Immune responses against persistent viral infections: possible avenues for immunotherapeutic interventions.
ABSTRACT 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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- "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. "
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.Virology 08/2011; 419(1):43-53. DOI:10.1016/j.virol.2011.08.002 · 3.28 Impact Factor
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ABSTRACT: Active vaccination strategies using viral vectors often give disappointing protection from tumor development, and usually require multiple immunizations. These approaches normally use viruses that cause acute infections, as they provoke potent CD8 T cell responses. Persistent virus vectors have not been used in this setting due to the perception that exhaustion of the T cell response occurs and would lead to poor anti-tumor protection. However, such exhaustion generally only occurs in high-load virus infections, whereas T cell function is intact in lower-load persistent infections. In fact, CD8 T cell responses in these infections, which are adapted for long-term immune surveillance, have properties that may make them more desirable for long-term anti-tumor immunity. In this report, we show that a persistent gammaherpesvirus vector provides superior protection against melanoma, relative to a non-persistent mutant of the same virus. These data suggest that vaccine vectors derived from persistent viruses may perform better than those from acute viruses at mediating anti-tumor protection.Cancer Immunology and Immunotherapy 11/2009; 59(5):707-13. DOI:10.1007/s00262-009-0790-8 · 3.94 Impact Factor
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ABSTRACT: Persistent levels of IL-10 play a central role in progressive immune dysfunction associated with chronic viral infections such as HIV, but the underlying mechanisms are poorly understood. Because IL-10 affects the phenotypic and functional properties of DCs, which are responsible for initiating adaptive immune responses, we investigated whether IL-10 induces changes in DC phenotype and function in the context of HIV infection. Here, we show that IL-10 treatment of immature and mature human DCs in culture induced contrasting phenotypic changes in these populations: immature DCs exhibited aberrant resistance to NK cell-mediated elimination, whereas mature DCs exhibited increased susceptibility to NKG2D-dependent NK elimination. Treatment of immature and mature DCs with HIV resulted in potent IL-10 secretion and the same phenotypic and functional changes observed in the IL-10-treated cells. Consistent with these in vitro data, LNs isolated from individuals infected with HIV exhibited aberrant accumulation of a partially "immature" DC population. Together, these data suggest that the progressive immune dysfunction observed in chronic viral infections might be caused in part by IL-10-induced reversal of DC susceptibility to NK cell-mediated elimination, resulting in the accumulation of poorly immunogenic DCs in LNs, the sites of adaptive immune response induction.The Journal of clinical investigation 06/2010; 120(6):1905-13. DOI:10.1172/JCI40913 · 13.77 Impact Factor