Postexposure immunoprophylaxis against B virus (Herpesvirus simiae) infection.

Local infiltration of antiserum into sites inoculated with B virus protected rabbits from an otherwise fatal encephalomyelitis. Treatment was effective when delayed for six hours but not after 24 hours. Homologous rabbit antisera were more effective than heterologous monkey antisera, and protection was unrelated to neutralisation titres. Protection apparently depended not on neutralisation of inoculated virus but on destruction of infected cells before they produced progeny virus. Normal human immunoglobulin able to neutralise B virus did not protect. Intravenously administered antibody was effective only if large doses were given. The findings suggest that persons bitten or scratched by monkeys latently infected with B virus may be treated successfully by immunoprophylaxis with specific antibody. Stocks of human or of more readily available simian antisera should be held in laboratories where such animals are used.     

Successful treatment of experimental B virus (Herpesvirus simiae) infection with acyclovir.

The efficacy of the new nucleoside analogue acyclovir against B virus (Herpesvirus simiae) was investigated in rabbits and Vero cells infected with 2-136 and 0.3-1.0 TCD50 of the virus respectively. In the Vero cells 1 mg of acyclovir/1 reduced the yield of virus by 90%, which was slightly less than the effect on herpes simplex virus. Results in the rabbits varied with the interval between doses, duration of treatment, and delay before starting treatment. Acyclovir controlled an otherwise lethal infection when given not less than eight-hourly for 14 days. Withdrawing treatment after 9-10 days resulted in late-onset fatal disease in some rabbits. Treatment begun within 24 hours after infection gave complete protection, and rabbits first treated up to five days after infection showed a significant reduction in mortality (p less than 0.001). The plasma half life of acyclovir is twice as long in man as in rabbits and progression of the disease is much slower. Hence acyclovir may be useful for post-exposure prophylaxis against B virus infection in man and possibly also for treatment of the disease.     

Herpesvirus simiae (B virus) antibody response and virus shedding in experimental primary infection of cynomolgus monkeys.

Four cynomolgus monkeys (Macaca fascicularis) were inoculated in the lips and tongues with B virus. Virus shedding and antibody responses were monitored for up to 50 days postinfection. Virus was isolated from the oral cavities of all monkeys at 6 days postinfection despite the absence of observable lesions. Virus was not isolated from genital swabs or serum. Antibodies to both B virus and herpes simplex virus were detected by neutralization between days 8 and 12. Virus-specific IgM and IgG antibodies were measured by antibody capture radioimmunoassay. IgM was first detected on day 6; by contrast, IgG did not appear until day 12. Antibodies reactive in a competitive radioimmunoassay appeared by day 12 and peaked at 30 to 40 days postinfection. This study provides data on which to base the diagnosis of primary B virus infection in cynomolgus monkeys.     

Activation of B virus (Herpesvirus simiae) in chronically immunosuppressed cynomolgus monkeys.

Three of 14 cynomolgus monkeys given the highest dose of an immunosuppressive drug in a 6-month toxicology study developed B virus (Herpesvirus simiae) oral lesions after 3 months of dosing. This necessitated early removal of all high-dose monkeys from the study due to concerns related to B virus. The incidence and severity of parasitic (Oesphagostomum sp.) lesions of the large intestine were also increased in high-dose animals. Both B virus and Oesophagostomum are enzootic in macaques, and the lesions caused by them were considered secondary to chronic immunosuppression caused by the highest dose of the test compound. Evidence of immunosuppression included decreased lymphocyte counts (B-cells; CD2 and CD8 T-cells), histopathologic evidence of lymphoid suppression, and serum-induced inhibition of lymphocyte mitogen responses. Pathogenesis of the B virus was apparently associated with both activation of latent virus as well as transmission of active virus. Approaches for virologic monitoring of primates and for ensuring optimal safety for primate handlers are discussed.     

Risk of occupational exposure to Herpesvirus simiae (B virus) in Quebec.

