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J. gen. Virol. (1984), 65, 1091-1093. Printed in Great Britain 1091 Key words: rabies~antibody-mediated enhancement/RFFIT Antibody-mediated Enhancement of Rabies Virus Infection in a Mouse Macrophage Cell Line (P388D1) By A. A. K I N G , * J. J. S A N D S AND J. S. P O R T E R F I E L D 1 Central Veterinary Laboratory, New Haw, Weybridge, Surrey and 1Sir William Dunn School of Pathology, University of Oxford, U.K. (Accepted 22 February 1984) SUMMARY The suggestion that antibodies might enhance rabies virus infection of macrophages through opsonization of immune complexes was tested in vitro by adaptation of the rapid fluorescent focus inhibition technique for the examination of a macrophage cell line (P388D1). Some enhancement of rabies virus infection was shown. The relationship between such enhancement with the 'early death' phenomenon and its occurrence in vivo is discussed. The precise way in which rabies vaccine confers protection against disease, and the pathogenesis of rabies virus infection are not fully understood. There are occasional failures even when vaccines of established potency have have used. In both monkeys and mice immunized with rabies vaccine and subsequently challenged with rabies virus, some die sooner than non-vaccinated controls given the same challenge (Sikes et al., 1971 ; Blancou et al., 1980). The mechanism underlying this 'early death' phenomenon is obscure, but it appears to be mediated by antibody, rather than by cell-mediated immune processes (Prabhakar & Nathanson, 1981). It has been suggested (Porterfield, 1981) that antibodies might enhance rabies virus infection of macrophages through their opsonization of immune complexes in a manner analogous to that which has been shown to occur with dengue, West Nile and several other viruses (Halstead & O'Rourke, 1977; Peiris & Porterfield, 1979, 1981). An example of antibody-mediated enhancement of viral infection in vivo occurs with feline infectious peritonitis virus (FIPV). When non-immune kittens received normal or FIPV immune feline serum intravenously followed 6 h later by intraperitoneal challenge with FIPV, the antibodysensitized animals developed clinical signs more rapidly and died earlier than did control animals (Weiss & Scott, 1981). We have studied the interaction between rabies virus strains and cells of the mouse macrophage cell line P388D1 (Koren et al., 1975), in the presence and absence of a number of different rabies virus antisera. Rabies virus does not induce lytic plaques in these cells, but we have been able to adapt the well-established rapid fluorescent focus inhibition test for rabies virus-neutralizing antibodies (Smith et al., 1973) by substituting P388D1 cells for the BHK21 cells normally used in this assay. Neutralization curves produced by incubating a fixed dose of rabies virus with serial dilutions of rabies virus antisera revealed a biphasic response; high serum concentrations neutralized infectivity, but on dilution the number of foci increased above the level produced by virus controls without antibody, falling again to reach control levels on further dilution (Fig. 1). This type of response was also seen when serum from a person vaccinated with human diploid cell vaccine (HDCV) was tested with five different rabies virus strains (CVS, ERA, PitmanMoore, Flury LEP and HEP 675). No such biphasic response was seen when similar tests were carried out in BHK21 cells. The magnitude of enhancement (two- to fourfold) is substantially less than that found in the same cell line with viruses of the Togaviridae and Bunyaviridae families, where 30- to 100-fold increases in plaque counts are regularly observed (Peiris & Porterfield, 1981). Table 1 shows the 0022-1317/84/0000-5923 $02.00 © 1984 SGM Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Wed, 03 May 2017 22:11:52 1092 Short communication 50 45 40 35 30 5 25 t. o -= 20 k~ 15 10 2 3 4 5 6 -log,0 Antiserum dilution 7 Fig. 1. Twenty-five ~tl of a suspension containing 100 TCIDso of Flury HEP 675 rabies virus was mixed with 25 ~tl of serial 0-5 log,o dilutions of International Standard rabies virus antiserum (initially 10 International Units/ml) in individual wells of a Costar 96-well microtitre plate. After 90 rain incubation at 35 °C, 25 ~tl of Leibovitz LI5 medium with 3% heat-inactivated (56 °C for 30 min) foetal calf serum containing 7.5 x 103 cells were added to each well, and the plates were re-incubated for 5.5 h. An overlay containing the same medium but including carboxymethylcellulose at a final concentration of 0-75% was then added, using 80 lal/well. After incubation at 35 °C for 4 days, the plates were fixed in 25% formalin for 15rain, washed in phosphate-buffered