Immunological determinants of the outcomes from primary hepatitis C infection

Individuals infected with hepatitis C virus (HCV) have two possible outcomes of infection, clearance or persistent infection, determined by a complex set of virus-host interactions. The focus of this review is the host mechanisms that facilitate clearance. Strong evidence points to characteristics of the cellular immune response as the key determinants of outcome, with evidence for the coordinated effects of the timing, magnitude, and breadth, as well as the intra-hepatic localisation of CD4+ and CD8+ T cell responses being critical. The recent discovery of viral evasion strategies targeting innate immunity suggests that interferon-stimulated gene products are also important. A growing body of evidence has implicated polymorphisms in both innate and adaptive immune response genes as determinants of viral clearance in individuals with acute HCV. Received 16 May 2008; received after revision 07 September 2008; accepted 30 September 2008     

Entry of herpesviruses into mammalian cells

The mechanism that herpesviruses use to enter cells is one of the most complex viral entry mechanisms studied so far. This complexity seems to mount as new participants, both cellular receptors and viral glycoproteins, are identified. Recent structural work on entry glycoproteins gD and gB from herpes simplex virus (HSV) 1 has illuminated the functional roles of these glycoproteins in the process of entry. In doing so, it provided information on the mechanism of two critical steps of HSV entry: receptor-mediated activation and membrane fusion. Remarkably, it is becoming clear that herpesviruses have a lot in common with other, simpler viruses.     

Specific interactions of the adenovirus proteinase with the viral DNA,an 11-amino-acid viral peptide,and the cellular protein actin

The adenovirus proteinase (AVP) is synthesized in an inactive form that requires cofactors for activation. The interaction of AVP with two viral cofactors and with a cellular cofactor, actin, is characterized by quantitative analyses. The results are consistent with a specific model for the regulation of AVP. Late in adenovirus infection, inside nascent virions, AVP becomes partially activated by binding to the viral DNA, allowing it to cleave out an 11-amino-acid viral peptide, pVIc, that binds to AVP and fully activates it. Then, about 70 AVP-pVIc complexes move along the viral DNA, via one-dimensional diffusion, cleaving virion precursor proteins 3200 times to render a virus particle infectious. Late in adenovirus infection, in the cytoplasm, the cytoskeleton is destroyed. The amino acid sequence of the C terminus of actin is homologous to that of pVIc, and actin, like pVIc, can act as a cofactor for AVP in the cleavage of cytokeratin 18 and of actin itself. Thus, AVP may also play a role in cell lysis.Received 14 November 2002; received after revision 28 April 2003; accepted 30 April 2003     

Impact of T cell selection methods in the success of clinical adoptive immunotherapy

Chemotherapy and/or radiotherapy regular regimens used for conditioning of recipients of hematopoietic stem cell transplantation (SCT) induce a period of transient profound immunosuppression. The onset of a competent immunological response, such as the appearance of viral-specific T cells, is associated with a lower incidence of viral infections after haematopoietic transplantation. The rapid development of immunodominant peptide virus screening together with advances in the design of genetic and non-genetic viral- and tumoural-specific cellular selection strategies have opened new strategies for cellular immunotherapy in oncologic recipients who are highly sensitive to viral infections. However, the rapid development of cellular immunotherapy in SCT has disclosed the role of the T cell selection method in the modulation of functional cell activity and of in vivo secondary effects triggered following immunotherapy.     

The implications of viral reservoirs on the elite control of HIV-1 infection

The mechanisms by which a small percentage of HIV-1 infected individuals known as elite suppressors or controllers are able to control viral replication are not fully understood. Early cases of viremic control were attributed to infection with defective virus, but subsequent work has demonstrated that infection with a defective virus is not the exclusive cause of control. Replication-competent virus has been isolated from patients who control viral replication, and studies have demonstrated that evolution occurs in plasma virus but not in virus isolates from the latent reservoir. Additionally, transmission pair studies have demonstrated that patients infected with similar viruses can have dramatically different outcomes of infection. An increased understanding of the viral factors associated with control is important to understand the interplay between viral replication and host control, and has implications for the design of an effective therapeutic vaccine that can lead to a functional cure of HIV-1 infection.     

Change in the envelope of a murine retrovirus produced in the presence of toyocamycin]

Toyocamycin (TMC), an adenosine analog, impairs qualitatively and quantitatively virus production in a cellular system chronically infected by Friend Virus. Viral particles released by cell cultures treated with 0.2 microgram/ml of the drug have lost most of their glycoprotein (gp 70) content. This phenomenon is likely to modify the viral envelope and could explain the loss of infectivity of the virus.     

Activation of GCN2 upon HIV-1 infection and inhibition of translation

Higher eukaryotic organisms have a variety of specific and nonspecific defense mechanisms against viral invaders. In animal cells, viral replication may be limited through the decrease in translation. Some viruses, however, have evolved mechanisms that counteract the response of the host. We report that infection by HIV-1 triggers acute decrease in translation. The human protein kinase GCN2 (eIF2AK4) is activated by phosphorylation upon HIV-1 infection in the hours following infection. Thus, infection by HIV-1 constitutes a stress that leads to the activation of GCN2 with a resulting decrease in protein synthesis. We have shown that GCN2 interacts with HIV-1 integrase (IN). Transfection of IN in amino acid-starved cells, where GCN2 is activated, increases the protein synthesis level. These results point to an as yet unknown role of GCN2 as an early mediator in the cellular response to HIV-1 infection, and suggest that the virus is able to overcome the involvement of GCN2 in the cellular response by eliciting methods to maintain protein synthesis.     

Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis

Molecular mimicry of viral antigens with self determinants has been proposed as one of the pathogenic mechanisms in autoimmune disease. Evidence of viral mimicry in animal models of autoimmunity is accumulating. Murine adenovirus, Semliki forest virus, lactate dehydrogenase-elevating virus, herpes simplex virus type-1, hepatitis B virus, encephalomyocarditis virus, Theiler's murine encephalomyelitis virus, Coxsackievirus and cytomegalovirus have been found to mimic physiologically important host proteins. However, epitope homology of a viral and self determinant is not in itself strong evidence for mimicry as a pathogenic mechanism. The mimicking determinant must also be capable of inducing disease in the absence of replicative virus. Animal models provide evaluation of the viral trigger, and development and therapy for autoimmune diseases. Identification of host proteins that can induce disease together with the knowledge of immune system dysregulation, genetic association and environmental factors may lead to improved immunotherapeutic strategies for human autoimmune diseases.     

Signalling in viral entry

Viral infections are serious battles between pathogens and hosts. They can result in cell death, elimination of the virus or latent infection keeping both cells and pathogens alive. The outcome of an infection is often determined by cell signalling. Viruses deliver genomes and proteins with signalling potential into target cells and thereby alter the metabolism of the host. Virus interactions with cell surface receptors can elicit two types of signals, conformational changes of viral particles, and intracellular signals triggering specific cellular reactions. Responses by cells include stimulation of innate and adaptive immunity, growth, proliferation, survival and apoptosis. In addition, virus-activated cell signalling boosts viral entry and gene delivery, as recently shown for adenoviruses and adeno-associated viruses. This review illustrates that multiple activation of host cells during viral entry profoundly impacts the elaborate relationship between hosts and viral pathogens. Received 13 September 2001; received after revision 23 October 2001; accepted 16 November 2001     

Induction of endogenous murine C-type viruses. Attempt at discrimination by the pI of polypeptide p30 and the aspect of cellular transformation]

Endogenous ecotropic and xenotropic murine C-type viruses induced in K-Balb-3T3 cells treated with iododeoxyuridine (IdU) were selected by infection of appropriate indicator cells. The isoelectric point (p1) of the major viral polypeptide (p30) was found to be 6.1 for the ecotropic virus (class I), and 5.7 for the xenotropic virus (class II). An isoelectric form (iso p30) of pl 6.5 was observed in the initial induction peak. In addition, the pattern of cellular alteration in NRK cells at its onset varied according to the pseudotype, the class I pseudotype inducing round cell foci while the foci associated with the class II pseudotype consisted of fusiform cells.     

Functional mechanisms of the cellular prion protein (PrPC) associated anti-HIV-1 properties

The cellular prion protein PrP(C)/CD230 is a GPI-anchor protein highly expressed in cells from the nervous and immune systems and well conserved among vertebrates. In the last decade, several studies suggested that PrP(C) displays antiviral properties by restricting the replication of different viruses, and in particular retroviruses such as murine leukemia virus (MuLV) and the human immunodeficiency virus type 1 (HIV-1). In this context, we previously showed that PrP(C) displays important similarities with the HIV-1 nucleocapsid protein and found that PrP(C) expression in a human cell line strongly reduced HIV-1 expression and virus production. Using different PrP(C) mutants, we report here that the anti-HIV-1 properties are mostly associated with the amino-terminal 24-KRPKP-28 basic domain. In agreement with its reported RNA chaperone activity, we found that PrP(C) binds to the viral genomic RNA of HIV-1 and negatively affects its translation. Using a combination of biochemical and cell imaging strategies, we found that PrP(C) colocalizes with the virus assembly machinery at the plasma membrane and at the virological synapse in infected T cells. Depletion of PrP(C) in infected T cells and microglial cells favors HIV-1 replication, confirming its negative impact on the HIV-1 life cycle.     

Endocytosis of hepatitis C virus non-enveloped capsid-like particles induces MAPK–ERK1/2 signaling events

Although HCV is an enveloped virus, naked nucleocapsids have been reported in the serum of infected patients. The HCV core particle serves as a protective capsid shell for the viral genome and recombinant in vitro assembled HCV core particles induce strong specific immunity. We investigated the post-binding mechanism of recombinant core particle uptake and its intracellular fate. In hepatic cells, these particles are internalized, most likely in a clathrin-dependent pathway, reaching early to late endosomes and finally lysosomes. The endocytic acidic milieu is implicated in trafficking process. Using specific phosphoantibodies, signaling pathway inhibitors and chemical agents, ERK_1/2 was found to be activated in a sustained way after endocytosis, followed by downstream immediate early genes (c-fos and egr-1) modulation. We propose that the intriguing properties of cellular internalization of HCV non-enveloped particles can induce specific ERK_1/2–MAPKs events that could be important in HCV life cycle and pathogenesis of HCV infection.     

Anti-apoptotic mechanisms of HIV: lessons and novel approaches to curing HIV

Past efforts at curing infection with the human immunodeficiency virus (HIV) have been blocked by the resistance of some infected cells to viral cytopathic effects and the associated development of a latent viral reservoir. Furthermore, current efforts to clear the viral reservoir by means of reactivating latent virus are hampered by the lack of cell death in the newly productively infected cells. The purpose of this review is to describe the many anti-apoptotic mechanisms of HIV, as well as the current limitations in the field. Only by understanding how infected cells avoid HIV-induced cell death can an effective strategy to kill infected cells be developed.     

Regulation of microRNA biogenesis and turnover by animals and their viruses

MicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes.