Exogenous Virus Research Articles

Human Cytomegalovirus Infection in Women With Preexisting Immunity: Sources of Infection and Mechanisms of Infection in the Presence of Antiviral Immunity.

Human cytomegalovirus (HCMV) infection remains an important cause of neurodevelopmental sequelae in infants infected in utero. Unique to the natural history of perinatal HCMV infections is the occurrence of congenital HCMV infections (cCMV) in women with existing immunity to HCMV, infections that have been designated as nonprimary maternal infection. In maternal populations with a high HCMV seroprevalence, cCMV that follows nonprimary maternal infections accounts for 75%-90% of all cases of cCMV infections as well as a large proportion of infected infants with neurodevelopmental sequelae. Although considerable effort has been directed toward understanding immune correlates that can modify maternal infections and intrauterine transmission, the source of virus leading to nonprimary maternal infections and intrauterine transmission is not well defined. Previous paradigms that included reactivation of latent virus as the source of infection in immune women have been challenged by studies demonstrating acquisition and transmission of antigenically distinct viruses, a finding suggesting that reinfection through exposure to an exogenous virus is responsible for some cases of nonprimary maternal infection. Additional understanding of the source(s) of virus that leads to nonprimary maternal infection will be of considerable value in the development and testing of interventions such as vaccines designed to limit the incidence of cCMV in populations with high HCMV seroprevalence.

Cytomegalovirus (CMV) and C-Reactive Protein (CRP) and their Association with Atherosclerosis in Patients with End Stage Renal Disease

Abstract Background ESRD (end stage renal disease) is associated with an increase in the risk for cardiovascular disease, which can only be partially explained by known classical risk factors. However, chronic inflammation and endothelial dysfunction are key events in the development of atherosclerosis; both are observed in ESRD patients . The significance of C-Reactive Protein (CRP) and inflammation has increased over time, especially in the ESRD population. From being a simple marker, it now shown that CRP has an active participation in pro-atherosclerotic phenomenon including local pro-inflammatory and thrombotic events. Studies in the general population indicate the usefulness of CRP in prognosis and in monitoring response to therapy. Cytomegalovirus (CMV) is an important pathogen in immunocompromised individuals. Patients with ESRD display signs of frequent CMV re-activation, which may be caused by the uraemia-associated defect in cellular immunity. It has been well documented that hemodialysis patients have impaired immune response, which may result in higher prevalence rates of viral infections, including CMV. Infections in these patients may be due to primary infection or, more commonly, by reactivation of latent virus or re-infection with exogenous virus, which may be introduced by blood transfusion or kidney transplant. Infection with CMV is also considered a risk factor for progression of atherosclerotic disease. Methods CRP and CMV IgG level was measured in the blood samples of sixty adult patients diagnosed as ESRD, 30 ESRD patients with atherosclerotic changes(Group I) and 30 ESRD patients without atherosclerotic changes (Group II) and in comparison with 30 control subjects(Group III) (Control Group). Results The mean value of CRP in the control group (6.0 ± 4.2), the mean value in the ESRD patients with atherosclerotic changes group (15.8 ± 5.6) and the mean value in the ESRD patients without atherosclerotic changes group (11.2 ± 3.9),thus the mean values of CRP in ESRD patients groups were significantly higher than that of the control group (P < 0.001) and the mean value of CRP in ESRD with atherosclerotic changes is significantly higher compared to ESRD without atherosclerotic changes group (P < 0.001). Regarding CMV IgG antibodies it was significantly higher in ESRD patients compared to the control group and was also significantly higher in ESRD with atherosclerotic changes compared to ESRD without atherosclerotic changes. Conclusions ESRD are at greater risk of inflammatory reaction against factors originating from graft, fistula, dialysis membrane, infection sites. These reactions are associated with increased levels inflammatory markers such as serum CRP. Serum CRP seems to have a contribution in the development of cardiovascular complications in ESRD patients.CMV seropositivity is also significantly associated with atherosclerotic disease in ESRD patients. Our data suggest that the risk for progressive atherosclerosis is specifically increased in patients with an inflammatory response to CMV and elevated CRP level.

