Silent Infection Research Articles

Parasite's Double Play Helps Evade Mouse Immune Response

Researchers estimate that about onethird of the world’s population has been infected by Toxplasma gondii. Most have silent infections; their immune system keeps the parasite in check and there are no clinical signs of disease. However, when T. gondii does cause illness, the resulting disease, toxoplamosis, can be unpleasant. Mild cases may feel like the flu, but more serious cases can result in eye infections and damage. Most importantly, pregnant women who become infected may miscarry, or the child may suffer neurological symptoms. Except for congenital transmission, the parasite does not appear to spread between people. Human infections generally result from handling or eating raw meat or from eating food or drinking water contaminated with the oocyst form of the parasite. Cats play a key role in T. gondii evolution. The parasite reproduces sexually when an infected animal is eaten by a cat, which then sheds oocysts in its feces; this is why pregnant women are often advised to have someone else change their cat’s litter box. Rodents, which cats eat, are therefore important intermediate hosts. New research by Martin Fleckenstein and colleagues examines the virulence of various T. gondii strains, and highlights the role mice play in the evolution of the parasite. The researchers demonstrate how some T. gondii strains deflect the mouse immune response and result in a symptomatic infection. They elucidate for the first time the role of a pseudokinase called ROP5, which is essential for virulence. Mice exposed to two of the three main strains of T. gondii develop a chronic infection with relatively mild symptoms. This is due to a class of proteins called interferon-gamma-inducible immunity-related GTPases (IRG proteins), which are key to the mouse immune response. Shortly after infection, IRGs attach to the vacuole surrounding the parasite and aid in its destruction, resulting in clearance of the parasite and thus restricting the spread of the infection. However, infection by one of the three strains (type I) can produce serious disease in mice. Researchers knew that this virulent T. gondii strain secretes a protein kinase called ROP18 that inactivates the mouse IRG proteins by phosphorylating specific sites. T. gondii also produces a pseudokinase called ROP5 when it invades mouse cells. Both these proteins are key to the progression of disease, but how ROP5 affected virulence was not understood. To understand ROP5’s role in virulence, the researchers began by demonstrating that ROP5 binds directly to IRG proteins in T. gondii–infected cells. Three ROP5 isoforms exist; all were identified in this assay. Then, researchers infected mouse cells with wild-type virulent parasites, and also parasites in which either ROP5 or ROP18 was deleted. The deletion strains did not phosphorylate IRG proteins, and as a result were not virulent. That the ROP5 deletion strain was avirulent suggested a necessary role in virulence for the protein. To demonstrate that the ROP5 loss was actually responsible for the loss of virulence in ROP5 deletion strains, the researchers took deletion strains and restored the expression of two isoforms, ROP5AIII and ROP5BIII. These restored parasites were as virulent as the wild-type strains. However, as ROP5 had previously been shown to not have an inherent catalytic activity, this suggests that it acts as a co-factor for ROP18. Finally, researchers identified where ROP5 binds to IRG proteins, and what conformational changes that binding produces. They found that ROP5 remained relatively rigid upon binding to IRG proteins—that is, they saw little change in ROP5’s structure in its bound and unbound states. The IRG proteins, however, do undergo a conformational change on binding, which could explain how ROP5 facilitates binding of ROP18 to these proteins. The scientists identified a likely binding site and inactive conformation of the IRG protein. Further work using mutagenesis showed that while the ROP5 binding site is near the IRG activation site, it is clearly distinct—and that the ROP5 binding site is also clearly distinct from ROP18 targets. That is, ROP5 binding may prepare the IRG

B7-H1, Which Represses EBV-Immortalized B Cell Killing by Autologous T and NK Cells, Is Oppositely Regulated by c-Myc and EBV Latency III Program at Both mRNA and Secretory Lysosome Levels

