Immune Responses Against Persistent Viral Infections: Possible Avenues for Immunotherapeutic Interventions

Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Critical Reviews in Immunology (Impact Factor: 3.7). 02/2008; 28(2):159-83. DOI: 10.1615/CritRevImmunol.v28.i2.40
Source: PubMed


Persistent viral infections present a significant threat to society, and treatment options for infected individuals are in urgent demand. During viral persistence, the balance between the virus and the host immune response is crucial. The immune system keeps the virus in check, and the virus counters by evading the immune response to avoid clearance, ultimately tipping the balance in favor of the virus and causing disease in many cases. Thus, efforts to tip the balance in favor of the host through immunotherapy holds promise for establishing control of viral replication. However, in most persistent viral infections, the continuous presence of the viral antigen renders virus-specific T cells to become dysfunctional. These differences can range from severe functional impairments in high-load persistent infections, to more subtle changes in infections with a lower virus burden. Recent work has shed light on immunoregulatory molecules or cytokines that affect viral persistence and/or T-cell function, and interventions that modulate these factors have led to effective viral control in experimental models. Exploitation of these experimental therapies may lead to treatments that would be of great clinical benefit to patients suffering from persistent virus infections, such as HIV, HBV, or HCV, or the herpesviruses CMV and EBV.

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    • "Past work has elegantly demonstrated that persistent high levels of antigen results in dramatic functional changes to CD8+ T cell populations [20], [40], but lower levels of persistent infection result in less impairment of the T cell response [41], [42], [43]. Specifically, the PD-1 receptor seems to be central in this functional impairment during chronic infections [44]. "
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    PLoS ONE 08/2014; 9(8):e106060. DOI:10.1371/journal.pone.0106060 · 3.23 Impact Factor
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    • "Biological samples and fitness assessments were taken on arrival to establish health status. Urine samples were tested for current infection with cytomegalovirus (CMV) and Epstein-Barr virus, persistent viruses that affect the immune system (46). Blood samples were drawn to measure serum levels of C-reactive protein (CRP) as a marker of inflammation (47). "
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    • "During evolution, metazoans have acquired a multitude of defense mechanisms that protect them against deleterious effects from pathogenic viruses. In spite of this, a number of viruses infecting diverse organisms are able to resist these defenses and establish persistent infections (Britt, 2008; Dasgupta et al., 1994; Fuse et al., 2008; Kuno, 2001; Oldstone, 2006). The molecular mechanisms underlying establishment of persistent infections remain incompletely understood, but they are likely based on an equilibrium between host defense responses and the counter-responses by the virus. "
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    ABSTRACT: Little is known about the molecular determinants causing and sustaining viral persistent infections at the cellular level. We found that Drosophila cells persistently infected (PI) with Flock House virus (FHV) invariably harbor defective viral RNAs, which are replicated by the FHV RNA-dependent RNA polymerase. Some defective RNAs encoded a functional B2 protein, the FHV suppressor of RNA interference, which might contribute to maintenance of virus persistence. Viral small interfering RNAs (vsiRNAs) of both polarities were detected in PI cells and primarily mapped to regions of the viral genome that were preserved in the isolated defective RNAs. This indicated that defective RNAs could represent major sources of vsiRNAs. Immunofluorescence analysis revealed that mitochondria and viral proteins are differentially distributed in PI cells and lytically infected cells, which may partly explain the reduction in infectious viral progeny. Our results provide a basis for further investigations of the molecular mechanisms underlying persistent infections.
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