Koala retrovirus viral load and disease burden in distinct northern and southern koala populations

Koala retrovirus (KoRV) displays features of both an endogenous and exogenous virus and is linked to neoplasia and immunosuppression in koalas. This study explores the apparent differences in the nature and impact of KoRV infection between geographically and genetically separated “northern” and “southern” koala populations, by investigating the disease status, completeness of the KoRV genome and the proviral (DNA) and viral (RNA) loads of 71 northern and 97 southern koalas. All northern animals were positive for all KoRV genes (gag, pro-pol and env) in both DNA and RNA forms, whereas many southern animals were missing one or more KoRV genes. There was a significant relationship between the completeness of the KoRV genome and clinical status in this population. The proviral and viral loads of the northern population were significantly higher than those of the southern population (P < 0.0001), and many provirus-positive southern animals failed to express any detectable KoRV RNA. Across both populations there was a positive association between proviral load and neoplasia (P = 0.009). Potential reasons for the differences in the nature of KoRV infection between the two populations are discussed.

Evolutionary analysis of exogenous and integrated HHV-6A/HHV-6B populations.

Human betaherpesviruses 6A and 6B (HHV-6A and HHV-6B) are highly prevalent in human populations. The genomes of these viruses can be stably integrated at the telomeres of human chromosomes and be vertically transmitted (inherited chromosomally integrated HHV-6A/HHV-6B, iciHHV-6A/iciHHV-6B). We reconstructed the population structures of HHV-6A and HHV-6B, showing that HHV-6A diverged less than HHV-6B genomes from the projected common ancestral population. Thus, HHV-6B genomes experienced stronger drift, as also supported by calculation of nucleotide diversity and Tajima’s D. Analysis of ancestry proportions indicated that HHV-6A exogenous viruses and iciHHV-6A derived most of their genomes from distinct ancestral sources. Conversely, ancestry proportions were similar in exogenous HHV-6B viruses and iciHHV-6B. In line with previous indications, this suggests the distinct exogenous viral populations that originated iciHHV-6B in subjects with European and Asian ancestry are still causing infections in the corresponding geographic areas. Notably, for both iciHHV-6A and iciHHV-6B, we found that European and American sequences tend to have high proportions of ancestry from viral populations that experienced considerable drift, suggesting that they underwent one or more bottlenecks followed by population expansion. Finally, analysis of HHV-6B exogenous viruses sampled in Japan indicated that proportions of ancestry components of most of these viruses are different from the majority of those sampled in the USA. More generally, we show that, in both viral species, both integrated and exogenous viral genomes have different ancestry components, partially depending on geographic location. It would be extremely important to determine whether such differences account for the diversity of HHV-6A/HHV-6B-associated clinical symptoms and epidemiology. Also, the sequencing of additional exogenous and integrated viral genomes will be instrumental to confirm and expand our conclusions, which are based on a relatively small number of genomes, sequenced with variable quality, and with unequal sampling in terms of geographic origin.

Factors Affecting the Tissue Damaging Consequences of Viral Infections.

Humans and animals are infected by multiple endogenous and exogenous viruses but few agents cause overt tissue damage. We review the circumstances which favor overt disease expression. These can include intrinsic virulence of the agent, new agents acquired from heterologous species, the circumstances of infection such as dose and route, current infection with other agents which includes the composition of the microbiome at mucosal and other sites, past history of exposure to other infections as well as the immune status of the host. We also briefly discuss promising therapeutic strategies that can expand immune response patterns that minimize tissue damaging responses to viral infections.