EBV-immortalized B cells induce a complex immune response such that the virus persists as a clinically silent infection for the lifetime of the infected host. B7-H1, also called PD-L1, is a cosignaling molecule of the B7 family that can inhibit activated T cell effectors by interaction with its receptor PD-1. In this work, we have studied the dependence of B7-H1 on NF-κB and c-Myc, the two main transcription factors in EBV latency III proliferating B cells, on various lymphoblastoid and Burkitt lymphoma cell lines, some of them being inducible or not for the EBV latency III program and/or for c-Myc. We found that B7-H1 repressed killing of EBV-immortalized B cells by their autologous T and NK cells. At the mRNA level, NF-κB was a weak inducer whereas c-Myc was a strong repressor of B7-H1 expression, an effect mediated by STAT1 inhibition. At the protein level, B7-H1 molecules were stored in both degradative and unconventional secretory lysosomes. Surface membrane B7-H1 molecules were constitutively internalized and proteolyzed in lysosomes. The EBV latency III program increased the amounts of B7-H1-containing secretory lysosomes and their export to the surface membrane. By repressing actin polymerization, c-Myc blocked secretory lysosome migration and B7-H1 surface membrane export. In addition to B7-H1, various immunoregulatory molecules participating in the immunological synapse are stored in secretory lysosomes. By playing on actin polymerization, c-Myc could thus globally regulate the immunogenicity of transformed B cells, acting on export of secretory lysosomes to plasma membrane.

A peptide talk between JC virus and the human host: from silent infection to autoimmunity

Analysis of JC virus (JCV) polyprotein for peptide sharing with the human proteome reveals that the virus has hundreds of pentapeptide sequences in common with the human proteins. The datum is interesting in light of the fundamental role exerted by short amino acid sequences in protein–protein interactions and, consequently, in biochemical reactions and immune recognition. Searching for new approaches to understand the JCV infection scenarios, from the immunoevasion phenomenon underlying the viral asymptomatic stay in the human host to the (re)activation phase and associated pathogenic sequelae, the present study describes the diffuse pentapeptide communication network between JCV and the human host.

Entry of Herpes Simplex Virus Type 1 (HSV-1) into the Distal Axons of Trigeminal Neurons Favors the Onset of Nonproductive, Silent Infection

Following productive, lytic infection in epithelia, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons that is interrupted by episodes of reactivation. In order to better understand what triggers this lytic/latent decision in neurons, we set up an organotypic model based on chicken embryonic trigeminal ganglia explants (TGEs) in a double chamber system. Adding HSV-1 to the ganglion compartment (GC) resulted in a productive infection in the explants. By contrast, selective application of the virus to distal axons led to a largely nonproductive infection that was characterized by the poor expression of lytic genes and the presence of high levels of the 2.0-kb major latency-associated transcript (LAT) RNA. Treatment of the explants with the immediate-early (IE) gene transcriptional inducer hexamethylene bisacetamide, and simultaneous co-infection of the GC with HSV-1, herpes simplex virus type 2 (HSV-2) or pseudorabies virus (PrV) helper virus significantly enhanced the ability of HSV-1 to productively infect sensory neurons upon axonal entry. Helper-virus-induced transactivation of HSV-1 IE gene expression in axonally-infected TGEs in the absence of de novo protein synthesis was dependent on the presence of functional tegument protein VP16 in HSV-1 helper virus particles. After the establishment of a LAT-positive silent infection in TGEs, HSV-1 was refractory to transactivation by superinfection of the GC with HSV-1 but not with HSV-2 and PrV helper virus. In conclusion, the site of entry appears to be a critical determinant in the lytic/latent decision in sensory neurons. HSV-1 entry into distal axons results in an insufficient transactivation of IE gene expression and favors the establishment of a nonproductive, silent infection in trigeminal neurons.

