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Antibody-Mediated Enhancement of Rabies Virus

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Antibody-Mediated Enhancement of Rabies Virus 542 Nature Vol. 290 16 April 1981 rearranged, K-chain gene, for example; region than the salivary gland mRNA. It is Are these findings at all relevant to the only one of these is destined to appear in possible that this affects the translation rabies 'early death' effect? Rabies viruses the mRNA, the remainder being removed efficiences of the mRNA (see 'Discussion' were thought to be serologically identical, by differential splicing. in Young et al.). Although the explanation but a number of rabies-related viruses are Why does the mouse go to all this for this fascinating genetic mechanism is now knownl2 , and antigenic variation trouble? Any explanation should consider the subject of future work, it is, of course, between rabies virus strains has been estab­ the fact that a-amylase mRNA accounts likely to be tied up with the primary lished I3 • Mice inoculated with Lagos Bat or for 2 per cent of the cytoplasmic mRNA in question - what determines the different Mokola viruses, two of the rabies-related the salivary gland, but only 0.02 per cent in level of a-amylase in two different tissues? viruses, and subsequently challenged with liver. This level may reflect the transcrip­ In the rat (and other mammals) the rabies virus, also died more quicklyl4. tion rate from the two genes; the 'salivary situation may be even more complicated. These findings suggest that it is not gland' promoter would then be consider­ MacDonald and his co-workers (Nature essential to have homologous neutralizing ably stronger than the 'liver' promoter. 287, 17; 1980) have analysed the rat antibodies to produce the rabies 'early Alternatively, the rate of RNA processing a-amylase genes and these studies point to death' effect, but that cross-reacting sera andlor export to the cytoplasm may be at least five non-allelic a-amylase genes or may also be active in this system as in the different for the two mRNAs. Another pseudogenes. The further elucidation of dengue system 10.15. Three monoclonal clue may reside in the fact that the liver the expression of the a-amylase gene family antibodies directed against the envelope mRNA has a much longer 5' -un translated remains a mouth-watering prospect. [j glycoprotein of West Nile virus will all enhance West Nile virus although only one of these has neutralizing activityl6. Monoclonal antibodies against known components of rabies virus and against rabies-related viruses are available, and it Antibody-mediated would be of great interest to determine which of these was capable of producing the enhancement of rabies virus 'early death' effect with rabies virus. It might be objected that rabies virus from J. S. Porterfield replicates in the central nervous system in cells that would not have Fc receptors, so THE long incubation period following and subsequently acquired natural that the mechanism of opsonization of naturally acquired rabies virus infection infection with that virus is well virus-antibody complexes could not allows time for manipulation of the host's documented, but still inadequately apply. Rabies virus is capable of replicating immune system in ways that can promote explained6. Dengue viruses normally in a wide variety of different cell types in protection. Louis Pasteur's treatment of produce a non-fatal illness with a rash, but addition to neurones, and it is certainly Joseph Meister was dramatically successful a proportion of children in South-East possible that macrophages within the brain almost a century ago, and since then, very Asia develop haemorrhagic manifestations or spinal cord might support replication, many others have benefited from rabies and may die from shock7. Although the following 'enhanced' uptake in the vaccines l . There are, however, occasional effector mechanism responsible for the presence of anti-rabies antibodies, failures, even when vaccine of established shock remains controversial, several although experiments with mouse potency has been used, and much remains laboratory studies related to haemorrhagic peritoneal macrophages lend little support obscure about the pathogenesis