CD4⁺T Cells and Gamma Interferon in the Long-Term Control of Persistent Friend Retrovirus Infection

Abstract

We have used the Friend virus model to determine the basic mechanisms by which the immune system can control persistent retroviral infections. Previously we showed that CD4 ؉ T cells play an essential role in keeping persistent retrovirus in check. The present in vitro experiments with a Friend virus-specific CD4 ؉ T-cell clone revealed that these cells produce gamma interferon (IFN-␥), which acts with two distinct mechanisms of antiviral activity. First, IFN-␥ had a direct inhibitory effect on virus production. This inhibitory effect was noncytolytic and, interestingly, was not associated with decreased cell surface expression of viral antigens. The second mechanism of IFN-␥-mediated antiviral activity was an enhancement of CD4 ؉ T-cell-mediated cytolytic activity. We also found an in vivo role for IFN-␥ in the control of persistent Friend virus infections. Neutralization of IFN-␥ in persistently infected mice resulted in significantly increased levels of virus in the spleen, and a significant percentage of IFN-␥-deficient mice were unable to maintain long-term control over Friend virus infections.The most serious problems caused by many retroviruses often result from the effects of persistent infection rather than the initial acute phases of infection. For example, the acute phase of infection with human immunodeficiency virus (HIV) is generally resolved relatively quickly, but the virus persists and after several years results in diminished CD4ϩ T-cell levels, loss of immune functions, and the onset of AIDS. As a model for studying persistent retrovirus infections, we have used Friend virus complex (FV) in strains of mice which generally recover from acute disease but develop lifelong, lowlevel persistent infections (6, 28). Many types of cells including erythroid precursors, monocytes, and lymphocytes are initially infected with FV during the acute phase of disease (28). Recovery from the acute phase is dependent on genes of the major histocompatibility complex (MHC) and complex immune responses including cytotoxic T-lymphocyte (CTL), CD4 ϩ T-helper, and antibody responses (reviewed in references 30 and 31). Following recovery from FV-induced splenomegaly and viremia, the infection in the spleen is reduced by over 1,000-fold and appears to be primarily restricted to a very small population of B cells (28).Most persistently infected mice live a normal life span, although for unknown reasons, approximately 5% of the mice eventually relapse with FV-induced erythroleukemia (6). Unlike HIV, FV infection does not deplete CD4 ϩ T-cell levels, but if mice with persistent FV are experimentally depleted of their CD4ϩ T cells, a large percentage of the mice relapse with acute disease and develop erythroleukemia (28). Thus, CD4 ϩ T cells play a critical role in containing persistent FV infections. In contrast, depletion of CD8 ϩ T cells does not induce relapse or increased levels of persistent virus, nor is there an additive effect from dual depletion of both CD4 ϩ and CD8 ϩ T cells (28). Furthermore, CD4 depletions do ...

Multiple Effector Functions Mediated by Human Immunodeficiency Virus-Specific CD4+T-Cell Clones

“…ϩ T-cell clones were shown to possess cytolytic activity and to inhibit the production of virus in vitro (19). The clones that we isolated secreted IFN-␥ and possessed cytolytic activity on specific stimulation, consistent with the Th1-type clones identified in murine studies.…”

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

“…Like the endogenous population of tetramer-positive CD8 ϩ T cells, adoptively transferred CD8 ϩ T cells that were suppressed before anti-CD137 therapy also up-regulated granzyme B. However, neither type of cell developed high IFN-␥ production as a result of anti-CD137 therapy, a cytokine known to be important in control of chronic FV infections (52,53). Although there was a slight but significant reduction in chronic virus levels in anti-CD137-treated mice without T cell transfers at the 2-wk time point ( p ϭ 0.0389), by 4 wk virus levels were back to normal (data not shown).…”

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

“…Recent studies in the Friend virus (FV) model of retroviral infection in mice have shown an association between T-cell production of IFN-␥ in vitro and recovery from acute infection in vivo (45). In addition, IFN-␥ has been shown to play an important role in controlling persistent FV infection (30). However, we still do not understand the role of IFN-␥ in virus spread and pathogenesis during the course of FV infection.…”