Prevalence of antibodies to Mycoplasma synoviae in laying hens and possible effects on egg shell quality

Mycoplasma synoviae (M. synoviae) can cause respiratory disease, synovitis, or result in a silent infection in chickens and turkeys. The importance of M. synoviae is well established in broilers but only a few studies have been conducted in layers. In the present study, the prevalence of M. synoviae in commercial layer flocks was estimated using ELISA. For this study, 19 commercial layer flocks were selected randomly from New South Wales and Queensland region of Australia from producers who were willing to participate in the survey. Sixty eggs per flocks were randomly collected, out of these 30 eggs were used for ELISA and remaining 30 eggs were used to estimate various egg shell quality parameters. Subsequently, association between the serological status of eggs for M. synoviae and egg shell quality was studied. In the flocks under study, seroprevalence of M. synoviae was found to be high at 69% (95% confidence interval (CI)=41.3–89.0). Statistical analysis showed an association between serological status for M. synoviae and egg quality parameters such as translucency, shell breaking strength, % shell reflectivity and shell deformation. On the other hand, there was no significant association between serological status for M. synoviae and other egg quality parameters such egg weight, egg shell weight, % egg shell or shell thickness.

Epidemiological studies on dengue virus type 3 in Playa municipality, Havana, Cuba, 2001–2002

Recognizing the uniqueness of secondary dengue virus (DENV)-1/3 dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) cases at an interval of 24 years, we sought to estimate DENV infections as well as the ratios between mild disease and DHF/DSS by DENV infection sequence in Playa District (Havana, Cuba) during the 2001-2002 outbreak of dengue virus type 3 (DENV-3). A retrospective seroepidemiological study was conducted in 2003 in Playa District. Blood samples were collected from a 1% random sample of residents and were studied for the prevalence of dengue neutralizing antibodies. DENV-3 was found to have infected 7.2% (95% confidence interval (95% CI) 6.0-8.4%) of susceptible individuals (the entire cohort), the majority of whom experienced silent infections. Virtually every individual who had a secondary infection in the sequence DENV-1 then DENV-3 became ill, with a ratio of severe to mild cases of 1:35 (95% CI 1:67-1:23). Secondary infections in the sequence DENV-2/3 were less pathogenic than DENV-1/3. Mild disease accompanying secondary DENV2/3 occurred at a ratio of 1:4.49 infections (95% CI 1:5.77-1:3.42) secondary infections. The results obtained highlight the role of the infecting serotype and also the sequence of the viral infection in the clinical outcome of a dengue infection.

Vaccine Control of Avian Influenza H5N1 in Poultry: Need for a Positive Marker

Highly pathogenic avian influenza (HPAI) H5N1 virus strains have emerged as zoonotic viral pathogens over the last decade and have eluded our serious attempts of control in domestic poultry by vaccination, with numerous countries continuing to have epidemic waves. Although the biology and genomics of H5N1 influenza viruses are well characterised, viral outbreaks still occur in domestic poultry, posing a dangerous threat of human transmission. There are two main types of current vaccines, inactivated whole virus vaccines and virus vaccines engineered by reverse genetics, both of which are administered with adjuvant to hatchlings and optimally require a booster. However, immunological determinants of vaccine efficacy need to be considered distinctly in chickens and ducks. Our futile attempts to control H5N1 viral outbreaks in domestic poultry flocks question our capacity for future achievements of eradicating circulating H5N1 influenza viruses. There is a need for detection of infection and vaccination of domestic poultry to control potentially deadly but silent infection in vaccinated flocks. A positive marker strategy using tetanus toxoid has several advantages over other negative markers to enable differentiation of infected from vaccinated animals (DIVA) for more effective control programs of HPAI in order to minimise the likelihood of an avian H5N1 influenza pandemic.

Postoperative disc space infection after discectomy: a report on thirty-five patients.