saline, and stained with fluorescein isothiocyanate-conjugated anti-rabies globulin. Fluorescent foci were counted using a Leitz SM Lux microscope illuminated by a 50 W mercury vapour lamp and employing filter system H2, BG38 and GG 455 edge filters and K530 barrier filters. Mean counts are plotted, based on eight replicates per serum dilution; bars represent standard deviations; - - - , control. degree of enhancement seen with a variety of different rabies antisera, together with details of n e u t r a l i z i n g a n t i b o d y titres as m e a s u r e d b y c o n v e n t i o n a l n e u t r a l i z a t i o n assays i n B H K 2 1 cells or mice. I n a s e p a r a t e e x p e r i m e n t it w a s s h o w n t h a t C V S v i r u s r e p l i c a t e d in, a n d i n f e c t i v e v i r u s w a s r e l e a s e d f r o m , t h e P 3 8 8 D 1 cells in t h e p r e s e n c e or a b s e n c e o f a n t i s e r u m . I n t e r e s t i n g l y , m o r e v i r u s w a s released in t h e p r e s e n c e o f a n t i s e r u m a t a d i l u t i o n o f 10 - 4 t h a n w a s r e l e a s e d in its absence (data not shown). A l t h o u g h t h e s e tests w e r e c a r r i e d o u t in vitro w i t h a c o n t i n u o u s line o f m a c r o p h a g e w h i c h m a y d i f f e r in a n u m b e r o f r e s p e c t s f r o m r e s i d e n t a n d elicited m a c r o p h a g e s , o u r results s u p p o r t t h e Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Wed, 03 May 2017 22:11:52 Short communication 1093 T a b l e 1. Ability o f various rabies antisera to enhance the titres o f rabies virus strain H E P 675 in P388D1 cells Species in which antiserum was prepared Horse Man Rabbit Mouse Guinea-pig Vaccine used CVS Human diploid cell Unknown Duck embryo vaccine Flury HEP 675 Serum neutralization titre* NT 10- 2 9 (H) 10 2.o (M) 10 -2.8 (M) 10 -2.9 (H) Dilution showing peak enhancement 10 3.5 10 -4 10 -4 10 4 10 -4 Enhancement ratiot 2.4 4.1 3.4 3.3 2.5 * Determined in BHK21 cells (H) or in mice (M). NT, Not tested. ~"Number of foci at peak serum dilution/number of foci in the absence of antibody. h y p o t h e s i s t h a t m a c r o p h a g e s are n o t only c a p a b l e o f s u p p o r t i n g the r e p l i c a t i o n o f r a b i e s virus, b u t m a y give e n h a n c e d yields o f r a b i e s virus in t h e p r e s e n c e o f r a b i e s virus a n t i s e r u m . I f t h i s c a n o c c u r in vitro, it m a y also o c c u r in vivo. T h u s , t h e i n t e r a c t i o n b e t w e e n virus a n d a n t i v i r a l a n t i b o d y d o e s n o t always result in the n e u t r a l i z a t i o n o f viral i n f e c t i v i t y , b u t m a y result in c o n s e q u e n c e s w h i c h are d e t r i m e n t a l to the host. The authors would like to thank Dr G] S. Turner of the Blood Products Laboratories for the gift of antisera used in this work. REFERENCES BLANCOU,J., ANDRAI.,B. & ANDRAI.,L. (1980). A model in mice for the study of the early death phenomenon after vaccination and challenge with rabies virus. Journal of General Virology 50, 433-435. HALSTEAD,S. B. & O'ROURKE,E. J. (1977). Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. Journal of Experimental Medicine 146, 201-217. KOREN, H. S., HANDWERGER, B. S. & WUNDERLICH, J. R. (1975). Identification of macrophage-like characteristics in a cultured murine tumor line. Journal of Immunology 114, 894-897. PEIRIS, J. S. M. & PORTERFIELD, J. S. (1979). Antibody-mediated enhancement of flavivirus replication in macrophage-like cell lines. Nature, London 282, 509-511. PEIRIS, J. S. M. & PORTERFIELD,J. S. (1981). Antibody-dependent enhancement of plaque formation on cell lines of macrophage origin - a sensitive assay for antiviral antibody. Journal of General Virology 57, 119-125. PORTERFIEI.D, J. S. (1981). Antibody-mediated enhancement of rabies virus. Nature, London 290, 542. PRABrIAKAR,B. S. &NATIJANSOt~,N. (1981). Acute rabies death mediated by antibody. Nature, London 290, 590-591. SIKES, R. K., CLEARY, W. F., KOPROWSKI, H., WIKTOR, T. J. & KAPLAN, M. M. (1971). Effective protection of monkeys against death from street rabies by post-exposure administration of tissue culture rabies vaccine. Bulletin of the Worm Health Organization 45, 1-11. SMITH, J. S., YAGER, P. A. & BAER, G. M. (1973). A rapid reproducible test for determining rabies neutralising antibodies. Bulletin of the World Health Organization 48, 535 541. WEISS, R. O. & SCOTT, F. W. (1981). Antibody mediated enhancement of disease in feline infectious peritonitis: comparisons with dengue haemorrhagic fever. Comparative Immunology, Microbiologyand Infectious Diseases 4, 175-189. (Received 5 September 1983) Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Wed, 03 May 2017 22:11:52