whole-genome scale. Analysis of individual gene-scale loci reveals a
striking dichotomy: while most of the genome is highly conserved, recombines essentially
freely and has evolved under purifying selection, 21 genes display extreme diversity,
structured into distinct genotypes that do not recombine with each other. Most of these
hyper-variable genes encode glycoproteins involved in cell entry or escape of host
immunity. Evidence that half of them have diverged through episodes of intense positive
selection suggests that rapid evolution of hyper-variable loci is likely driven by
interactions with host immunity. It appears that this process is enabled by recombination
unlinking hyper-variable loci from strongly constrained neighboring sites. It is
conceivable that viral mechanisms facilitating super-infection have evolved to promote
recombination between diverged genotypes, allowing the virus to continuously diversify at
key loci to escape immune detection, while maintaining a genome optimally adapted to its
asymptomatic infectious lifecycle.
Corneal HSV-1 isolates are mixtures of acyclovir-sensitive and acyclovir-resistant viruses that share the same genotype but have different TK sequences. Recovery of the same acyclovir-resistant virus during consecutive herpetic keratitis episodes suggests that acyclovir-resistant HSV-1 establishes latency and reactivates intermittently to cause acyclovir-refractory RHK.
The data suggest that long-term ACV prophylaxis predisposes to ACV-refractory disease due to the emergence of corneal ACV(R) HSV-1. ACV-susceptibility testing is warranted during follow-up of rHK patients.
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