A model of human endogenous retrovirus (HERV) activation in mental health and illness

Despite strong evidence for the heritability of major depressive disorder (MDD), efforts to identify causal genes have been disappointing. Furthermore, although there is strong support for life stress as a major predictor of MDD, there are also considerable individual differences in susceptibility and resilience that remain poorly understood. Efforts to identify specific gene-by-environment risk factors produced results that were initially encouraging, but that were not supported by later large-scale studies. Here I propose a novel mechanism that could address the “missing heritability” of MDD, the role of environmental risk factors, and individual differences in susceptibility and resilience. This mechanism focuses on a class of transposable elements, Human Endogenous Retroviruses (HERVs), which make up approximately 8% of the human genome as the result of ancient retroviral infections that entered mammalian germ lines throughout the course of evolution. My primary hypothesis is that exposure to either exogenous viruses or traumatic experiences can activate HERVs in the brain to cause depressive (and possibly other psychiatric) symptoms. My secondary hypothesis is that individual differences in vulnerability or resilience result from the balance of activated HERVs with pathogenic versus protective functions in the brain. Future research can test these hypotheses by analysis of postmortem human brain tissue from donors with known viral or trauma histories; animal studies manipulating HERV expression; cell culture studies examining regulatory mechanisms of HERV expression; and from brain imaging studies of individuals with known HERV-expression. Such research may reveal novel functions of HERVs in neural tissue and may lead to a new generation of psychiatric interventions designed to target aberrant HERV activation.

Ancient foes and helpers: Research sheds new light on the role that retroviruses play in disease, innate immunity and neural plasticity.

Ancient retrovirus infections played a role in human evolution and are still involved in innate immunity and neural plasticity.

A complex evolutionary relationship between HHV-6A and HHV-6B.

Human betaherpesviruses 6A and 6B (HHV-6A and HHV-6B) are highly prevalent in human populations. The genomes of these viruses can be stably integrated at the telomeres of human chromosomes and be vertically transmitted (inherited chromosomally integrated HHV-6, iciHHV6). We reconstructed the population structure of HHV-6 and we show that HHV-6A genomes diverged less than HHV-6B genomes from the ancestral common HHV-6A/B population. Analysis of ancestry proportions indicated that HHV-6A exogenous viruses and iciHHV-6A derived most of their genomes from distinct ancestral sources. Conversely, exogenous viral and iciHHV-6B populations were similar in terms of ancestry components, with no evident geographic structuring. Most HHV-6B genomes sampled to date derive from viral populations that experienced considerable drift. However, a population of HHV-6 exogenous viruses, currently classified as HHV-6B and sampled in New York state, formed a separate cluster (NY cluster) and harbored a considerable portion of HHV-6A-like ancestry. Recombination detection methods identified these viruses as interspecies recombinants, but phylogenetic reconstruction indicated that the recombination signals are due to shared ancestry. In analogy to iciHHV-6A, NY cluster viruses have high nucleotide diversity and constant population size. We propose that HHV-6A sequences and the NY cluster population diverged from an ancestral HHV-6A-like population. A relatively recent bottleneck of the NY (or a related) population with subsequent expansion originated most HHV-6B genomes currently sampled. Our findings indicate that the distinction between HHV-6A and -6B is not as clear-cut as previously thought. More generally, epidemiological and clinical surveys would benefit from taking HHV-6 genetic diversity into account.

Retraction to: A complex evolutionary relationship between HHV-6A and HHV-6B.

[This retracts the article DOI: 10.1093/ve/vez043.].

Assessing the Diversity of Endogenous Viruses Throughout Ant Genomes.

Endogenous viral elements (EVEs) can play a significant role in the evolution of their hosts and have been identified in animals, plants, and fungi. Additionally, EVEs potentially provide an important snapshot of the evolutionary frequency of viral infection. The purpose of this study is to take a comparative host-centered approach to EVE discovery in ant genomes to better understand the relationship of EVEs to their ant hosts. Using a comprehensive bioinformatic pipeline, we screened all nineteen published ant genomes for EVEs. Once the EVEs were identified, we assessed their phylogenetic relationships to other closely related exogenous viruses. A diverse group of EVEs were discovered in all screened ant host genomes and in many cases are similar to previously identified exogenous viruses. EVEs similar to ssRNA viral proteins are the most common viral lineage throughout the ant hosts, which is potentially due to more chronic infection or more effective endogenization of certain ssRNA viruses in ants. In addition, both EVEs similar to viral glycoproteins and retrovirus-derived proteins are also abundant throughout ant genomes, suggesting their tendency to endogenize. Several of these newly discovered EVEs are found to be potentially functional within the genome. The discovery and analysis of EVEs is essential in beginning to understand viral–ant interactions over evolutionary time.

