Human herpesvirus 7 meningitis in an adolescent with normal immune function:A case report

BACKGROUND Human herpesvirus type 7(HHV-7)is a less common herpes virus that usually causes mild,self-limiting illnesses.However,in recent years,there have been increasing reports of HHV-7 causing serious central nervous system infections,especially meningitis.The pathogenesis and clinical features of HHV-7 meningitis,particularly in adolescents with normal immune function,remain incompletely studied.Therefore,the purpose of this report is to share a case of HHV-7 meningitis in an immunocompetent adolescent with a view to deepening our understanding of the disease.CASE SUMMARY A 12-year-old female was admitted with fever,headache,and vomiting.4 d before admission,the patient developed a fever without obvious induction,with a temperature up to 39.5℃,no convulsions,accompanied by chills,headaches,fatigue,and no muscle aches.The patient was treated with fever reduction,which could be reduced to 38℃;repeated high fever,accompanied by vomiting 7-8 times;and no abdominal pain or diarrhea.The patient was diagnosed with"acute suppurative tonsillitis"in a local hospital,and the blood routine was generally normal.The patient was given symptomatic support treatment such as"ceftriaxone sodium"and antiemetic rehydration for 2 d,and his condition did not improve.The patient's physical examination showed pharyngeal congestion,bilateral tonsil grade I hypertrophy,regression of purulent secretions,and cervical resistance.Ocular B-ultrasound:Opacity of the vitreous body and edema of the optic disc in both eyes.Optical coherence tomography examination showed that the macular fovea was generally normal in both eyes,with edema of the optic disc.DNA virus monitoring results:HHV-7.We gave ganciclovir antiviral therapy,dexamethasone anti-inflammatory treatment,mannitol to reduce cranial pressure,omeprazole to protect gastrointestinal mucosa,and calcium and potassium supplementation.CONCLUSION This study reports a case of HHV-7 meningitis in an adolescent with normal immune function.Through comprehensive analysis of the clinical manifestations,laboratory tests,and treatment methods of the patient,it is found that early identification and antiviral treatment are essential for the outcome of the disease.This case suggests that despite normal immune function,adolescents may still suffer from herpes virus type 7 meningitis,so clinicians should be vigilant and take effective treatment measures in time.

Genotypic analysis on the ORF-K1 gene of human herpesvirus 8 from patients with Kaposi's sarcoma in Xinjiang,China

Human herpesvirus 8 （HHV-8） is thought to be essential for the development of all forms of Kaposi＇s sarcoma （KS）. HHV-8 DNA is present virtually in all KS tumor biopsy samples. Genes at both ends of the HHV-8 genome have been shown to vary considerably. Seven major molecular subtypes of HHV-8 were defined based on the amino acid sequence of the open reading frame K1 （ORF-K1）, generally known as A, B, C, D, E, F, and Z. Most strains collected worldwide were clustered into two subtypes （A and C）. Here, the K1/VRI region of HHV-8 was amplified by nested PCR in 22 （81.48%） of 27 cases from Xinjiang Uygur Autonomous Region, a province in northwestern China. Phylogenetic analysis on the basis of the K1/VR1 amino acid sequence indicated that the majority of these KS patients were infected by subtype C HHV-8 （n = 18, including 15 belonging to the C2 group）, and several by subtype A （n = 4, including 3 being the A1 group）. This is the first report of subtype A HHV-8 in China. Furthermore, the correlations between different forms and lesions of KS and different subtypes of HHV-8 were analyzed. The findings showed that subtype A HHV-8 resulted in significantly more frequent mucosal KS lesions than subtype C. However, there was no obvious correlation between different forms of KS and different subtypes of HHV-8.

Isolation and Identification of a Specific cDNA Mapping to the Bam HI-I2 and -LFragments within the Inverted Repeats ofUnique Long Re-gion (IRL) in the Genom e ofMarek′s Disease Herpesvirus (MDV) Oncogenic Strain Beijing-1

Objective\ To understand the transcription of BamHI L DNA fragment from genome of strong virulent GA strain of Marek′s disease herpesvirus (MDV) in lymphoblastoid tumor tissue induced by oncogenic strain Beijing 1 (a specific local strain in China) of MDV. Methods\ Two oligonucleotide primers were synthesized according to the reported sequence of \%meq\% gene an ideal oncogenic candidate and our previously determined sequence of BamHI L fragment of Marek′s disease herpesvirus (MDV), respectively. Reverse transcriptase PCR(RT PCR) assay was performed by using these primers and the mRNA as a template which was isolated from visceral lymphoblastoid tumors obtained from chickens artificially infected with strain Beijing 1 of oncogenic MDV. Southern blot molecular hybridization was further carried out to detect the product of RT PCR with digoxigenin labeled nucleotide probe from BamHI I2 and L fragment in the gene library of MDV strain GA, respectively. Results\ Two probes could simultaneously hybridize this cDNA amplified by RT PCR with a length of about 730 bp. Conclusion\ It is suggested that \%meq\% transcription could extend from the right hand end of BamHI I2 to the adjacent BamHI L, and the BamHI L region was likely to be transcribed in MDV induced lymphoblastoid tumors.

Prevalence of Kaposi's sarcoma-associated herpesvirus in Uygur and Han populations from the Urumqi and Kashgar regions of Xinjiang, China

Kaposi's sarcoma-associated herpesvirus(KSHV) is the infectious etiologic agent associated with Kaposi's sarcoma(KS), primary effusion lymphoma, and multicentric Castleman disease. It has been shown that high KSHV prevalence and high incidence of both classic KS and AIDSassociated KS are found mostly among people of Uygur ethnicity in Xinjiang, while people of Han ethnicity in Xinjiang have a higher KSHV seroprevalence than those of other Han populations in China's Mainland. However, it is still unclear why there is such geographical and population variation in KSHV distribution in China. In this work, we focused on the populations in the Kashgar region and Urumqi area, where a total of 1294 research subjects were randomly selected to investigate the potential correlation between KSHV prevalence and different ethnicities in endemic areas of Xinjiang, and to determine risk factors that may affect KSHV infection rates or KS incidence. We identified a high seroprevalence of KSHV and high peripheral blood DNA infection in the general Uygur and Han populations in both Urumqi and Kashgar regions of Xinjiang, and determined that advancing age, low education level, and stationary population status affect KSHV infection rates. Further, KSHV-positive Uygur participants were shown to have higher prevalence of neutralizing antibodies and neutralizing antibody titers than KSHV-positive Han participants.

Extracellular vesicles： novel vehicles in herpesvirus infection

Herpesviruses are remarkable pathogens that have evolved multiple mechanisms to evade host immunity, ensuring their proliferation and egress. Among these mechanisms, herpesviruses utilize elaborate extracellular vesicles, including exosomes, for the intricate interplay between infected host and recipient cells. Herpesviruses incorporate genome expression products and direct cellular products into exosomal cargoes. These components alter the content and function of exosomes released from donor cells, thus affecting the downstream signalings of recipient cells. In this way, herpesviruses hijack exosomal pathways to ensure their survival and persistence, and exosomes are emerging as critical mediators for virus infection-associated intercellular communication and microenvironment alteration. In this review, the function and effects of exosomes in herpesvirus infection will be discussed, so that we will have a better understanding about the pathogenesis of herpesviruses.

Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology

Human herpesviruses （HVs） have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system （CNS）. The ability of HVs to enter a state of latency, a defining char- acteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain. Under constant immune pressure, these infections are largely asymptomatic in healthy hosts. However, many neurotropic HVs have been directly connected with CNS pathology in the context of other stressors and genetic risk factors. In this review, we discuss the potential mechanisms by which neurotropic HVs contribute to neurodegenerative disease （NDD） patholo- gy by highlighting two prominent members of the HV family, herpes simplex virus 1 （HSV-1） and human herpesvirus 6 （HHV-6）. We （i） introduce the infectious pathways and replicative cycles of HSV-1 and HHV-6 and then （ii） review the clinical evidence supporting associations between these viruses and the NDDs Alzheimer＇s disease （AD） and multiple sclerosis （MS）, respectively. We then （iii） highlight and dis- cuss potential mechanisms by which these viruses exert negative effects on neurons and glia. Finally, we （iv） discuss how these viruses could interact with other disease-modifying factors to contribute to the initiation and/or progression of NDDs.

Reactivation of Latent Infection of Human Herpesvirus 8 in BC-3 Cells from Primary Effusion Lymphoma by Recombinant CytokinesSimilar to that Produced by HIV-1-infected T Cells

Objective: To study and confirm that recombinant cytokines similar to those produced by HIV-1 infected T cells induced lytic cycle replication of human herpesvirus 8 (HHV-8) in BC-3 cells, another cell line from primary effusion lymphama(PEL). Methods: The persistent stimulation of BC-3 was conducted by several cytokines known to be produced by HIV-1-infected T cells and important in growth and proliferation of Kaposi's sarcoma(KS)cells in vitro, such as the interferon-γ (IFN-γ) , tlie hepatocyte growth factor/scatter factor (HGF / SF) , the Oncostain M(OSM) , and the tumor necrosis factor-α (TNF-α)which is not produced by HIV-1-infected T cells. Treated and untreated BC-3 cells were collected at the 3rd and 7th day of persistent stimulation, respectively. Immuno-histochemical (IHC) staining, Northern blot, quantitative PCR (real- time PCR ) and electron microscopy (EM) were carried out to detect the expression of immunogenic protein ORF59, messenger RNA (mRNA) of minor capsid protein ORF26, and the presence of viral particles of HHV-8 from treated and untreated BC-3 cells. Results: It showed that IFN-γ, HGF/SF, OSM, and TNF-α were found to induce an increase in mRNA expression of ORF26 when added individually to BC-3 cells. Particularly, ORF26 expression stimulated with IFN-γ and TNF-α respectively, increased 6. 1 and 2. 5-fold(from real-time PCR results)at the 7th day when compared with untreated BC-3 cells. Meanwhile, about 20% of IFN-γ stimulated BC-3 cells expressed ORF59 at the 7th day as compared with 1. 5% of untreated BC-3 cells when IHC staining was employed. In addition, viral particles of HHV-8 were readily identified in BC-3 cells stimulated with IFN-γ at the 7th day with EM analysis. Conclusion;TNF-α and recombinant cytokines being similar to those produced by HIV- 1 infected T Cells could really induce HHV- 8 lytic cycle replication in BC-3 cells, another cell line of PEL.

Role of the virion host shutoff protein in neurovirulence of monkey B virus(Macacine herpesvirus 1)

Monkey B virus(Macacine herpesvirus 1; BV) is noted for its extreme neurovirulence in humans. Since the vhs protein encoded by the UL41 gene has been shown to be a neurovirulence factor in the related human herpes simplex viruses, the role of the UL41 gene in BV neurovirulence was investigated. BV mutants were constructed that lacked the entire UL41 ORF(Δ41) or had the RNase active site mutated(Δ41A). Neither mutant shut off host protein synthesis, degraded β-actin mRNA, or prevented an IFN-β response, indicating that the vhs protein and its RNase activity are both necessary for these activities. Replication of both mutants in primary mouse cells was impaired and they exhibited a prolonged disease course in mice. Whereas Δ41 infected mice were euthanized for symptoms related to central nervous system(CNS) infection, Δ41A infected mice were euthanized primarily for symptoms of autonomic nervous system dysfunction. While neuroinvasiveness was not affected, lesions in the CNS were more limited in size, anatomical distribution, and severity than for wild-type virus. These results indicate that the vhs protein affects the general replicative efficiency of BV in vivo rather than being a specific neurovirulence factor critical for invasion of or preferential replication in the CNS.

Regulation of Wnt/β-catenin signaling by herpesviruses

The Wnt/β-catenin signaling pathway is instrumental in successful differentiation and proliferation of mammalian cells. It is therefore not surprising that the herpesvirus family has developed mechanisms to interact with and manipulate this pathway. Successful coexistence with the host requires that herpesviruses establish a lifelong infection that includes periods of latency and reactivation or persistence. Many herpesviruses establish latency in progenitor cells and viral reactivation is linked to host-cell proliferation and differentiation status. Importantly, Wnt/β-catenin is tightly connected to stem/progenitor cell maintenance and differentiation. Numerous studies have linked Wnt/β-catenin signaling to a variety of cancers, emphasizing the importance of Wnt/β-catenin pathways in development, tissue homeostasis and disease. This review details how the alpha-, beta-, and gammaherpesviruses interact and manipulate the Wnt/β-catenin pathway to promote a virus-centric agenda.

Human herpesvirus 6A induces apoptosis of HSB-2 cellsvia a mitochondrion-related caspase pathway

Apoptosis plays an important role in the pathogenesis of viral infections.In this study,we investigated the cell death processes during productive HHV-6A infection and the underlying mechanisms.Annexin V-PI staining and electron microscopy indicated that HHV-6A is a strong inducer of apoptosis.HHV-6A infection decreased mitochondrial transmembrane potential and led to morphological changes of mitochondria.The cell death was associated with activation of caspase-3 and cleavage of DNA repair enzyme poly （ADP-ribose） polymerase,which is known to be an important substrate for activated caspase-3.Caspase-9 was activated significantly in HHV-6A-infected cells,whereas caspase-8 was not activated obviously.Moreover,HHV-6A infection upregulated Bax and downregulated Bcl-2.This is the first demonstration of mitochondrion-mediated,caspase-dependent apoptosis in HHV-6A-infected cells.

