Genetic Variability of Bovine Viral Diarrhea Virus and Evidence for a Possible Genetic Bottleneck during Vertical Transmission in Persistently Infected Cattle

Abstract

Bovine viral diarrhea virus (BVDV), a Pestivirus in the family Flaviviridae, is an economically important pathogen of cattle worldwide. The primary propagators of the virus are immunotolerant persistently infected (PI) cattle, which shed large quantities of virus throughout life. Despite the absence of an acquired immunity against BVDV in these PI cattle there are strong indications of viral variability that are of clinical and epidemiological importance. In this study the variability of E2 and NS5B sequences in multiple body compartments of PI cattle were characterized using clonal sequencing. Phylogenetic analyses revealed that BVDV exists as a quasispecies within PI cattle. Viral variants were clustered by tissue compartment significantly more often than expected by chance alone with the central nervous system appearing to be a particularly important viral reservoir. We also found strong indications for a genetic bottleneck during vertical transmission from PI animals to their offspring. These quasispecies analyses within PI cattle exemplify the role of the PI host in viral propagation and highlight the complex dynamics of BVDV pathogenesis, transmission and evolution.

Molecularly barcoded Zika virus libraries to probe in vivo evolutionary dynamics

“…Both the number of founder viruses and Ne have not been estimated for any step of the ZIKV infection and/or transmission cycle, but we postulate that a single or limited number of infectious particles likely contribute to the infection of the fetus during vertical transmission. Strong bottlenecks have been observed previously during vertical transmission in plant virus systems [ 30 , 31 ] and during mother-to-offspring transmission of HIV-1 [ 32 , 33 ] and bovine viral diarrhea virus [ 34 ]. In these studies, the vast majority of offspring harbored a single or few viral variants, which suggested a stringent population bottleneck associated with vertical transmission.…”

Identification of Conserved Amino Acid Substitutions During Serial Infection of Pregnant Cattle and Sheep With Bovine Viral Diarrhea Virus

“…Altogether, these results revealed that many substitutions were introduced in the BVDV genome during the establishment of serial persistent infections in sheep and suggest that BVDV infections in pregnant small ruminants may serve as a significant source of viral genetic diversity. Previous studies demonstrated severe reduction in RNA virus populations during vector-borne transmission and when viruses spread within a single host ( Navas et al, 1998 ; Forrester et al, 2012 ; Dow et al, 2015 ). There are several host barriers and defense mechanisms that limit virus infection and spread in a heterologous host and therefore cross-species infections are likely to impose severe bottlenecks on virus populations.…”

“…Similar findings were reported in goats with 95% of nucleotide substitutions observed in the isolate of a PI goat kid that were detected in the isolate of its dam whereas 60% of changes observed in the isolate of another PI goat kid were not detected in the isolate of its dam ( Passler et al, 2014 ). Considering the existence of a viral quasispecies in PI cattle, it is possible that the substitutions observed in isolates from offspring might have been first established in pregnant dams in a limited number of viral mutants that were subsequently selected in PI offspring ( Dow et al, 2015 ; Ridpath et al, 2015 ). Fluctuations in minor variants within the viral quasispecies may partially explain the discrepancies observed between and within studies performed in cattle and other species.…”

Bovine viral diarrhoea virus loses quasispecies diversity rapidly in culture

“…While this may be more error-prone that an amplification-free approach, it clearly has value where the amount or complexity of input material makes direct sequencing difficult. The use of PCR and clone counting approaches (55,56) to assess quasispecies variation supports the view that read-counting within NGS data from such PCR products may yield accurate quantitative data. This suggests that analysis of quasispecies variation in pestiviruses (and potentially other RNA viruses) could focus on uncultured samples from infected individuals rather than after virus isolation, potentially taking advantage of amplification methods to derive genome level quasispecies data.…”

“…Specific studies of BVD virus quasispecies variation have generally focused on individual genes, by counting clones of PCR products reflecting sequence variation within an E1/E2 fragment (55) or in the E2 and NS5B genes (56). Other studies have compared the virus consensus sequences between sequentially-infected individuals, inferring the nature and rates of quasispecies variation between hosts (39).…”