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
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.
Available from: Joshua J Obar
- "Past work has elegantly demonstrated that persistent high levels of antigen results in dramatic functional changes to CD8+ T cell populations , , but lower levels of persistent infection result in less impairment of the T cell response , , . Specifically, the PD-1 receptor seems to be central in this functional impairment during chronic infections . "
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ABSTRACT: Intracellular pathogens are capable of inducing vigorous CD8+ T cell responses. However, we do not entirely understand the factors driving the generation of large pools of highly protective memory CD8+ T cells. Here, we studied the generation of endogenous ovalbumin-specific memory CD8+ T cells following infection with recombinant vesicular stomatitis virus (VSV) and Listeria monocytogenes (LM). VSV infection resulted in the generation of a large ovalbumin-specific memory CD8+ T cell population, which provided minimal protective immunity that waned with time. In contrast, the CD8+ T cell population of LM-ova provided protective immunity and remained stable with time. Agonistic CD40 stimulation during CD8+ T cell priming in response to VSV infection enabled the resultant memory CD8+ T cell population to provide strong protective immunity against secondary infection. Enhanced protective immunity by agonistic anti-CD40 was dependent on CD70. Agonistic anti-CD40 not only enhanced the size of the resultant memory CD8+ T cell population, but enhanced their polyfunctionality and sensitivity to antigen. Our data suggest that immunomodulation of CD40 signaling may be a key adjuvant to enhance CD8+ T cell response during development of VSV vaccine strategies.
PLoS ONE 08/2014; 9(8):e106060. DOI:10.1371/journal.pone.0106060 · 3.23 Impact Factor
Available from: Cindy C Hagan
- "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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ABSTRACT: Infectious diseases are the most common and cost-intensive health complications associated with drug addiction. There is wide belief that drug-dependent individuals expose themselves more regularly to disease-related pathogens through risky behaviors such as sharing pipes and needles, thereby increasing their risk for contracting an infectious disease. However, evidence is emerging indicating that not only lifestyle but also the immunomodulatory effects of addictive drugs, such as cocaine, may account for their high infection risk. As feelings of disgust are thought to be an important psychological mechanism in avoiding the exposure to pathogens, we sought to investigate behavioral, physiological, and immune responses to disgust-evoking cues in both cocaine-dependent and healthy men.
All participants (N = 61) were exposed to neutral and disgust-evoking photographs depicting food and nonfood images while response accuracy, latency, and skin conductivity were recorded. Saliva samples were collected before and after exposure to neutral and disgusting images, respectively. Attitudes toward disgust and hygiene behaviors were assessed using questionnaire measures.
Response times to disgust-evoking photographs were prolonged in all participants, and specifically in cocaine-dependent individuals. While viewing the disgusting images, cocaine-dependent individuals exhibited aberrant skin conductivity and increased the secretion of the salivary cytokine interleukin-6 relative to control participants.
Our data provide evidence of a hypersensitivity to disgusting stimuli in cocaine-dependent individuals, possibly reflecting conditioned responses to noningestive sources of infection. Coupled with a lack of interoception of bodily signals, aberrant disgust responses might lead to increased infection susceptibility in affected individuals.
Biological psychiatry 09/2013; 75(2). DOI:10.1016/j.biopsych.2013.08.004 · 10.26 Impact Factor
Available from: Juan Jovel
- "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.
Virology 08/2011; 419(1):43-53. DOI:10.1016/j.virol.2011.08.002 · 3.32 Impact Factor
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