Modeling HIV-1 Latency Using Primary CD4+ T Cells from Virally Suppressed HIV-1-Infected Individuals on Antiretroviral Therapy.

The low frequency of latently HIV-infected cells in vivo limits the testing of potential HIV cure strategies using cells from successfully suppressed individuals. To date, primary cell models of latency use cells infected in vitro Primary CD4+ T cell models carrying an individual's endogenous HIV reservoir that recapitulate in vivo conditions of HIV latency are still outstanding. We developed a primary CD4+ T cell model of HIV latency derived from memory CD4+ T cells isolated from virally suppressed HIV-infected individuals that recapitulates HIV-1 latency and viral reactivation events. This model is based on the expansion of primary CD4+ T cells up to 300-fold in cell number. These cells reestablish a resting state without active virus production after extended culture and maintain a stable number of total HIV proviruses. The ability of these cells to respond to various classes of latency-reversing agents is similar to that of ex vivo CD4+ T cells directly isolated from blood. Importantly, viral outgrowth assays confirmed the ability of these expanded cells to produce replication-competent endogenous virus. In sum, this model recapitulates ex vivo viral reactivation conditions, captures the variability between individuals with different HIV reservoirs, and provides large numbers of cells for testing multiple agents from a single donor. The use of this novel model will allow accurate exploration of novel cure approaches aimed either at promoting viral reactivation or maintaining sustained latency.IMPORTANCE Primary cell models of HIV latency have been very useful to identify mechanisms contributing to HIV latency and to evaluate potential HIV cure strategies. However, the current models utilize in vitro infection with exogenous virus that does not fully recapitulate virus reactivation profiles of endogenous HIV in in vivo-infected CD4+ T cells. In contrast, obtaining sufficient amounts of CD4+ T cells from HIV-infected individuals to interrogate the HIV reservoir in vitro requires leukapheresis. In the model we propose here, in vitro expansion and extended culture of primary CD4+ T cells isolated from virally suppressed HIV-infected individuals enable obtaining large numbers of cells harboring endogenous latent HIV reservoirs without performing leukapheresis. This model captures the variability of HIV reservoirs seeded in different individuals and should be useful to evaluate future HIV cure strategies.

Synergetic pathogenicity of Newcastle disease vaccines LaSota strain and contaminated chicken infectious anemia virus

Newcastle disease virus (NDV)-attenuated vaccine has been widely used to prevent ND in poultry flocks, while many reports also mentioned the exogenous virus contamination in attenuated vaccines, which might be the reason for the widespread of some contagious diseases. Recently, the chicken infectious anemia virus (CIAV) contamination in the NDV-attenuated vaccine was also found in China, though no systemic study has studied the pathogenicity or infection mechanism of this special transmission route. Accordingly, simulation experiments were launched using CIAV isolated from a contaminated NDV-attenuated vaccine. Results showed that using NDV-attenuated vaccine contaminated with CIAV could cause CIA in chickens with obvious symptoms, including anemia, hemorrhage, lymphoatrophy, and growth retardation, while the synergistic reaction of CIAV and LaSota prompted their multiplication in vivo and disturbed the production of antibodies against each other. And CIAV could significantly reduce the NDV antibody titers and decrease the protective effectiveness. This study showed the synergetic pathogenicity of CIAV and LaSota strain after using contaminated NDV-attenuated vaccine, helping us to understand how the CIAV causes infection and induces severe diseases with a relatively low dose through the mouth, as well as reminding us that the damage of an attenuated vaccine contaminated with CIAV even in extremely low dose is not insignificant.

Assessment on reticuloendotheliosis virus infection in specific-pathogen-free chickens based on detection of yolk antibody.