The focus of this study was to analyse the patient with disc space infection and the need for re-exploration. Thirty-five patients were analysed within the period from April 1992 and May 2011. The diagnosis was confirmed by the cardinal clinical features, raised erythrocyte sedimentation rate [ESR], raised C-reactive protein and MRI findings. All received 500-mg intravenous amikacin and one gram ceftriaxone at the time of anaesthetic induction and six hours after surgery. Age range was between 25-62 years. The appearance of symptoms was between four days and three weeks. Nine patients had silent chronic urinary tract infection. Twenty-nine patients had re-exploration while the others did well on conservative treatment. Neurological deficit was not recorded. All recovered well within six to nine months. Re-exploration is recommended if no response is achieved after four day's conservative treatment for or if the patient's condition is critical.

Checkpoints in productive and latent infections with herpes simplex virus 1: conceptualization of the issues

The fundamental question posed here is why in dorsal root ganglia herpes simplex viruses (HSV) can establish a silent infection in which only latency associate transcripts (LAT) and miRNAs are expressed and the neuronal cell survives whereas in non-neuronal cells HSV replicates and destroys the infected cells. Current evidence indicates that in productive infection there are two checkpoints. The first is at activation of α genes and requires a viral protein (VP16) that recruits HCF-1, Oct1, LSD1, and the CLOCK histone acetyl transferase to demethylate histones and initiate transcription. The second checkpoint involves activation of β and γ genes. An α protein, ICP0, activates transcription by displacing HDAC1 or 2 from the HDAC/CoREST/LSD1/REST repressor complex at its DNA binding sites. Current data suggest that in dorsal root ganglia VP16 and HCF-1 are not translocated to neuronal nucleus and that the HDAC/CoREST/LSD1/REST complex is not suppressed-a first step in silencing of the viral genome and establishment of heterochromatin. The viral genome remains in a state of equilibrium with respect to viral gene expression. The function of both LAT and the micro RNAs is to silence low level expression of viral genes that could reactivate the latent genomes.

Diagnosis of Mesh Infection after Abdominal Wall Hernia Surgery - Role of Radionuclide Methods

The aim of this investigation was to evaluate the role of detection of late mesh infection following incisional hernia repair with radiolabeled antigranulocyte antibodies. Mesh infection diagnoses were set up with clinical examination and laboratory analysis and confirmed by ultrasonography (US), computerized tomography (CT), scintigraphy with 99mTc-antigranulocyte antibodies and microbiological examination. Of the 17 patients investigated, 6 had a late mesh infection, and 11 had both mesh infection and recurrent incisional hernia. Clear clinical signs of late mesh infection were present in 13 patients. Four remaining patients had non-specific discomfort and recurrent incisional hernia without clinical manifestation of mesh infection ('silent infection'). US was positive in 12/17 patients, CT in 13/17 patients, while scintigraphy with antigranulocyte antibodies in 17/17 patients. Therefore, sensitivity of US was 71%, of CT 76% and of scintigraphy 100%. In four patients late mesh infection was confirmed exclusively by 99mTc-antigranulocyte antibody scintigraphy, while US and CT did not indicate the infection. According to the present results, scintigraphy with 99mTc antigranulocyte antibodies is a useful method for the detection of 'silent' abdominal wall infections after surgery, which is very important for prompt and appropriate therapy.

Improved Detection and Quantitation of Human BK Polyomavirus by PCR Assay

Human polyomavirus BK (BKPyV) has been identified as a main causal agent of nephropathy in renal transplant patients. The detection and quantitation of BKPyV are crucial, as they guide clinical decisions to prevent renal allograft dysfunction or loss by this otherwise silent infection. Recently,

Population Genetic Structure of Clinical and Environmental Isolates of Blastomyces dermatitidis, Based on 27 Polymorphic Microsatellite Markers

