Abstract
Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) are prevalent human pathogens of clinical relevance that establish long-life latency in the nervous system. They have been considered, along with the Herpesviridae family, to exhibit a low level of genetic diversity during viral replication. However, the high ability shown by these viruses to rapidly evolve under different selective pressures does not correlates with that presumed genetic stability. High-throughput sequencing has revealed that heterogeneous or plaque-purified populations of both serotypes contain a broad range of genetic diversity, in terms of number and frequency of minor genetic variants, both in vivo and in vitro. This is reminiscent of the quasispecies phenomenon traditionally associated with RNA viruses. Here, by plaque-purification of two selected viral clones of each viral subtype, we reduced the high level of genetic variability found in the original viral stocks, to more genetically homogeneous populations. After having deeply characterized the genetic diversity present in the purified viral clones as a high confidence baseline, we examined the generation of de novo genetic diversity under culture conditions. We found that both serotypes gradually increased the number of de novo minor variants, as well as their frequency, in two different cell types after just five and ten passages. Remarkably, HSV-2 populations displayed a much higher raise of nonconservative de novo minor variants than the HSV-1 counterparts. Most of these minor variants exhibited a very low frequency in the population, increasing their frequency over sequential passages. These new appeared minor variants largely impacted the coding diversity of HSV-2, and we found some genes more prone to harbor higher variability. These data show that herpesviruses generate de novo genetic diversity differentially under equal in vitro culture conditions. This might have contributed to the evolutionary divergence of HSV-1 and HSV-2 adapting to different anatomical niche, boosted by selective pressures found at each epithelial and neuronal tissue.
Highlights
Herpes simplex virus (HSV) is well-known for being one of the most prevalent neurotropic pathogens worldwide, causing a broad range of diseases in humans
We show that Herpes simplex virus 2 (HSV-2) mutates much faster than HSV-1, when compared under similar and controlled cell culture conditions
Since HSV-1 and HSV-2 exhibit a preference for infecting different anatomical areas, together with a hypothetically distant evolutionary origin, it is reasonable to think that the selective pressures during each cycle of latency and reactivation might have contributed differentially to their evolution in humans, adapting their life cycle to each epithelial and neuronal niche
Summary
Herpes simplex virus (HSV) is well-known for being one of the most prevalent neurotropic pathogens worldwide, causing a broad range of diseases in humans. The virus periodically reactivates from latent to replicative stage, traveling anterogradely back to the epithelial tissue, where recurrent infection and transmission occur, exhibiting associated disease symptoms [8]. During these multiple cycles of latency and reactivation, the virus may reinfect the nervous system or be transmitted to a new host, finding numerous chances to expand its genetic repertoire for subsequent reactivation cycles [9,10]. Since HSV-1 and HSV-2 exhibit a preference for infecting different anatomical areas, together with a hypothetically distant evolutionary origin, it is reasonable to think that the selective pressures during each cycle of latency and reactivation might have contributed differentially to their evolution in humans, adapting their life cycle to each epithelial and neuronal niche
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