Reticuloendotheliosis virus (REV) is the most frequent exogenous virus that contaminates attenuated vaccines. Therefore, it is extremely important to select REV-free specific-pathogen-free (SPF) chicken embryos. Generally, REV infection is assessed by detecting REV antibodies in SPF chickens. This present study seeks to evaluate REV infection by replacing serum antibody detection with yolk antibody detection. A cohort of 40 nineteen-week-old SPF chickens were artificially inoculated with REV, with 32 SPF chickens raised in another isolation environment served as a blank control. Eggs and serum from 23-week-old chickens were sampled, and yolks were diluted separately to ratios of 1:150, 1:200, 1:300 and 1:400, which were detected together with serum. We found that the yolk antibody detection findings at a dilution of 1:300 had the highest coincidence rate compared with that based on serum antibody measurements. At a dilution ratio of 1:300 for yolk antibody, 72 chickens were continuously observed for 10 weeks from 25- to 34-weeks-old. Our findings were based on serum antibody or yolk antibody detection, and the evaluation results were completely consistent. Therefore, all serum antibody-positive chickens were yolk antibody-positive, and vice versa. Accordingly, vaccine producers can estimate REV cleanliness in a poultry farm by sampling yolk antibody titers.

Induction of neutrophil extracellular traps during tissue injury: Involvement of STING and Toll-like receptor 9 pathways.

ObjectivesNeutrophils are thought to release neutrophil extracellular traps (NETs) to form in response to exogenous bacteria, viruses and other pathogens. However, the mechanisms underlying NET formation during sterile inflammation are still unclear. In this study, we would like to identify neutrophil extracellular traps formation during sterile inflammation and tissue injury and associated pathways and its mechanism.Materials and methodsWe identified different injuries such as chemical‐induced and trauma‐induced formation of NETs and investigated mechanism of the formation of NETs in vitro and in vivo during the treatment of mtDNA.ResultsHere, we find the release of mitochondrial DNA (mtDNA) and oxidized mtDNA in acute peripheral tissue trauma models or other chemically induced lung injury, and moreover, endogenous mtDNA and oxidized mtDNA induce the formation of NETs and sterile inflammation. Oxidized mtDNA is a more potent inducer of NETs. Mitochondrial DNA activates neutrophils via cyclic GMP‐AMP synthase (cGAS)‐STING and the Toll‐like receptor 9 (TLR9) pathways and increases the production of neutrophil elastase and extracellular neutrophil‐derived DNA in NETs. Mitochondrial DNA also increases the production of reactive oxygen species (ROS) and expression of the NET‐associated proteins Rac 2 and peptidylarginine deiminase 4 (PAD4).ConclusionsAltogether, these findings highlight that endogenous mitochondrial DNA inducted NETs formation and subsequent sterile inflammation and the mechanism associated with NET formation.

The impact of childhood varicella vaccination on the incidence of herpes zoster in the general population: modelling the effect of exogenous and endogenous varicella-zoster virus immunity boosting