Blastomyces dermatitidis, a thermally dimorphic fungus, is the etiologic agent of North American blastomycosis. Clinical presentation is varied, ranging from silent infections to fulminant respiratory disease and dissemination to skin and other sites. Exploration of the population genetic structure of B. dermatitidis would improve our knowledge regarding variation in virulence phenotypes, geographic distribution, and difference in host specificity. The objective of this study was to develop and test a panel of microsatellite markers to delineate the population genetic structure within a group of clinical and environmental isolates of B. dermatitidis. We developed 27 microsatellite markers and genotyped B. dermatitidis isolates from various hosts and environmental sources (n=112). Assembly of a neighbor-joining tree of allele-sharing distance revealed two genetically distinct groups, separated by a deep node. Bayesian admixture analysis showed that two populations were statistically supported. Principal coordinate analysis also reinforced support for two genetic groups, with the primary axis explaining 61.41% of the genetic variability. Group 1 isolates average 1.8 alleles/locus, whereas group 2 isolates are highly polymorphic, averaging 8.2 alleles/locus. In this data set, alleles at three loci are unshared between the two groups and appear diagnostic. The mating type of individual isolates was determined by PCR. Both mating type-specific genes, the HMG and α-box domains, were represented in each of the genetic groups, with slightly more isolates having the HMG allele. One interpretation of this study is that the species currently designated B. dermatitidis includes a cryptic subspecies or perhaps a separate species.

Cost effectiveness of screening immigrants for hepatitis B

The prevalence of chronic hepatitis B (CHB) infection among the immigrants of North America ranges from 2 to 15%, among whom 40% develop advanced liver disease. Screening for hepatitis B surface antigen is not recommended for immigrants. The objective of this study is to estimate the health and economic effects of screening strategies for CHB among immigrants. We used the Markov model to examine the cost-effectiveness of three screening strategies: (i) 'No screening'; (ii) 'Screen and Treat' and (iii) 'Screen, Treat and Vaccinate' for 20-65 years old individuals who were born abroad but are currently living in Canada. Model data were obtained from the published literature. We measured predicted hepatitis B virus (HBV)-related deaths, costs (2008 Canadian Dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Our results show that screening all immigrants will prevent 59 HBV-related deaths per 10, 000 persons screened over the lifetime of the cohort. Screening was associated with an increase in quality-adjusted life expectancy (0.024 QALYs) and cost ($1665) per person with an ICER of $69, 209/QALY gained compared with 'No screening'. The 'Screen, Treat and Vaccinate' costs an additional $81, generates an additional 0.000022 QALYs per person, with an ICER of $3, 648,123/QALY compared with the 'Screen and Treat'. Sensitivity analyses suggested that the 'Screen and Treat' is likely to be moderately cost-effective. We show that a selective hepatitis B screening programme targeted at all immigrants in Canada is likely to be moderately cost-effective. Identification of silent CHB infection with the offer of treatment when appropriate can extend the lives of immigrants at reasonable cost.

XMRV replicates preferentially in mucosal sites in vivo: Relevance to XMRV transmission?

Xenotropic Murine Leukemia Virus-related Retrovirus (XMRV) was identified from prostate cancer tissue using DNA based ViroChip technology as well as in a cohort of chronic fatigue syndrome patients. To delineate the infection dynamics and dissemination in vivo, we have thus far infected 7 healthy rhesus macaques and 2 pigtailed macaques. Results show that XMRV induces a chronic and clinically silent infection that is nevertheless persistent and susceptible to reactivation in vivo. While XMRV seems rapidly cleared from the blood circulation in healthy macaques, XMRV protein positive CD4+ T cells were detected in all lymphoid organs throughout infection. However, among all organs subjected to in situ detection, mucosal sites overall and sexual organs showed markedly higher frequencies of XMRVgag positive cells, including gastrointestinal mucosa, pulmonary environment and organs from the reproductive tract. Of interest, the lineage of cells that were XMRV positive markedly differed among the different sites, including CD4+ T cells in the GI mucosa, alveolar macrophages in the lung, epithelial cells in the prostate, seminal gland, vagina and cervix and interstitial cells in the testes. The latter were consistently observed during acute and chronic infection, suggesting the potential for sexual transmission of XMRV. In fact, a single atraumatic mucosal exposure with a high dose of XMRV virus into the urethra resulted in infection of 1 out of 4 macaques providing proof of concept that such transmission is possible. However, additional work is needed to fully investigate potential modes of XMRV infection.

