Large, Stable, Contemporary Interspecies Recombination Events in Circulating Human Herpes Simplex Viruses

Abstract

Background: The ubiquitous human pathogens, herpes simplex virus (HSV)-1 and HSV-2, are distinct viral species that diverged approximately 6 million years ago. At least 4 small, ancient HSV-1 × HSV-2 interspecies recombination events have affected the HSV-2 genome, with recombinants and nonrecombinants at each locus circulating today. However, it is unknown whether interspecies recombination can affect other loci and whether new recombinants continue to be generated.

Methods: Using 255 newly sequenced and 230 existing HSV genome sequences, we comprehensively assessed interspecies recombination in HSV.

Results: Our findings show that the sizes and locations of interspecies recombination events in HSV-2 are significantly more variable than previously appreciated and that they can impact species-specific T-cell recognition of HSV.

Conclusions: We describe 2 large (>5 kb) recombination events, one of which arose in its current host, demonstrating that interspecies recombination continues to occur today. These results raise concerns about the use of live-attenuated HSV-2 vaccines in high HSV-1 prevalence areas.

Keywords: T-cells; genome; herpes simplex virus; phylogeny; recombination.

Figure 1.

Herpes simplex virus (HSV)-1 and HSV-2 phylogenetic trees. (A) Phylogenetic tree of all available HSV-1 genomes (only 1 genome included per person) color-coded by geographic origin. The strain names for some genomes are included next to their location in the tree for reference. Clades I–VI are labeled. (B) Phylogenetic tree of all available HSV-2 genomes (only 1 genome included per person) color-coded by geographic origin. The strain names for some genomes are included next to their location in the tree for reference. Clades I–V are labeled as are clusters defined by UL29, UL30, and UL39 genotype.

Figure 2.

Seattle1 (UL29–UL31) recombinant. (A) Schematic showing the size and position of the recombination event relative to the herpes simplex virus (HSV)-2 genome and within its genic neighborhood. Green represents coding regions and purple represents noncoding regions. The recombinant region is represented by a blue bar. (B) List of all sequenced samples collected from the person carrying the Seattle1 (UL29–UL31) recombinant with the day of sample collection relative to the collection date of the first sample. (C) Phylogenetic tree of the recombinant region extracted from HSV-1 sequences and from the Seattle1 (UL29–UL31) recombinant. The bar below the tree shows the extracted region (colored in bright blue and enlarged) relative to the rest of the genome (faded out). The branch representing the UL29–UL31 recombinants is marked with blue circle. (D) Phylogenetic tree of HSV-2 genomes without UL29, UL30, and UL31. The bar below the tree shows the extracted regions (colored in bright green and enlarged) relative to the rest of the genome (faded out). All 3 HSV-2 sequences from the person carrying the Seattle1 (UL29–UL31) recombinant clustered on the branch marked with the blue circle.

Figure 3.

Seattle2 (UL47–UL50) recombinant. (A) Schematic showing the size and position of the recombination event relative to the herpes simplex virus (HSV)-2 genome and within its genic neighborhood. Green represents coding regions and purple represents noncoding regions. The recombinant region is represented by a blue bar. (B) List of all sequenced samples collected from the person carrying the Seattle2 (UL47–UL50) recombinant with the day of sample collection relative to the collection date of the first sample. (C) Phylogenetic tree of the recombinant region extracted from all HSV-1 and HSV-2 sequences. The bar below the tree shows the extracted region (colored in bright blue and enlarged) relative to the rest of the genome (faded out). The branches marked with colored circles represent the position in the tree of the various samples collected from the person carrying the Seattle2 (UL47–UL50) recombinant. These colors correspond to those in B. (D) Phylogenetic tree of HSV genomes without UL47, UL48, UL49, UL49a, and UL50. The bar below the tree shows the extracted regions (colored in bright green and enlarged) relative to the rest of the genome (faded out). The branches marked with colored circles represent the position in the tree of the various samples collected from the person carrying the Seattle2 (UL47–UL50) recombinant. These colors correspond to those in B.