Abstract
Alphaherpesviruses are widespread in the human population, and include herpes simplex virus 1 (HSV-1) and 2, and varicella zoster virus (VZV). These viral pathogens cause epithelial lesions, and then infect the nervous system to cause lifelong latency, reactivation, and spread. A related veterinary herpesvirus, pseudorabies (PRV), causes similar disease in livestock that result in significant economic losses. Vaccines developed for VZV and PRV serve as useful models for the development of an HSV-1 vaccine. We present full genome sequence comparisons of the PRV vaccine strain Bartha, and two virulent PRV isolates, Kaplan and Becker. These genome sequences were determined by high-throughput sequencing and assembly, and present new insights into the attenuation of a mammalian alphaherpesvirus vaccine strain. We find many previously unknown coding differences between PRV Bartha and the virulent strains, including changes to the fusion proteins gH and gB, and over forty other viral proteins. Inter-strain variation in PRV protein sequences is much closer to levels previously observed for HSV-1 than for the highly stable VZV proteome. Almost 20% of the PRV genome contains tandem short sequence repeats (SSRs), a class of nucleic acids motifs whose length-variation has been associated with changes in DNA binding site efficiency, transcriptional regulation, and protein interactions. We find SSRs throughout the herpesvirus family, and provide the first global characterization of SSRs in viruses, both within and between strains. We find SSR length variation between different isolates of PRV and HSV-1, which may provide a new mechanism for phenotypic variation between strains. Finally, we detected a small number of polymorphic bases within each plaque-purified PRV strain, and we characterize the effect of passage and plaque-purification on these polymorphisms. These data add to growing evidence that even plaque-purified stocks of stable DNA viruses exhibit limited sequence heterogeneity, which likely seeds future strain evolution.
Highlights
Alphaherpesviruses are widespread in the human population, with herpes simplex virus 1 (HSV1) and 2 causing oral and genital lesions, respectively, while varicella zoster virus (VZV) causes chicken pox and shingles [1,2,3]
pseudorabies virus (PRV) and VZV primarily infect via the respiratory mucosa, while herpes simplex virus 1 (HSV-1) primarily infects at the oral mucosa
Since short sequence repeats (SSRs) have not been comprehensively examined in other DNA virus families, we extended these analyses to include the genomes of a wide variety of human herpesviruses, including HSV-1, VZV, human betaherpesvirus cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and Kaposi’s sarcoma-associated herpesvirus (KSHV) (Table 4 and Figure 6B– D)
Summary
Alphaherpesviruses are widespread in the human population, with herpes simplex virus 1 (HSV1) and 2 causing oral and genital lesions, respectively, while varicella zoster virus (VZV) causes chicken pox and shingles [1,2,3]. VZV infection includes a viremic phase that yields widespread vesicular lesions, while PRV and HSV are usually non-viremic and spread predominantly by mucosal infection and neuronal innervation. These alphaherpesviruses are widespread in the population because of their tendency to infect neurons: they establish lifelong latency in the host peripheral nervous system. These latent neuronal infections may occasionally reactivate and spread back the mucosal surfaces where the infection initiated. The viruses can spread to new hosts
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