of rabies dengue are relevant to the 'early death' to this view l7 . virus infection, and about the precise way phenomenon. Monkeys inoculated with These comments in no way detract from in which rabies vaccine confers protection. dengue virus mixed with sub-neutralizing the unquestionable efficacy of present One puzzling effect, seen in both monkeys concentrations of anti-dengue antibodies post-exposure treatments of rabies, which and mice immunized with rabies vaccine show higher levels of viraemia than control combine the use of human diploid cell and subsequently challenged with rabies animals given dengue virus only8. Dengue vaccine with human rabies immune virus, has been termed the 'early death' virus replicates poorly in normal human or globulin 18-20. They emphasize a continuing phenomenon, since some vaccinated monkey peripheral blood white cell prepar­ need for investigation of the complex inter­ animals die sooner than non-vaccinated ations, but shows enhanced yields of virus actions involved in the pathogenesis of controls given the same. chaJlenge2,3. when exposed to infectious virus-antibody rabies virus infection. C Following earlier work which indicated mixtures9. This antibody-mediated that both bone marrow-derived B lympho­ enhancement of viral replication is not I. Pasteur, L. c.r. hebd. Seanc. A cad. Sci .. Paris 101, 765 (1885). cytes and thymus-derived T lymphocytes restricted to dengue virus, but has also been 2. Sikes, R.K. etal, Bull. Wid Hith Org. 45. I (1971). contributed to the clearance of rabies virus demonstrated in continuous cell lines of l. Blancou, J., Andral. B. & Andral, L. 1. gen. Virol.50.433 4 5 (1980). from the central nervous system . , mouse and human macrophages with West 4. Miller,A., Morse. H,C. III, Winkelstein, J. & Nathanson, Prabhakar and Nathanson now present Nile virus 10 , with other Togaviridae and J. 1. lmmun. 121.321, (1978). evidence, on p. 590 of this issue of Nature, Bunyaviridaell • Halstead first suggested 5. Smith, J.S.lnJecl.lmmun. 31,297 (1981) 6. McIntosh, K. & Fishaut. 1.M. Prog. med. Virol. 26,94 that 'early death' in mice is mediated that the mechanism involved in the human (1980). through antibodies, and is not a cell­ monocyte system depended on an 7. Halstead, 5.B. Bull. WldHith Org. 58. I (1980). 8. Halstead, S.B. J. inject. Dis. 140,527 (1980). mediated effect involving T lymphocytes; increased uptake of virus complexed with 9. Halstead, S.B. & O·Rourke. E.J. J. expo Med. 146.201 they do not, however, explain the antibody through Fc receptors (present on (1977). 10. Peiris, J.5.M. & Porterfield, J.S. Nature 282, 509 (1979). mechanism whereby antibody produces these cells but absent from most other 11. Peiris. l.S.M., Gordon, S., Unkelcss. J.e. & Ponerfield, this paradoxical response. cells), the internalized virus escaping J.S. Nature 289. 189 (1981). Apart from rabies, there are a number of destruction by the phagocytes and 12. Matthews. R.E.F.lntervirology 12. Il2 (1979). 13. Wiktor. T.]. & Koprowski, H. J. expo Med. 152,99(1980). other infections in which antibodies appear replicating within them9. Using the simpler 14. Tignor, G.H., Shope, R.E., Gershon, R.K. & Waksman. to produce effects which are detrimental to model system with mouse macrophage-like B.H. J. Immun. 112.260 (1974). IS. Flamand, A., WikrOf. T.J, & Koprowski. H. J. gen. Virol, the host. The increased risk of severe cell lines, Peiris et al. II showed that the 48, 105 (1980). bronchiolitis and pneumonia seen in antibody-mediated enhancement of West 16. Peiris. J.S,M. thesis, UniversilY of Oxford (1980). infants who had been vaccinated with 17. Turner, 0.5. & Ballard. R. J, gen. Virol. 30,223 (1976). Nile virus replication was specifically 18. World Health Organizarion: Working Group 2 DevJ Bioi. killed respiratory syncytial virus vaccine blocked by monoclonal antibodies directed Stand. 40,268 (1978). against Fc receptors on the cells they were 19. Aoki, F.Y., Tyrrell, D.A.J., Hill, 1..E. & Turner, O.S. J. S. Porterfield is in the Sir William Dunn Lancet i, 660 (1975). School of Pathology, University of Oxford. using. 20. Anderson. L.J. et al. J. inject. Dis. 142. 133 (1980). 0028-0836/81/160542·01 SOI.OO :c) 1981 Macmillan Journals Ltd .
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