[Show abstract][Hide abstract] ABSTRACT: When a virus infects a host, a complex immune response develops to eliminate the invading pathogen. Viruses, in turn, have evolved a profusion of strategies to escape from the immune system. Mechanisms of viral evasion can be separated into those that occur at the cellular level and those that are important at the systemic level. Viruses can avoid detection by both innate and adaptive immune responses. Pattern recognition receptors in infected cells, interferons, dendritic cells, T cell receptors and antibodies are all targets of viral evasion proteins. Viruses can express proteins that directly interfere with host processes or mimic host proteins and compete to bind specific receptors. Pathogens are also able to directly deplete immune cells, and prevent their recruitment to the site of infection. In a state of latency, viruses remain dormant and undetectable in host cells. The diversity of these mechanisms has allowed us to dissect the immune system further and understand how viruses persist despite such a strong counterattack by the immune system. Key Concepts: Viruses have evolved a plethora of mechanisms to inhibit every step of the innate and adaptive immune responses.Viruses avoid detection by pattern recognition receptors, T cell receptors and antibodies by modifying the ligands for these receptors.Different viruses target every stage of antigen processing and presentation by MHC molecules, thus inhibiting recognition by T cells.Interferons, cytokines and chemokines are mimicked or blocked by viral proteins to prevent the efficient development of an immune response.Through repression of their replication, viruses are able to enter latency and remain dormant inside the cell, remaining undetectable.Keywords:virus;immune evasion;escape;antigen presentation;cellular response MHC;immune response;antibodies;latency;interferons
[Show abstract][Hide abstract] ABSTRACT: PARV4 is a small DNA human virus that is strongly associated with hepatitis C virus (HCV) and HIV infections. The immunologic control of acute PARV4 infection has not been previously described. We define acute onset of PARV4 infection and the characteristics of the acute and memory immune response to PARV4 in a group of HCV-HIV-negative, active intravenous drug users. 98 individuals at risk of blood borne infections were tested for PARV4 IgG. IFN-γ ELISpots, intracellular cytokine staining and a tetrameric HLA-A2-peptide complex were used to define the T cell populations responding to PARV4 peptides in those individuals who acquired infection during the study. 35 individuals were found to be PARV4 seropositive at the end of the study, 8 of whom were found to be seronegative at a baseline sample. Persistent and functional T cell responses were detected in acute infection. These responses had an active, mature, and cytotoxic phenotype and were maintained several years after infection. Thus, PARV4 infection is common in individuals exposed to blood borne infections, independent of their HCV or HIV status. Since PARV4 elicits strong, broad and persistent T cell responses, understanding the processes responsible may prove useful for future vaccine design.
Journal of Virology 01/2013; 87(6). DOI:10.1128/JVI.02793-12 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus infection is a major cause of chronic liver disease. CD4(+) T cells play a key role in disease outcome. However, the critical functions and associated phenotypes of intrahepatic CD4(+) T cells are not well defined. We have previously shown that CD8(+) T cells expressing the C type lectin CD161 are highly enriched in the human liver, especially during chronic hepatitis. These cells are associated with a type 17 differentiation pattern and express cytokines including IL-17A, IL-22, and IFN-γ. We therefore analyzed expression of CD161 on CD4(+) T cells in blood and liver and addressed the relevant phenotype and functional capacity of these populations. We observed marked enrichment of CD161(+)CD4(+) T cells in the liver during chronic hepatitis such that they are the dominant subtype (mean 55% of CD4(+) T cells). IL-22 and IL-17 secreting CD4(+) T cells were readily found in the livers of HCV(+) and NASH donors, although not enriched compared to blood. There was, however, specific enrichment of a novel subset of IL-22/IFN-γ dual secretors (p = 0.02) compared to blood, a result reconfirmed with direct ex vivo analyses. These data indicate the dominance of CD161(+) expressing lymphocyte populations within the hepatic infiltrate, associated with a distinct cytokine profile. Given their documented roles as antiviral and hepatoprotective cytokines respectively, the impact of co-secretion of IFN-γ and IL-22 in the liver may be particularly significant.
Frontiers in Immunology 11/2012; 3:346. DOI:10.3389/fimmu.2012.00346
[Show abstract][Hide abstract] ABSTRACT: Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and HCV-infected individuals (n = 469) and the correlations with disease status. We found that PARV4 infection frequently occurred in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms, although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet clear.
The Journal of Infectious Diseases 04/2012; 205(12):1816-20. DOI:10.1093/infdis/jis291 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Parvovirus 4 (PARV4) is a recently identified human virus that has been found in livers of patients infected with hepatitis C virus (HCV) and in bone marrow of individuals infected with human immunodeficiency virus (HIV). T cells are important in controlling viruses but may also contribute to disease pathogenesis. The interaction of PARV4 with the cellular immune system has not been described. Consequently, we investigated whether T cell responses to PARV4 could be detected in individuals exposed to blood-borne viruses.