BackgroundA controversy exists about the potential effect of childhood varicella vaccination on Herpes Zoster (HZ) incidence. Mathematical models projected temporary HZ incidence increase after vaccine introduction that was not confirmed by real-world evidence. These models assume that absence of contacts with infected children would prevent exogenous boosting of Varicella-Zoster-Virus (VZV) immunity and they do not include an endogenous VZV immunity-boosting mechanism following asymptomatic VZV reactivation. This study aims to explore the effect of various assumptions on exogenous and endogenous VZV immunity-boosting on HZ incidence in the general population after introduction of routine childhood varicella vaccination.MethodsAn age-structured dynamic transmission model was adapted and fitted to the seroprevalence of varicella in France in absence of vaccination using the empirical contact matrix. A two-dose childhood varicella vaccination schedule was introduced at 12 and 18 months. Vaccine efficacy was assumed at 65%/95% (dose 1/dose 2), and coverage at 90%/80% (dose 1/dose 2). Exogenous boosting intensity was based on assumptions regarding HZ-immunity duration, age-dependent boosting effect, and HZ reactivation rates fitted to observed HZ incidence. Endogenous boosting was the same as pre-vaccination exogenous boosting but constant over time, whilst exogenous boosting depended on the force of infection. Five scenarios were tested with different weightings of exogenous (Exo) - endogenous (Endo) boosting: 100%Exo–0%Endo, 75%Exo–25%Endo, 50%Exo–50%Endo, 25%Exo–75%Endo, 0%Exo–100%Endo.ResultsHZ incidence before varicella vaccination, all ages combined, was estimated at 3.96 per 1000 person-years; it decreased by 64% by year 80 post vaccine introduction, for all boosting assumptions. The 100%Exo-0%Endo boosting scenario, predicted an increase in HZ incidence for the first 21 years post vaccine introduction with a maximum increase of 3.7% (4.1/1000) at year 9. However, with 0%Exo-100%Endo boosting scenario an immediate HZ decline was projected. The maximum HZ incidence increases at 10, 3, and 2 years post vaccination were 1.8% (75%Exo-25%Endo), 0.8% (50%Exo-50%Endo) and 0.2% (25%Exo-75%Endo), respectively.ConclusionsAssuming modest levels of endogenous boosting, the increase in HZ incidence following childhood varicella vaccination was smaller and lasted for a shorter period compared with 100%Exo-0%Endo boosting assumption. Endogenous boosting mechanism could partly explain the divergence between previous HZ-incidence projections and real-world evidence.

The intracorporal interaction of fowl adenovirus type 4 and LaSota strain significantly aggravates the pathogenicity of one another after using contaminated Newcastle disease virus-attenuated vaccine.

In the past five years, inclusion body hepatitis-hydropericardium syndrome caused by fowl adenovirus type 4 (FAdV-4) has been rampant in China and is still an epidemic at present. We had found the contamination of FAdV-4 in Newcastle disease virus (NDV)-attenuated vaccine from a large farm with aforementioned disease, and then conjectured that the use of this contaminated vaccine might be an important reason for the outbreak of the FAdV-4 infection. To assess the pathogenicity of this contaminated vaccine and the interaction between FAdV and LaSota, systemic animal experiments were launched with FAdV infection via the contaminated vaccine, as well as FAdV direct infection. Results showed that no chicks died after FAdV direct infection, while a 16.7% mortality rate appeared after FAdV infection through the contaminated vaccine; the synergistic reaction of FAdV and LaSota aggravated their inhibitory action for weight growth of SPF chickens, enhanced one another's capacity for immune system destruction, promoted their multiplication in vivo, and restrained antibody production. This study demonstrated the intracorporal interaction and enhanced pathogenicity of FAdV-4 and LaSota strain in contaminated NDV-attenuated vaccine, illustrating how the exogenous virus causes infection and induces severe diseases, which reminds us that the damage of attenuated vaccine contaminated with FAdV-4 even in extremely low dose is not insignificant.

Expressional activation and functional roles of human endogenous retroviruses in cancers.

SummaryHuman endogenous retroviruses (HERVs) are widely believed to be remnants of ancestral germ line infections by exogenous retroviruses. Although HERVs are deemed as “nonfunctional DNAs” due to loss of most of their viral protein coding capacity during evolution as part of the human genome, cumulative evidences are showing the expressional activation and potential roles of HERVs in diseases especially cancers. Work by other researchers and us has observed the dysregulation of HERVs in cancers, identified new HERV‐related genes, and revealed their potential importance in cancer development. Here, we summarized the current knowledge on the mechanisms of the expressional activation and functional roles of HERVs, with a focus on the H family HERV (HERV‐H), in carcinogenesis. HERV expression is regulated by external chemical or physical substances and exogenous virus infection, as well as host factors such as epigenetic DNA methylation, transcription factors, cytokines, and small RNAs. Diverse roles of HERVs have been proposed by acting in the forms of noncoding RNAs, proteins, and transcriptional regulators during carcinogenesis. However, much remains to be learnt about the contributions of HERVs to human cancers. More investigation is warranted to elucidate the functions of these “fossil remnants” yet important viral DNAs in the human genome.

