A single viral gene determines lethal cross-species neurovirulence of baboon herpesvirus HVP2

Abstract

Alpha-herpesviruses can produce more severe infections in non-natural host species than in their natural host. Isolates of the baboon alpha-herpesvirus Papiine herpesvirus 2 (HVP2) are either very neurovirulent in mice (subtype nv) or non-virulent (subtype ap), but no such difference is evident in the natural baboon host. Comparative genome sequencing was used to identify subtype-specific sequence differences (SSDs) between HVP2nv and HVP2ap isolates. Some genes were identified that despite exhibiting sequence variation among isolates did not have any SSDs, while other genes had comparatively high levels of SSDs. Construction of genomic recombinants between HVP2nv and HVP2ap isolates mapped the mouse neurovirulence determinant to within three genes. Construction of gene-specific recombinants demonstrated that the UL39 ORF is responsible for determining the lethal neurovirulence phenotype of HVP2 in mice. These results demonstrate that differences in a single viral gene can determine the severity of herpesvirus infection in a non-natural host species.

Genome sequence variation among isolates of monkey B virus ( Macacine alphaherpesvirus 1) from captive macaques

“…As shown in Figure 2, the level of BVrh protein sequence variation is markedly less than the level of variation in proteins of its phylogenetically closest relative virus of baboons, HVP2. (Black et al, 2014) Two BVrh strains isolated from the same monkey (26896-O & -G, oral and genital isolates, resp.) had identical genome sequences except for the number of repeat unit iterations in UL36, R L R2, R L R5 and R S R1.…”

“…(Black et al, 2014; Brush et al, 2014) This model relies on the virus undergoing sufficient replication in the skin to reach titers high enough to invade sensory neurons via unmyelinated nerve endings in the epidermis with subsequent ascension to the dorsal root ganglia and from there into the CNS. As summarized in Table 1, LD 50 values for BVrh isolates ranged from 10 3.8 – 10 5.4 PFU, with an average value of 10 4.1 PFU.…”

“…(Black et al, 2014; Brush et al, 2014; Rogers, 2006) Briefly, the left flank of 10–12 gm female Balb/c mice was shaved, lightly scarified with an 18 Gg needle, and 10 ul of virus applied to the scarified area. Ten-fold dilutions of virus ranging from 10 6 –10 3 PFU/10 ul were tested.…”

“…For each isolate the dose required to induce neurological symptoms (CNSD 50 ), death/euthanasia (LD 50 ) or infection (ID 50 ; based on clinical signs plus positive serology in survivors) in 50% of inoculated mice was determined as described. (Black et al, 2014; Ritchey et al, 2005)…”

Genome sequence of a pathogenic isolate of monkey B virus (species Macacine herpesvirus 1)

“…All work with infectious BV was performed in accordance with the Oklahoma State University Select Agent Program as approved by the US Centers for Disease Control and Prevention. Viral DNA used for sequencing and PCR reactions was purified from infected Vero cells as described [3]. Initial genomic sequencing utilized cloned restriction fragments and Sanger dideoxy sequencing performed by the Oklahoma Medical Research Foundation DNA Sequencing Facility (Oklahoma City, OK) and at Nagasaki University.…”