Interferon γ (IFN-γ) enzyme-linked immunospot assay, intracellular cytokine staining, and a tetrameric HLA-A*0201-peptide complex were used to define the lymphocyte populations responding to PARV4 NS peptides in 88 HCV-positive and 13 HIV-positive individuals. Antibody responses were tested using a recently developed PARV4 enzyme-linked immunosorbent assay.
High-frequency T cell responses against multiple PARV4 NS peptides and antibodies were observed in 26% of individuals. Typical responses to the NS pools were >1000 spot-forming units per million peripheral blood mononuclear cells.
PARV4 infection is common in individuals exposed to blood-borne viruses and elicits strong T cell responses, a feature typically associated with persistent, contained infections such as cytomegalovirus. Persistence of PARV4 viral antigen in tissue in HCV-positive and HIV-positive individuals and/or the associated activated antiviral T cell response may contribute to disease pathogenesis.
The Journal of Infectious Diseases 05/2011; 203(10):1378-87. DOI:10.1093/infdis/jir036 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CD8 T cells are central to the control of hepatitis C virus (HCV) although the key features of a successful CD8 T cell response remain to be defined. In a cohort of Irish women infected by a single source, a strong association between viral clearance and the human lecucocyte (HLA)-A*03 allele has been described, and the aim of this study was to define the protective nature of the associated CD8 T cell response.
A sequence-led approach was used to identify HLA-A*03-restricted epitopes. We examine the CD8 T cell response associated with this gene and address the likely mechanism underpinning this protective effect in this special cohort, using viral sequencing, T cell assays and analysis of fitness of viral mutants.
A strong 'HLA footprint' in a novel NS3 epitope (TVYHGAGTK) was observed. A lysine (K) to arginine (R) substitution at position 9 (K1088R) was seen in a significant number of A*03-positive patients (9/12) compared with the control group (1/33, p=0.0003). Threonine (T) was also substituted with alanine (A) at position 8 (T1087A) more frequently in A*03-positive patients (6/12) compared with controls (2/33, p=0.01), and the double substitution of TK to AR was also observed predominantly in HLA-A*03-positive patients (p=0.004). Epitope-specific CD8 T cell responses were observed in 60% of patients three decades after exposure and the mutants selected in vivo impacted on recognition in vitro. Using HCV replicons matched to the viral sequences, viral fitness was found to be markedly reduced by the K1088R substitution but restored by the second substitution T1087A.
It is proposed that at least part of the protective effect of HLA-A*03 results from targeting of this key epitope in a functional site: the requirement for two mutations to balance fitness and escape provides an initial host advantage. This study highlights the potential protective impact of common HLA-A alleles against persistent viruses, with important implications for HCV vaccine studies.
Gut 05/2011; 60(11):1563-71. DOI:10.1136/gut.2010.228403 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PARV4 is a human parvovirus that was first detected in and cloned from an individual with a human immunodeficiency virus (HIV) seroconversion-like illness and that subsequently persisted in the lymphoid tissue and bone marrow. In contrast to human parvovirus B19 infections, PARV4 infections are most frequently detected in injection drug users (IDUs), particularly those who are coinfected with HIV type 1 (HIV-1). To investigate the routes of transmission of PARV4 and to ascertain whether infections are acquired through plasma-derived blood products, we developed a novel anti-PARV4 enzyme-linked immunosorbent assay (ELISA) to determine its seroprevalence in subjects with parenteral exposure.
PARV4 viral protein 2 (VP2) was expressed and used as antigen in an indirect ELISA, to detect anti-PARV4 immunoglobulin G.
All 50 adult control subjects who were nonparenterally exposed to PARV4 were anti-PARV4 negative, in contrast to HIV-infected and HIV-uninfected IDUs, who had antibody frequencies of 67% and 33%, respectively. Predominantly parenteral transmission was confirmed by the finding of similar frequencies of infection among HIV-coinfected and HIV-uninfected hemophiliacs (11 of 20 individuals and 4 of 15 individuals, respectively) who were treated with nonvirally inactivated factor VIII/factor IX, whereas all but 1 of the 35 nonhemophiliac siblings of these siblings were found to be seronegative (despite having close household contact).
The present study provides convincing evidence that PARV4 is primarily transmitted parenterally. Evidence for widespread infection of hemophiliacs treated with nonvirally inactivated clotting factor creates fresh safety concerns for plasma-derived blood products, particularly because parvoviruses are relatively resistant to virus inactivation.
The Journal of Infectious Diseases 09/2009; 200(7):1119-25. DOI:10.1086/605646 · 6.00 Impact Factor