Transmission of Plasmodium vivax in South-Western Uganda: Report of Three Cases in Pregnant Women

Plasmodium vivax is considered to be rare in the predominantly Duffy negative populations of Sub-Saharan Africa, as this red blood cell surface antigen is essential for invasion by the parasite. However, despite only very few reports of molecularly confirmed P. vivax from tropical Africa, serological evidence indicated that 13% of the persons sampled in Congo had been exposed to P. vivax. We identified P. vivax by microscopy in 8 smears from Ugandan pregnant women who had been enrolled in a longitudinal study of malaria in pregnancy. A nested polymerase chain reaction (PCR) protocol was used to detect and identify the Plasmodium parasites present. PCR analysis confirmed the presence of P. vivax for three of the women and analysis of all available samples from these women revealed clinically silent chronic low-grade vivax infections for two of them. The parasites in one woman carried pyrimethamine resistance-associated double non-synonymous mutations in the P. vivax dihydrofolate reductase gene. The three women found infected with P. vivax were Duffy positive as were nine of 68 women randomly selected from the cohort. The data presented from these three case reports is consistent with stable transmission of malaria in a predominantly Duffy negative African population. Given the substantial morbidity associated with vivax infection in non-African endemic areas, it will be important to investigate whether the distribution and prevalence of P. vivax have been underestimated in Sub-Saharan Africa. This is particularly important in the context of the drive to eliminate malaria and its morbidity.

Usutu virus in ITALY: An emergence or a silent infection?

A two year study (2008–2009) was carried out to monitor the Usutu virus (USUV) circulation in Italy. Sentinel horses and chickens, wild birds and mosquitoes were sampled and tested for the presence of USUV and USUV antibodies within the WND National Surveillance plan. Seroconversion evidenced in sentinel animals proved that in these two years the virus has circulated in Tuscany, Emilia Romagna, Veneto and Friuli Venezia Giulia regions. In Veneto USUV caused a severe blackbird die-off disease involving at least a thousand birds. Eleven viral strains were detected in organs of 9 blackbirds (52.9%) and two magpies (0.5%) originating from Veneto and Emilia Romagna regions. USUV was also detected in a pool of Culex pipiens caught in Tuscany. According to the alignment of the NS5 partial sequences, no differences between the Italian USUV strains isolated from Veneto, Friuli and Emilia Romagna regions were observed. The Italian North Eastern strain sequences were identical to those of the strain detected in the brain of a human patient and shared a high similarity with the isolates from Vienna and Budapest. Conversely, there were few differences between the Italian strains which circulated in the North Eastern regions and the USUV strain detected in a pool of C. pipiens caught in Tuscany. A high degree of similarity at both nucleotide and amino acid level was also found when the full genome sequence of the Italian North Eastern isolate was compared with that of the strains circulating in Europe. The North Eastern Italian strain sequence exhibited 97% identity to the South African reference strain SAAR-1776. The deduced amino acid sequences of the Italian strain differed by 10 and 11 amino-acids from the Budapest and Vienna strains, respectively, and by 28 from the SAAR-1776 strain. According to this study two strains of USUVs are likely to have circulated in Italy between 2008 and 2009. They have developed strategies of adaptation and evolution to spread into new areas and to become established.

