Enhancing Antibodies, Macrophages and Virulence in Mouse Cytomegalovirus Infection

Abstract

SUMMARYThe infectivity of tissue culture-passed mouse cytomegalovirus (MCMV) for resident mouse peritoneal macrophages in the presence of serial dilutions of antiviral antibody was studied by fluorescent antibody staining and virus yields. Although MCMV was neutralized by high concentrations of antiserum, there was a twofold enhancement of infectivity by subneutralizing antibody concentrations. On further dilution of antiserum, significant neutralization appeared again. When F(ab')_, fragments of anti-MCMV IgG were used or when macrophages were pretreated with monoclonal antibody to Fc receptor, there was no enhancement, and no neutralization at high dilutions of antiserum. This suggests that both enhancement and high dilution neutralization are mediated via the Fc portion of IgG and Fc receptors of macrophages. Tissue culture-passed virus whose infectivity for macrophages was reduced by high dilutions of antibody was converted to a more infectious state by addition of anti-mouse immunoglobulin. Similar results were obtained with salivary gland virus, which is less infectious for macrophages and is coated with nonneutralizing antibody. Tissue culture-passed virus is known to be less virulent for suckling mice and more infectious for macrophages than salivary gland-passed virus. When tissue culture-passed virus was coated with appropriately diluted antiviral antibody, not only was its infectivity for macrophages reduced, but it also became more virulent than control virus treated with normal mouse serum. These results are interpreted in terms of the optimal density of Fc on the virus-immunoglobulin complex in relation to the density of Fc receptors on macrophages.

Isolation and Preliminary Characterization of Temperature-sensitive Mutants of Mouse Cytomegalovirus of Differing Virulence for 1-week-old Mice

“…Virulence of cell-grown virus was increased on passage from >2.8 x 105 p.f.u./LD50 to 450 p.f.u./LDso after one passage and 310 p.f.u./LD50 after two passages but was still considerably less virulent (10-fold) than SGV (Table 2). It seems likely that a cell-adapted variant has been selected since the cellgrown virus has now been passaged up to 20 times in MEF cultures (Inada et al, 1985). This contrasts with the original studies where cell-grown viruses had been passaged a maximum of five times and is supported by the observation that non-ts PP330/1, passaged up to seven times in tissue culture as the ts mutants were, was fully virulent after one mouse passage (Table 2).…”

“…This may also explain the reduced virulence of the acyclovir-resistant mutants and the avirulence of ts6 (Table 2) which were derived from cell-grown virus (Sandford et al, 1985 ;Sandford & Burns, 1988). Finally, although the presence of antibody does enhance the virulence of cell-grown virus passaged 10 to 20 times, it does not fully restore virulence to that of SGV (Inada et al, 1985;Inada & Mims, 1985). Together these observations clearly suggest that factors in addition to virion-bound non-neutralizing antibody acquired in vivo are involved in MCMV virulence.…”

“…However this approach, like the first, tells us little about virulence determinants, because the virulence of MCMV is lost or regained on a single passage in cultured cells or in salivary glands, presumably owing to phenotypic rather than genetic changes in the virus (Osborn & Walker, 1971 ;Eizura & Minamishima, 1979;Selgrade et al, 1981 ;Jordan & Takagi, 1983). Apparently only SGV is virulent (Jordan & Takagi, 1983) since it becomes coated in a non-neutralizing antibody (Chong et al, 1981 ;Inada et al, 1985;Inada & Mims, 1985) inhibiting neutralization by a neutralizing antibody and inhibiting the susceptibility of (and presumably uptake by) macrophages (Inada & Mires, 1985).…”

Association of Virulence of Murine Cytomegalovirus with Macrophage Susceptibility and with Virion-bound Non-neutralizing Antibody

“…Strains of MCMV, virus assay method, strain of mice, macrophage culture method, preparation of anti-MCMV serum and fluorescent antibody (FA) methods are described in the accompanying paper (Inada et al, 1985).…”

Host Range and Tissue Tropisms: Antibody-Dependent Mechanisms

“…In other families, studies have been limited to relatively few viruses, but ADE has been reported with the following: rabbit pox virus [1], family Poxviridae; rabies virus and fish rhabdoviruses, family Rhabdoviridae [15]; Reovirus type 3, family Reoviridae; murine cytomegalovirus, family Herpesviridae [16]; and feline infectious pancreatitis virus, family Coronaviridae [17]. Failure to detect ADE has been reported with only two viruses, Mengo virus, family Picornaviridae, and herpes simplex virus, family Herpesviridae [4].…”