Herpesvirus simiae (B virus) causes a mild infection in macaques. Transmission to humans may result in life-threatening encephalomyelitis. To evaluate the risk of occupational exposure to B virus we surveyed the directors of 11 biomedical laboratories in Quebec that use monkeys. Information was obtained on the monkey population and on the use of infection control measures recommended by the US Centers for Disease Control (CDC), Atlanta. Of the 519 monkeys belonging to susceptible species the serologic status was positive in 264 (51%), all captured in the wilds, and it was unknown in 24 (5%). All of the monkeys were caged individually, and newly acquired ones were quarantined for 2 to 8 weeks. Of the 84 workers 52 (62%) handled monkeys whose serologic status was either positive or unknown. Only five laboratories (representing 61% of the workers) complied fully with the CDC guidelines. Nine of the laboratories had a wound management protocol, but only six had a designated specialist for consultation and prophylaxis. Although no cases of B virus infection have been reported from Quebec the severity of human illness necessitates strict adherence to infection control measures and expert management of occupational exposure to susceptible monkeys.     

Axonal and transsynaptic (transneuronal) spread of Herpesvirus simiae (B virus) in experimentally infected mice.

In order to study the pathogenesis of B virus infection of the nervous system, newborn and young mice were inoculated by four different routes: 1. Intramuscular (i.m.) in the forelimb; 2. I.m. in the hindlimb; 3. Subcutaneous (s.c.) in the abdominal wall; 4. Intraperitoneal (i.p.). Spread of virus was followed by immunohistochemical demonstration of viral antigen in tissue sections of the peripheral and central nervous system. Three distinct patterns emerged: 1. After i.m. limb inoculations, virus progressed along the ipsilateral dorsal column, the bilateral spinothalamic and bilateral spinoreticular systems and along central autonomic pathways. 2. After s.c. inoculation, the dorsal column was spared, otherwise the spread was similar to that following i.m. inoculations. 3. After i.p. inoculation, virus spread in the spinal cord bilaterally, mainly along spinothalamic and central autonomic pathways. The peripheral motoneurons were conspicuously spared, even in the i.m. inoculation mode. In the brain stem, B virus antigen appeared bilaterally, at multiple sites. In the cerebrum, virus infected cells appeared first in the thalamus, hypothalamus and the motor cortex. The mode of spread from spinal levels was mainly orthograde along the ascending systems (dorsal columns, spinothalamic, spinoreticular tracts), but also retrograde along descending systems (pyramidal tract, central autonomic pathways). Oligosynaptic systems transmitted virus more quickly than the polysynaptic ones. In the involvement of various neuronal systems in virus spread, a certain selectivity, sparing the peripheral motoneuron and the cerebellar systems, could be assessed.     

Persistent reduction of B virus (Herpesvirus simiae) seropositivity in rhesus macaques acquired for a study of renal allograft tolerance.

One hundred and two rhesus macaques were used in a study of renal allograft tolerance. Each animal was monitored serologically more than one time to determine its B virus (Herpesvirus simiae) antibody status. The follow-up period for some individuals was 3 years, extending from 1986 to 1989. The accumulated test results eventually provided an opportunity to retrospectively support a contention that a small research colony of rhesus macaques could become and remain B virus seronegative if the animals were housed individually, monitored periodically, acquired only if they were seronegative, and culled if they converted to positive status. It was also possible that the test results might disclose useful information about the influence of acute immunosuppression on the reliability of determining B virus antibody status by serologic methods, and help formulate guidelines for selecting donor-recipient pairs. A review of the serologic test results disclosed that antibody status before the initiation of experimental therapy, and subsequent seroreactivity, did not change throughout the experimental lifetime of 92 monkeys. The few exceptions were six juveniles that lost detectable antibody, and four other juveniles that converted to positive. Preliminary data suggested that total lymphoid irradiation (TLI) and splenectomy were associated with the loss of detectable antibody; however, further study is needed to establish the validity and significance of this association. No other unexpected or unexplained results were associated with concomitant periods of acute immunosuppression. The number of seropositive animals in the colony was reduced to three through attrition and culling by the end of 1989.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased oxidative damage of RNA in liver injury caused by hepatitis B virus (HBV) infection

