Viruses capable of causing persistent infection have developed sophisticated mechanisms for evading host immunity, and understanding these processes can reveal novel features of the host immune system. One such virus, human pegivirus (HPgV), infects ~15% of the global human population, but little is known about its biology beyond the fact that it does not cause overt disease. We passaged a pegivirus isolate of feral brown rats (RPgV) in immunodeficient laboratory mice to develop a mouse-adapted virus (maPgV) that established spontaneous persistent life-long infection in a majority of normal lab mice. maRPgV viremia was detected in the blood of mice for >300 days without apparent disease, closely recapitulating the hallmarks of chronic HPgV infection in humans. We found a pro-viral role for type-I interferon in chronic infection; a lack of PD-1-mediated tolerance to PgV infection; and multiple mechanisms by which PgV immunity can be achieved by an immunocompetent host. These data indicate that the PgV immune evasion strategy has aspects that are both common and unique among persistent viral infections. The creation of maPgV represents the first PgV infection model in wild-type mice, thus opening the entire toolkit of the mouse host to enable further investigation of persistent RNA infections.

Each tab in the .csv file corresponds to the data from a figure in the corresponding manuscript. RPgV= rat pegivirus; maPgV= mouse-adapted PgV; DPI= days post infection; gc= genome copies; All blank cells are left intentionally blank.

Figure 1B: Serum RPgV viral load (log10-transformed gc/mL of serum) in mice with different genetic backgrounds over time.

Figure 1C: Serum RPgV viral load (log10-transformed gc/mL of serum) in mice with additional genetic backgrounds over time.

Figure 2: Serum maPgV viral load (log10-transformed gc/mL of serum) in mice infected via different doses and by different routes.

Figure 3: Whole-genome sequencing of RPgV during adaptation to mice. Red bars show the frequency of non-synonymous single-nucleotide polymorphisms (SNPs); blue bars show the frequency of synonymous single-nucleotide polymorphisms (SNPs); grey indicates coverage at each genome position (log10 scale).

Figure 4: Whole-genome sequencing of RPgV during adaptation to mice. Red squares show consensus-level non-synonymous single-nucleotide polymorphisms (SNPs); blue squares show consensus-level synonymous single-nucleotide polymorphisms (SNPs); grey indicates that coverage at each genome position is ≥100 reads at each site. Only sites with variation in at least 1 sequence are shown. Graphical data showing the frequency of SNPs and coverage (as in Figure 3) for each individual sequence summarized in this figure can be found in Supplemental Figure 1, and in the .txt files associated with this submission. Each txt file shows the frequency of non-synonymous mutation (second column), synonymous mutation (third column) and sequencing coverage (fourth column) at each nucleotide position of the RPgV genome (first column). Nucleotide positions with no mutation frequency listed have the RPgV consensus nucleotide at >99% frequency.

Figure 6. Predicted RPgV vs. maPgV RNA genome structure, computed using RNAfold and RNA structure score (RSS; frequency of the MFE/ensemble diversity) and z-score of the RSS.

Figure 7: Serum maPgV viral load (log10-transformed gc/mL of serum) in mice with different immunocompromising genetic backgrounds, over time.

Figure 8A: Serum maPgV viral load (log10-transformed gc/mL of serum) in PD1-knockout mice over time.

Figure 8B: Weight change (as percent of starting weight) of Mock vs. maPgV vs. LCMV-infected PD-1-knockout vs. wild-type mice, over time.

Figure 8C: Cleaved-caspase 3 staining in PD-1-knockout mice that were Mock, maPgV-, or LCMV-infected.

Figure 9A: Serum maPgV viral load (log10-transformed gc/mL of serum) over time in individual mice that cleared maPgV infection.

Figure 9B: Serum maPgV viral load (log10-transformed gc/mL of serum) at 15dpi in previously maPgV naive mice that received transfer of serum vs. splenocytes from mice that controlled maPgV in Figure 9A.

Figure 9C: Serum maPgV viral load (log10-transformed gc/mL of serum) over time in Rag-KO mice chronically-infected with maPgV, following transfer of splenocytes from mice that controlled maPgV in Figure 9A.

Determinants of Pegivirus persistence, cross-species infection, and adaptation in the laboratory mouse

Data files

Abstract

Determinants of Pegivirus persistence, cross-species infection, and adaptation in the laboratory mouse

Data files

Abstract

README: Determinants of Pegivirus persistence, cross-species infection, and adaptation in the laboratory mouse