Replication of Beta- and Gammaretroviruses Is Restricted in I/LnJ Mice via the Same Genetic Mechanism

Abstract

Mice of the I/LnJ inbred strain are unique in their ability to mount a robust and sustained humoral immune response capable of neutralizing infection with a betaretrovirus, mouse mammary tumor virus (MMTV). Virus-neutralizing antibodies (Abs) coat MMTV virions secreted by infected cells, preventing virus spread and hence the formation of mammary tumors. To investigate whether I/LnJ mice resist infection with other retroviruses besides MMTV, the animals were infected with murine leukemia virus (MuLV), a gammaretrovirus. MuLV-infected I/LnJ mice produced virus-neutralizing Abs that block virus transmission and virally induced disease. Generation of virus-neutralizing Abs required gamma interferon but was independent of interleukin-12. This unique mechanism of retrovirus resistance is governed by a single recessive gene, virus infectivity controller 1 (vic1), mapped to chromosome 17. In addition to controlling the antivirus humoral immune response, vic1 is also required for an antiviral cytotoxic response. Both types of responses were maintained in mice of the susceptible genetic background but congenic for the I/LnJ vic1 locus. Although the vic1-mediated resistance to MuLV resembles the mechanism of retroviral recovery controlled by the resistance to Friend virus 3 (rfv3) gene, the rfv3 gene has been mapped to chromosome 15 and confers resistance to MuLV but not to MMTV. Thus, we have identified a unique virus resistance mechanism that controls immunity against two distinct retroviruses.

Expression of Murine APOBEC3 Alleles in Different Mouse Strains and Their Effect on Mouse Mammary Tumor Virus Infection

“…Mouse strains like C57BL/6 that lack the MHC class II I-E gene are relatively resistant to infection by most MMTVs because of poor Sag presentation (4,32); an exception to this is MMTV(RIII) (used in the current study), which is infectious in C57BL/6 mice and both activates Sag-cognate T cells (presumably through MHC class II I-A) and causes tumors (42). Other mechanisms of resistance to lymphocyte infection and virus spread include a hyperimmune antibody response that occurs in I/LnJ mice and increased viral clearance by T cells in YBr/Ei mice (8,9,33). The lymphoid tissues of mice lacking endogenous copies of the MMTV provirus are also resistant to MMTV infection, although the mechanism for this resistance is not known (5,6).…”

Vital Role for CD8 + Cells in Controlling Retroviral Infections

“…To detect anti-MMTV and anti-MuLV Abs in mouse sera, an ELISA was performed as previously described (9,47). Briefly, virions were treated with 0.1% Triton X-100 and bound to plastic in borate-buffered saline (pH 8.0) overnight.…”

“…ϩ T cells, produce antivirus neutralizing Abs and eliminate the virus in a single generation (9). In contrast, MuLV-infected ␤ 2 M Ϫ/Ϫ I/LnJ mice failed to control the infection and developed splenomegaly, even though they produced anti-MuLV Abs (9).…”

“…Susceptible animals develop splenomegaly and succumb to leukemia (50). Like MMTV-infected I/LnJ mice, MuLV-infected I/LnJ mice become virus infected but restrain the virus via the same immune mechanism and thus resist virally induced disease (9).…”

“…Our laboratory has previously reported a unique retroviral resistance mechanism in I/LnJ mice. These mice mount a prolonged neutralizing immune response against both mouse mammary tumor virus (MMTV) and murine leukemia virus (MuLV) that blocks viral transmission and virally induced disease (9,10,18,47).…”