VARICELLA-ZOSTER VIRUS CNS DISEASE CLINICAL FEATURES IN UKRAINIAN PATIENTS. PROSPECTIVE STUDY

Introduction: Herpes zoster (HZ), or shingles, is localized disease characterized by unilateral radicular pain and a vesicular rash limited to the area of skin innervated by a single dorsal root or cranial sensory ganglion. Whereas varicella, or chickenpox, results from primary exogenous varicella-zoster virus (VZV) infection, HZ is caused by reactivation of endogenous VZV that has persisted in latent form within sensory ganglia following an earlier episode of chickenpox. The aim: To explore the clinical features, diagnosis, and treatment of CNS injury caused by VZV infection in a prospective single center study from January 2014 to January 2018. Materials and methods: 117 adult patients, among which young women predominated with confirmed VZV infection were analyzed in the study. CSF and blood contents, antibody for herpes zoster M and G classes, and MRI scans have been studied, but the crucial diagnostic sign was the presence of specific viral DNA in the CSF or blood. The main clinical manifestations of the disease were ganglionitis and ganglioradiculoneuritis. Another brain lesion like uveitis, encephalitis and vasculitis were observed also. A clinical case of an unusual course of VZV-infection is given. Results and conclusions: The most common clinical variants of HZ were ganglionitis (69.7%). Cranial localization was observed in 31% of patients, spinal one - in 38.7%, injury to the meninges was found in 16.3% of patients.

Induction of Proinflammatory Multiple Sclerosis-Associated Retrovirus Envelope Protein by Human Herpesvirus-6A and CD46 Receptor Engagement.

The aberrant expression of human endogenous retrovirus (HERV) elements of the HERV-W family has been associated with different diseases, including multiple sclerosis (MS). In particular, the expression of the envelope protein (Env) from the multiple sclerosis-associated retrovirus (MSRV), a member of HERV-W family and known for its potent proinflammatory activity, is repeatedly detected in the brain lesions and blood of MS patients. Furthermore, human herpesvirus 6 (HHV-6) infection has long been suspected to play a role in the pathogenesis of MS and neuroinflammation. We show here that both HHV-6A and stimulation of its receptor, transmembrane glycoprotein CD46, induce the expression of MSRV-Env. The engagement of extracellular domains SCR3 and SCR4 of CD46-Cyt1 isoform was required for MSRV-env transactivation, limiting thus the MSRV-Env induction to the CD46 ligands binding these domains, including C3b component of complement, specific monoclonal antibodies, and both infectious and UV-inactivated HHV-6A, but neither HHV-6B nor measles virus vaccine strain. Induction of MSRV-Env required CD46 Cyt-1 singling and was abolished by the inhibitors of protein kinase C. Finally, both membrane-expressed and secreted MSRV-Env trigger TLR4 signaling, displaying thus a proinflammatory potential, characteristic for this viral protein. These data expand the specter of HHV-6A effects in the modulation of the immune response and support the hypothesis that cross-talks between exogenous and endogenous viruses may contribute to inflammatory diseases and participate in neuroinflammation. Furthermore, they reveal a new function of CD46, known as an inhibitor of complement activation and receptor for several pathogens, in transactivation of HERV env genes, which may play an important role in the pathogenesis of inflammatory diseases.

Tumor suppressor Interferon Regulatory Factor 1 selectively blocks expression of endogenous retrovirus

Endogenous retroviruses (ERVs) comprise 10% of the genome, with many of these transcriptionally silenced post early embryogenesis. Several stimuli, including exogenous virus infection and cellular transformation can reactivate ERV expression via a poorly understood mechanism. We identified Interferon Regulatory Factor 1 (IRF-1), a tumor suppressor and an antiviral host factor, as a suppressor of ERV expression. IRF-1 decreased expression of a specific mouse ERV in vitro and in vivo. IRF-3, but not IRF-7, also decreased expression of distinct ERV families, suggesting that suppression of ERVs is a relevant biological function of the IRF family. Given the emerging appreciation of the physiological relevance of ERV expression in cancer, IRF-1-mediated suppression of specific ERVs may contribute to the overall tumor suppressor activity of this host factor.