Temporal Effects of Gamma Interferon Deficiency on the Course of Friend Retrovirus Infection in Mice

Self Cite

Chronic viral infections cause high levels of morbidity and mortality worldwide, making the development of effective therapies a high priority for improving human health. We have used mice infected with Friend virus as a model to study immunotherapeutic approaches to the cure of chronic retroviral infections. In chronic Friend virus infections CD4+ T regulatory (Treg) cells suppress CD8+ T cell effector functions critical for virus clearance. In this study, we demonstrate that immunotherapy with a combination of agonistic anti-CD137 Ab and virus-specific, TCR-transgenic CD8+ T cells produced greater than 99% reductions of virus levels within 2 wk. In vitro studies indicated that the CD137-specific Ab rendered the CD8+ T cells resistant to Treg cell-mediated suppression with no direct effect on the suppressive function of the Treg cells. By 2 weeks after transfer, the adoptively transferred CD8+ T cells were lost, likely due to activation-induced cell death. The highly focused immunological pressure placed on the virus by the single specificity CD8+ T cells led to the appearance of escape variants, indicating that broader epitope specificity will be required for long-term virus control. However, the results demonstrate a potent strategy to potentiate the function of CD8+ T cells in the context of immunosuppressive Treg cells.

Section: Discussionmentioning

confidence: 99%

CD137 Costimulation of CD8+ T Cells Confers Resistance to Suppression by Virus-Induced Regulatory T Cells

Robertson

Messer

Carmody

et al. 2008

Self Cite

“…Second, IFN-␥-deficient I/LnJ mice are susceptible to MMTV infection, remain infected throughout their lifetimes, and do not produce anti-virus Abs of any isotype (16). On the contrary, MuLV-infected IFN-␥-deficient B6 mice make antivirus-neutralizing Abs of the IgM isotype and demonstrate a temporal recovery from infection (45). B6 and B10 mice are resistant to MMTV because of the nonpermissive MHC haplotype (47).…”

Section: Discussionmentioning

confidence: 99%

Molecular and Cellular Basis of the Retrovirus Resistance in I/LnJ Mice

Case

Purdy

Golovkina

2005

Previously, we showed that IFN-γ elicited by mouse mammary tumor virus (MMTV) infection in I/LnJ mice stimulated production of virus-neutralizing Abs, mostly of the IgG2a isotype. These Abs coated virions secreted by infected I/LnJ cells, and thus completely prevented virus transmission to offspring. However, the mechanism of virus neutralization by isotype-specific Abs remained unknown. Ab coating is capable of blocking virus infection by interfering with receptor-virus binding, by virus opsonization, by complement activation, and via FcγR-mediated effector mechanisms. The aim of the studies described in this work was to uncover the cellular basis of anti-virus Ab production, to evaluate the importance of the IgG2a subclass of IgGs in virus neutralization, and to investigate which of the blocking mechanisms plays a role in virus neutralization. We showed that I/LnJ-derived bone marrow cells, specifically IFN-γ-producing CD4+ T cells, were key cells conferring resistance to MMTV infection in susceptible mice upon transfer. We also established that a unique bias in the subclass selection toward the IgG2a isotype in infected I/LnJ mice was not due to their potent neutralizing ability, as anti-virus Abs of other isotypes were also able to neutralize the virus, but were a product of virally induced IFN-γ. Finally, we demonstrated that F(ab′)2 of anti-MMTV IgGs neutralized the virus as efficiently as total IgGs, suggesting that Ab-mediated interference with viral entry is the sole factor inhibiting virus replication in I/LnJ mice. We propose and discuss possible mechanisms by which infected I/LnJ mice eradicate retrovirus.

“…Real-time PCR (RT-PCR) analysis to quantify FV infection levels of cells was performed as described previously (51). RT-PCR for detection of OAS1a and PKR mRNA was performed using Qiagen One Step RT-PCR kit and Qiagen Quanti Tect Primer assay for OAS1a and PKR.…”

Section: Real-time-pcrmentioning

confidence: 99%

Polyinosinic-Polycytidylic Acid Treatment of Friend Retrovirus-Infected Mice Improves Functional Properties of Virus-Specific T Cells and Prevents Virus-Induced Disease

Gibbert

Dietze

Zelinskyy

et al. 2010

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The induction of type I IFN is the most immediate host response to viral infections. Type I IFN has a direct antiviral activity mediated by antiviral enzymes, but it also modulates the function of cells of the adaptive immune system. Many viruses can suppress type I IFN production, and in retroviral infections, the initial type I IFN is weak. Thus, one strategy of immunotherapy in viral infection is the exogenous induction of type I IFN during acute viral infection by TLR ligands. Along these lines, the TLR3/MDA5 ligand polyinosinic-polycytidylic acid [poly(I:C)] has already been used to treat viral infections. However, the immunological mechanisms underlying this successful therapy have not been defined until now. In this study, the Friend retrovirus (FV) mouse model was used to investigate the mode of action of poly(I:C) in antiretroviral immunotherapy. Postexposure, poly(I:C) treatment of FV-infected mice resulted in a significant reduction in viral loads and protection from virus-induced leukemia. This effect was IFN dependent because type I IFN receptor-deficient mice could not be protected by poly(I:C). The poly(I:C)-induced IFN response resulted in the expression of antiviral enzymes, which suppressed FV replication. Also, the virus-specific T cell response was augmented. Interestingly, it did not enhance the number of virus-specific CD4+ and CD8+ T cells, but rather the functional properties of these cells, such as cytokine production and cytotoxic activity. The results demonstrate a direct antiviral and immunomodulatory effect of poly(I:C) and, therefore, suggests its potential for clinical treatment of retroviral infections.