Risk of infection in patients with lymphoma receiving rituximab: systematic review and meta-analysis

BackgroundThe addition of Rituximab (R) to standard chemotherapy (C) has been reported to improve the end of treatment outcome in patients affected by CD-20 positive malignant lymphomas (CD20+ ML). Nevertheless, given the profound and prolonged immunosuppression produced by R there are concerns that severe infections may arise. A systematic review and meta-analysis were performed to determine whether or not the addition of R to C may increase the risk of severe infections in adults undergoing induction therapy for CD20+ ML.MethodsOnly randomised controlled trials comparing R-C to C standard alone in adult patients with CD20+ ML were included. Meta-analysis was performed on overall incidence of severe infection, risk of dying as the consequence of infection, risk of febrile neutropenia, risk of severe leucopenia, risk of severe granulocytopenia and overall response assuming a fixed effect model. Heterogeneity was investigated, if present and I2 >20%, according to several predefined baseline characteristics of the study populations.ResultsSeveral relevant results have emerged. First, the addition of R to standard C does not increase the overall risk of severe infections (RR = 1.00; 95% CI 0.87 to 1.14) nor does it increase the risk of dying as a consequence of infection (RR = 1.60; 95% CI 0.68 to 3.75). Second, we confirmed that the addition of R to standard C increases the proportion of overall response (RR = 1.12; 95% CI 1.09 to 1.15), but it also increases the risk of severe leucopenia (RR = 1.24; 95% CI 1.12 to 1.37) and granulocytopenia (RR = 1.07; 95% CI 1.02 to 1.12).ConclusionsR-C is superior to standard C in terms of overall response and it does not increase the overall incidence of severe infection. However, data on special groups of patients (for example, HIV positive subjects and HBV carriers) are lacking. In our opinion more studies are needed to explore the potential effect of R on silent and chronic viral infections.

Virus Reactivation: a Panoramic View in Human Infections

Viruses are obligate intracellular parasites, relying to a major extent on the host cell for replication. An active replication of the viral genome results in a lytic infection characterized by the release of new progeny virus particles, often upon the lysis of the host cell. Another mode of virus infection is the latent phase, where the virus is 'quiescent' (a state in which the virus is not replicating). A combination of these stages, where virus replication involves stages of both silent and productive infection without rapidly killing or even producing excessive damage to the host cells, falls under the umbrella of a persistent infection. Reactivation is the process by which a latent virus switches to a lytic phase of replication. Reactivation may be provoked by a combination of external and/or internal cellular stimuli. Understanding this mechanism is essential in developing future therapeutic agents against viral infection and subsequent disease. This article examines the published literature and current knowledge regarding the viral and cellular proteins that may play a role in viral reactivation. The focus of the article is on those viruses known to cause latent infections, which include herpes simplex virus, varicella zoster virus, Epstein-Barr virus, human cytomegalovirus, human herpesvirus 6, human herpesvirus 7, Kaposi's sarcoma-associated herpesvirus, JC virus, BK virus, parvovirus and adenovirus.

The Checkpoints of Viral Gene Expression in Productive and Latent Infection: the Role of the HDAC/CoREST/LSD1/REST Repressor Complex

At the portal of entry into the body, herpes simplex viruses (HSV) vigorously multiply and spread until curtailed by the adaptive immune response. At the same time, HSV invades nerve ending-abutting infected cells and is transported in a retrograde manner to the neuronal nucleus, where it establishes a latent (silent) infection. At intervals, as a consequence of physical or metabolic stress, the virus is activated and transported in an anterograde manner to the body surface. The progression of infection is regulated at four checkpoints. In cell culture or at the portal of entry into the body, HSV uses components of the HDAC1- or HDAC2/CoREST/LSD1/REST repressor complex to activate α genes (checkpoint 1) and then uses an α protein, ICP0, to suppress the same repressor complex from silencing post-α gene expression (checkpoint 2). In neurons destined to harbor latent virus (checkpoint 3), HSV hijacks the same repressor complex to silence itself as a first step in the establishment of the latent state. Suppression of histone deacetylases (HDACs) plays a key role in the reactivation from latency (checkpoint 4). HSV has evolved a strategy of using the same host repressor complex to meet its diverse lifestyle needs.

Evolution of Hepatitis B and C serum markers: a still challenging issue

Evolution of Hepatitis B and C serum markers: a still challenging issue