Mechanism of Differences in Pathogenicity between Two Variants of a Laboratory Strain of Herpes Simplex Virus Type 1

Abstract

The mechanisms responsible for the difference in neurovirulence to inbred mice between two variants of the Miyama strain of herpes simplex virus type 1 (HSV-1) were studied. After intraperitoneal (i.p.) inoculation, the +GC (LPV) variant reached the spinal cord and the brain, and caused death. Conversely, the -GCr variant lacked the ability to gain access to the central nervous system (CNS) after the same route of infection and failed to kill susceptible mice. The initial virus growth after i.p. inoculation, as indicated by the number of infective centers (ICs) produced by the peritoneal exudate cells (PECs), was compared between these two variants. The virulent +GC (LPV) strain induced much more ICs than the attenuated -GCr variant. When the attenuated variant was preinoculated i.p. 24 hr before the challenge inoculation with the virulent variant by the same route, the production of ICs by the pathogenic variant was highly inhibited, and growth of this variant did not occur in the CNS. Thus, mice were protected from lethal infection by the virulent variant by preinoculation with the attenuated one. Moreover, the ability of mice to resist i.p. infection by HSV-1 was shown to be age-dependent.Herpes simplex virus (HSV) causes a number of diseases in man which may be manifestations of either acute exogenous infection or recurrent endogenous infection. (11). Defense of the host against HSV is complex and probably depends on a number of cellular and humoral factors interacting to restrict and clear the infection. The mechanisms involved can be classified as being either antigen-specific or non.-specific with respect to the ability to recognize a particular agent. The latter, i.e., natural resistance mechanisms, probably play important roles in the early phase of primary infection (13).The Miyama strain of type 1 HSV (HSV-1) was isolated in 1958 by one of the authors (17). Using two variants derived from this strain, Shimizu et al (23) compared the virulence in mice after intraperitoneal (i.p.) inoculation and found that the +GC variant was highly virulent while the -GCr variant was attenuated. We comparatively studied the in vitro cytopathology and the neurovirulence to inbred mice of five variants of the same strain and revealed that neurovirulence is positively 1259

Pathogenicity of Different Baboon Herpesvirus Papio 2 Isolates Is Characterized by either Extreme Neurovirulence or Complete Apathogenicity

“…The complete lack of any histological lesions in the CNS of mice infected with HVP2ap strains suggests that either these viruses are unable to reach the CNS or, if they do, they are unable to replicate and produce pathological lesions. From studies on HSV, it appears that the amount of virus present at the peripheral site is directly related to the ability of the virus to enter sensory neurons and thus invade the CNS (29). The results of ELISA for detection of anti-HVP2 IgG in serum imply that HVP2ap isolates do not undergo sufficient replication at the site of inoculation to stimulate a robust immune response, suggesting that the block in HVP2ap infection occurs very early after inoculation.…”

Type I IFN response to Papiine herpesvirus 2 (Herpesvirus papio 2; HVP2) determines neuropathogenicity in mice

“…Since the level of virus in the lumbar spinal cord and associated DRGs represents the earliest point in the pathogenic process that is demonstrably different for HVP2ap and HVP2nv in wild-type 129 mice, it is likely that the ability of the host to delay and/or lessen entry of virus into the CNS plays a critical role in the dichotomous outcome of infection with the two HVP2 subtypes. In contrast, studies with HSV have shown that replication of the virus at the inoculation site appears to be important in that this replication amplifies the amount of virus thereby increasing the likelihood of viral entry into unmyelinated nerve fibers present in the skin to provide access to the CNS (Cunningham et al, 2006; Mossman and Ashkar, 2005; Yamada et al, 1986). While differences in the amount of HVP2ap vs. HVP2nv in skin were statistically significant only at 3 DPI, levels of HVP2ap were lower than those of HVP2nv at 2 and 4 DPI.…”

“…In addition, both viral dose and route of inoculation can influence the ability of a virus to establish a productive infection within a given host (Breshears, Eberle, and Ritchey, 2005; Weeks et al, 2000). In HSV infection of mice, the efficiency of viral replication at the peripheral site of infection is directly related to the ability of the virus to enter sensory neurons and invade the CNS (Yamada et al, 1986). However, once a virus has gained entry to a host organism, the most important host determinant of pathogenicity is likely the host innate immune response (Mossman and Ashkar, 2005; Simons and Nash, 1984).…”

Effect of recombinant mouse interferon-? on acute and latent herpes simplex infection in mice

“…However, rMuIFN-J3 was not effective against the establishment and maintenance of latent infection. In previous studies [24,26], we have examined the mechanism responsible for the difference in pathogenicity to mice between virulent and attenuated variants of the Miyama strain of HSV-1. The extent of the initial viral growth in the peritoneal cavity was one of the most critical factors determining the outcome of IP infection of mice with HSV.…”