Retroviruses cause lethal diseases in humans by defeating host immune responses. While studies of inherited resistance to retroviruses in human populations are enormously difficult, the variations in the susceptibility of inbred mice to retroviral infections make the mouse an excellent model for mapping mammalian susceptibility/resistance genes. Mouse Mammary Tumor Virus (MMTV) and Murine Leukemia Virus (MuLV) are retroviruses that are not efficiently eliminated by the immune system of susceptible mouse strains. In contrast, 1/LnJ mice infected with either virus are capable of producing lgG2a virus-neutralizing antibodies, sustain this response throughout their life, and prevent infection of the progeny by coating secreted virions with anti-virus antibodies. Although an initial polyisotypic anti-virus immune response was observed in susceptible mice it was short-lived and did not class switch to the lgG2a specific response as it did in resistant ILn/J mice. We established that antibody-mediated interference with viral entry into host cells is the sole factor inhibiting virus replication in 1/LnJ mice. Further investigation revealed that IFN-y-producing CD4+ T cells were absolutely indispensable for the virus resistance in 1/LnJ mice. IFN-y signaling induces a number of immune response-related genes which play a vital role in eradication of pathogens. However, it also stimulates expression of its own inhibitor, suppressor of cytokine signaling 1 (SOCS1). We found that cells from susceptible mice produced high levels of IFN-yand up-regulated SOCS1 expression in response to retroviruses. In drastic contrast, resistant l/LnJ mice produced significantly less virally-elicited IFN-y resulting in a weak up-regulation of SOCS1 expression that was insufficient to suppress the IFN-y signaling. We hypothesize that low, but persistent production of IFN-y, that is uninhibited by a negative regulatory mechanism, results in a steady anti-retroviral immune response in 1/LnJ mice. A genetic approach allowed us to establish that anti-virus immunity in l/LnJ mice is influenced by two recessive genes (virus infectivity controller 1 or vid) and vic2 mapped to Chromosome 17 and 15, respectively. Unlike l/LnJ mice, susceptible C3H/HeN mice inherit the dominant allele of the vie genes, which do not allow an anti-virus immune response. We hypothesize that the vie genes monitor the levels of I FN-y production in response to retroviruses and subsequently control anti-virus immunity. The elucidation of the mechanism of resistance in l/LnJ mice is of fundamental importance and will ultimately lead to increased knowledge about variations in susceptibility to viral infections in humans and to development of the most effective vaccines against human viruses, and other diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA089116-06S1
Application #
7495822
Study Section
Virology Study Section (VR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2001-06-01
Project End
2008-05-31
Budget Start
2007-08-01
Budget End
2008-05-31
Support Year
6
Fiscal Year
2007
Total Cost
$36,820
Indirect Cost
Name
University of Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Kane, Melissa; Case, Laure K; Golovkina, Tatyana V (2011) Vital role for CD8+ cells in controlling retroviral infections. J Virol 85:3415-23
Case, Laure K; Petell, Lydia; Yurkovetskiy, Leonid et al. (2008) Replication of beta- and gammaretroviruses is restricted in I/LnJ mice via the same genetic mechanism. J Virol 82:1438-47
Case, Laure K; Purdy, Alexandra; Golovkina, Tatyana V (2005) Molecular and cellular basis of the retrovirus resistance in I/LnJ mice. J Immunol 175:7543-9
Pobezinskaya, Yelena; Chervonsky, Alexander V; Golovkina, Tatyana V (2004) Initial stages of mammary tumor virus infection are superantigen independent. J Immunol 172:5582-7
Purdy, Alexandra; Case, Laure; Duvall, Melody et al. (2003) Unique resistance of I/LnJ mice to a retrovirus is due to sustained interferon gamma-dependent production of virus-neutralizing antibodies. J Exp Med 197:233-43