Comparative genomics of HSV-1 from cerebrospinal fluid of clinical encephalitis patients

Herpes Simplex Virus 1 (HSV-1) infects more than 70% of people around the world, and causes painful skin blisters (‘cold sores’) around the mouth and genitals. Infection is lifelong and mostly benign. HSV is the commonest viral cause of encephalitis and is fatal in 70% of cases, with brain damage in many survivors. To investigate whether viruses that infect the brain are genetically distinct, we recovered virus directly from patient samples without the need for prior culture. We used RNA oligonucleotides to purify HSV-1 DNA, from which we derived high-quality sequence genomes. Analysis of swabs taken from different sites in a single patients showed almost identical profiles of population variants, a signature consistent with auto-inoculation with seeding of new lesions with large populations of diverse viruses. We found evidence that HSV-1 viruses recombine their genomes at high frequency. However, we also found that certain parts of the genome seem to recombine less frequently, with recombination-resistant regions concentrated in the vicinity of genes US7 and US8 in viruses from brain and genes US9-12 in viruses from skin swabs. This pattern is suggestive of different constraints imposed on the viruses at different body sites and opens the way for new insights into the pathogenesis of HSV-1 disease.