New Findings about Rhabdoviruses from 1999-2000

Human Rabies Virus-neutralizing Antibodies

Development of human rabies virus-specific monoclonal antibodies may provide a safer replacement for human rabies immune globulin (HRIG). Using B cells of volunteers who had received a rabies vaccine (HDCV), Champion et al. prepared mouse-human heterohybrid myeloma cells that produced rabies virus-specific human monocolonal antibodies. These antibodies provide a number of advantages over HRIG, which is currently used in post-exposure treatment for rabies. First of all antibodies will eliminate the possibility of anaphylaxis and will not be affected by reduced bioavailability or supply limitations. Human monoclonal antibodies will also reduce the likelihood of infectious contaminants. In addition, antibody specificities may be selected to target epitopes important in recognition of rabies virus strains, and also to ensure that passive antibody administration will not interfere with active immunization.
(Champion, et al., 2000)

Chromatographically Purified Rabies Vaccine

A two-stage clinical trial carried out in the Philippines suggests that chromatographically purified rabies vaccine (CPRV) is an effective and improved immunization for patients with severe confirmed exposure. The chromatographic procedure purifies the current rabies vaccine prepared from Vero-cell culture (PVRV). The clinical trial provided post-exposure treatment that included five injections of vaccine together with a dose of rabies immunoglobulin. In stage 1, 231 subjects treated with CPRV and PVRV displayed equivalent immunogenicity. Of the 132 subjects included in stage 2, 62 were followed for a year. There were no reports of severe local or systemic reactions in either stage, and no treatment-related adverse events occurred.
(Quiambao, et al., 2000)

Spread of Rabies Virus Across Europe

An analysis of the nucleotide sequences of 245 isolates of rabies virus nucleoprotein and glycoprotein genes suggests a possible path by which the virus evolved and spread across Europe during this century. Through the use of gene sequence data, Bourhy et al. determined distinct phylogenetic groups associated with geographical areas. The pattern indicated a spread westwards and southwards across Europe over the last 100 years. Physical barriers enabled localized evolution, most likely due to restricted movement of infected hosts. In addition, there were two changes of host species involving dogs and foxes.
(Bourhy et al., 1999)

Folding of Rabies Virus Glycoprotein Ectodomain

The ectodomain of the rabies virus glycoprotein was investigated in order to determine the specifics of its folding. The trimeric transmembrane glycoprotein mediates recognition of the virus receptor and membrane fusion. pH plays an important role in the equilibrium of the three structurally different states. The native (N) state is detected at the virus surface and is responsible for receptor binding. The activated hydrophobic (A) state interacts with the target membrane as fusion begins. The fusion-inactive (I) state is the predominant conformation at low pH. When glycoprotein is synthesized to exclude transmembrane and intracytoplasmic domains, it will be secreted in an I-like state. In addition, membrane anchorage by this domain is sufficient to fold the ectodomain into the N state. These results suggest that the G transmembrane domain may be important in ectodomain folding, and could assist in determining how to attack the virus at points of receptor recognition and fusion.
(Gaudin et al., 1999)

Role of p75NTR as a Rabies Virus Receptor

Previously it was hypothesized that the low-affinity neurotrophin (NT) receptor, p75NTR was a rabies virus receptor in cultured BSR cells. A study by Jackson and Park investigated rabies infection in p75NTR-deficient mice. The mice developed a fatal encephalitis similar to that of wild-type mice. This suggests that p75NTR is not an important receptor for animals infected with rabies, because otherwise it would have been expected that the knockout mice would have diminished neuropathologic disease features. Jackson and Park concluded that either p75NTR is not an important receptor or there are other receptors in brain neurons that recognize rabies virus.
(Jackson and Park, 1999)

Dynamics of rabies virus quasispecies

A study of the quasispecies structure of the nucleoprotein and glycoprotein genes of rabies virus explored how the rabies virus may adapt and infect new hosts through mutations and genetic rearrangements. 'Quasispecies' is a term used when a virus exhibits heterogenous population structure within a single individual. Kissi et al. obtained gene sequences from the brain and salivary glands of a European fox, and then from mice, dogs, cats, and cell culture after allowing for serial infection. At the quasispecies level, two mechanisms of evolution were found: accumulation of limited mutations with no replacement, and rapid elective overgrowth of certain favored variants. This selective process allows rabies to adapt to new host species. This investigation also supported previous findings that when large virus populations are used in passages, subtle replicative differences only affect long-term dominance of virus subpopulations.
(Kissi et al., 1999)

Structural model of rhabdovirus glycoproteins

Walker and Kongsuwan aligned the G protein sequences of fourteen animal rhabdoviruses. Their analysis indicates that the structural features of the G protein have been highly preserved. Some of the preserved features include cysteine residues, antigenic sites, and elements of secondary structures. The pattern of cysteine residue preservation was used to suggest a model for the G protein structure. This predicted structure accounts for preservation of conformational antigenic sites and supports genus-specific variations.
(Walker and Kongsuwan, 1999)

Postexposure booster injections

In this study, Jaijaroensup et al. administered preexposure purified chick embryo rabies vaccinations to 138 veterinary students. One group received intradermal vaccinations, and the other group received intramuscular vaccinations. After one year, the students received booster injections. The students who had received intradermal vaccinations had lower postexposure booster antibody responses than the students who had received intramuscular vaccinations. In addition, while all the students had antibody titers above the recommended level of 0.5 IU/mL at the time of the booster, residual neutralizing antibodies were significantly higher in the intramuscular group. The authors concluded that subjects receiving intradermal vaccinations may not be fully protected during the first five days after exposure.
(Jaijaroensup et al., 1999)

Apoptotic cell death in brain neurons of bax-deficient mice Jackson reports on the occurrence of apoptosis in brain neurons associated with rabies infection in mice missing the Bax protein in the hippocampus and cerebral cortex. Bax-deficient mice were inoculated with challenge virus standard (CVS) or the RV194-2 (avirulent) variant of rabies virus. While the clinical disease was similar, CVS produced apoptosis that was more marked in neurons of the dentate gyrus and cortical neurons in the cerebral cortex, hippocampus, and cerebellum of the bax-deficient mice compared to the wild-type mice. Since apoptosis occurred in all cases, this suggests that Bax protein plays an important role in rabies-induced apoptosis, but additional modulators are likely to be important.
(Jackson, 1999)

ELISA for detection of rabies virus antibodies following vaccination

ELISA was used to examine sera from humans vaccinated with cell-culture vaccine or suckling-mouse-brain vaccine. Results were compared to resutls from the virus neutralization test. Sensitivity, specificity, and agreement values were 87.5%, 92.4%, and 88.5%, respectively. There were no significant differences in these values between the two vaccinated groups. The authors suggest that these results indicate that this ELISA method may be used as a screening test in rabies laboratories, regardless of the kind of vaccine used in immunization.
(Piza et al., 1999)
Rhabdovirus Homepage