To evaluate the urinary levels of 8-oxo-7,8-dihydro-2′deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) in liver injury patients with hepatitis B virus (HBV) infection and to explore the relationship between urinary 8-oxo-dGsn or 8-oxo-Gsn and degree of liver damage. We enrolled 138 liver injury patients with HBV infection and 169 age- and sex-matched healthy controls in this study. A sensitive and accurate isotope-diluted liquid chromatograph mass spectrometer/mass spectrometer (LC-MS/MS) method was used to measure the urinary levels of 8-oxo-Gsn and 8-oxo-dGsn. Simultaneously, pathological analysis of liver biopsy tissues was carried out, and immunohistochemistry was carried out for 8-oxo-Guo, 8-oxo-dGuo and MTH1 protein in some liver injury tissues. We analysed the correlation between the degrees of inflammation and fibrosis and levels of 8-oxo-Gsn and 8-oxo-dGsn. We also analysed the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn with clinical data of HBeAg, HBsAg, and HBV genotype and detected the levels of plasma aspartate aminotransferase, alanine aminotransferase (AST), platelet, alkaline phosphatase, prothrombin time (PT) and HBV DNA, and calculated the aspartate amino transferase-to–platelet ratio index (APRI) score. Nonparametric correlations were used to evaluate the correlation between 8-oxo-Gsn, 8-oxo-dGsn or APRI and various laboratory biochemical indicators. Results showed that the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn in patients with liver injury were significantly higher than those of healthy controls (both p?p?=?.013, p?=?.026 and p?=?.049). The receiver operating characteristic curves of 8-oxo-Gsn were 0.696 (0.632–0.759) and 0.731 (0.672–0.790) for inflammatory activity and fibrosis, respectively. Patients with higher levels of urinary 8-oxo-Gsn are more likely to have a high degree of fibrosis and urinary 8-oxo-Gsn may have a great potential in assessing liver fibrosis.     

Subpopulation of peripheral blood lymphocytes in human encephalitis caused by group B arboviruses (Dengue, West Nile and Japanese B encephalitis.

Sera from twenty patients with clinically diagnosed viral encephalitis were studied during the acute and convalescent phases of illness for evidence of group B arboviral infection by demonstrating a rise in the titre of haemagglutination inhibiting (HI) antibodies. The immune status of these individuals was studied by quantitating peripheral T, T and 'null' lymphocytes. The percentage of total T cells in arboviral encephalitic (AE) group decreased significantly while that of B cells and 'active' T cells remained unaltered when compared to that of normal individuals. The null cell percentage, on the other hand increased significantly in the AE group. The absolute number of circulating T and B cells did not alter in the AE group while that of null cells rose significantly. The percentage and concentration of T. B and null cells during the convalescent phase of AE did not differ significantly when compared to those of the acute phase.     

Comparison and significance of specific and non-specific cellular immunity in patients with chronic hepatitis B caused by infection with genotypes B or C of hepatitis B virus

The present study was designed to investigate possible relationships between the genotypes of hepa-titis B virus (HBV) and the HBV-specific cytotoxic T lymphocyte (CTL) responses. HBV genotypes, HBV specific CTL HBV DNA and other markers of HBV infection were determined in 138 patients with chronic hepatitis B. The results showed that the patients infected with genotype C (n=62) had a significantly lower HBV-specific CTL response than those who were infected with HBV genotype B (P<0.01). HBV DNA titer was higher in patients infected with HBV genotype C than in those infected with HBV geno-type B (P<0.01). Both alanine aminotransferase (ALT) and total bilirubin (TBIL) were higher in HBV genotype C infected patients than in those infected with genotype B (P<0.01 and <0.05, respectively). These results suggest that compared with CHB patients infected with HBV genotype B, the higher HBV DNA level and more severe liver damages in the patients infected with genotype C of HBV may be as-sociated with genotype C of the virus.     

RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection

Dengue virus (DV) infection is one of the most common mosquito-borne viral diseases in the world. The innate immune system is important for the early detection of virus and for mounting a cascade of defense measures which include the production of type 1 interferon (IFN). Hence, a thorough understanding of the innate immune response during DV infection would be essential for our understanding of the DV pathogenesis. A recent application of the microarray to dengue virus type 1 (DV1) infected lung carcinoma cells revealed the increased expression of both extracellular and cytoplasmic pattern recognition receptors; retinoic acid inducible gene-I (RIG-I), melanoma differentiation associated gene-5 (MDA-5) and Toll-like receptor-3 (TLR3). These intracellular RNA sensors were previously reported to sense DV infection in different cells. In this study, we show that they are collectively involved in initiating an effective IFN production against DV. Cells silenced for these genes were highly susceptible to DV infection. RIG-I and MDA5 knockdown HUH-7 cells and TLR3 knockout macrophages were highly susceptible to DV infection. When cells were silenced for only RIG-I and MDA5 (but not TLR3), substantial production of IFN-β was observed upon virus infection and vice versa. High susceptibility to virus infection led to ER-stress induced apoptosis in HUH-7 cells. Collectively, our studies demonstrate that the intracellular RNA virus sensors (RIG-I, MDA5 and TLR3) are activated upon DV infection and are essential for host defense against the virus.