Development of a sandwich ELISA for the detection of bovine herpesvirus type 1

Objective:To develop a standard enzyme-linked immunosorbent assay（ELJSA） for the detection of bovine herpesvirus type 1（BHV-1）.Methods:The assay was based on hyperimmune rabbit and guinea pig antisera raised against purified BHV-1.Polyethylene glycol precipitation and sucrose density gradient methods were adopted for viral concentration and purification.Antisera were raised using Freund’s adjuvant followed by extraction of IgG of high purity.Results: Optimum antisera dilutions as determined by titrations were chosen as 14 000,whereas the conjugate was used at 1:2 000 dilution.Using 95 clinical specimens,the ELISA test showed a sensitivity and specificity of 91.90%and 93.10%,respectively when compared to PCR.The cutoff value was fixed at 0.15490) and a P/N ratio of】1.30 indicated a significant positive reaction. Conclusions:The results have demonstrated that this ELISA could efficiently detect BHV-1 and can be used as an important diagnostic tool.

Prevalence of human herpesvirus 8 infection in patients undergoing hemodialysis using nested-PCR

Objective:To study the prevalence of HHV-8 infection in patients undergoing hemodialysis.Methods:In this study,blood samples of 89 patients undergoing hemodialysis were collected.DNA was extracted from peripheral blood mononuclear cells and HHV-8 DNA was evaluated by nested-PCR.Results:Of total 89 patients,51(57.3%)were males and 38(42.7%)were females.The patients'age ranged from 24 to 90 years and the mean age was(57.5±1.4)years.HHV-8 DNA was found in 9 of 89(10.1%)peripheral blood mononuclear cell samples,8/51(15.7%)in males and 1/38(2.6%)in females(P=0.07).All patients who were positive for HHV8-DNA were more than 50 years old.Conclusions:This study shows high prevalence of HHV-8.Since hemodialysis patients are candidates for kidney transplantation and due to the possibility of HHV8-reactivation and its serious complications in immunocompromised patients,routine screening for detection of the virus should be implemented for all hemodialysis patients.

Molecular Cloning and Sequencing of a Specific cDNA Mapping to the Bam HI-I2 and -LFragments within the Inverted Repeats of Unique Long Region(IRL) from the Genom e of the Marek′s Disease Herpesvirus (MDV) Oncogenic Strain Beijing-1

Isolation and identification of a specific cDNA mapping to the BamHI I2 and L fragments from the inverted repeats of unique long region(IRL) in the genome of Marek′s disease herpesvirus (MDV) oncogenic strain Beijing 1 had been previously performed by us. In this study, the specific cDNA was cloned into phagemid vectors PUC118 and 119 on the basis of prefabricated two recognized sites in synthesized primers. Recombinants were further identified with restriction pattern, molecular hybridization, and DNA sequencing analysis. It was demonstrated that this cDNA with 720 base pair (bp) contained sequences including a potentially incomplete open reading frame (ORF) encoded a 238 amino acids (aa) predicted polypeptide which was significantly homologous not only to part of N terminus of meq, but also to that of XbaI ClaI subfragment of BamHI L. In accordance with these data, following results could be deduced:①the 720 bp cDNA represented a spliced transcript;②meq transcription could be extended from the right hand end of BamHI I2 to the adjacent BamHI L fragment;③the L region was transcribed in varying degrees\ in MDV induced lymphoblastoid tumors.

Effectof the Local Strain CN5 of Human Herpesvirus 6 on CD Molecule Expression and PHA-Induced Proliferation of Cord Blood or Peripheral Blood Mononuclear Cells

Cord blood mononuclear cells (CBMC's) and adult peripheral blood mononuclear cells (PBMCs), cultured with RPMI 1640 medium containing 20% fetal calf serum plus 5 mg/L PHA and 10 mg/L IL-Z, were inoculated with CN5 strain of human herpesvirus 6 (HHV 6 ) isolated from a Chinese patient with exanthem subitum and the CN5 infected cell lysates were added to cultures of CBMCs and PBMCs, so as to observe the effects of the local strain CN5 on expression of CD molecule or on proliferation of mononuclear cells by the methods of APAAP staining and MTT assay.The results were as follows: ①Expressions of some CD antigens of CBMCs and PBMCs could change after CN5 strain infection. In both cases, CD3 expresion was down-regulated while CD4 expression was up-regulated. There were no significant differences of CD2, CD8 and CD45RA expressions between the two groups with and without CN5 infection. But the ratio of CD4 to CD8 sigmificantly rose because of the increasing of CD4 positiveity. ②The lysates of CB5-infected CBMCs inhibited the liferation of PBMCs, not of CBMCs, in a protein concentration-dependent pattern. This inhibition was partially neutralized by specific antiserum to CN5, not by antisera to INF-α and TNF-α.

The Role of Human Herpesvirus 8 Molecular Characterization in the Management of HIV Infected Patients Diagnosed with Malignancies Associated with Its Infection

Despite the progress has been reached with Human herpesvirus 8 (HHV-8) research, there are gaps in the knowledge of viral induced oncogenesis. The aim of the present study was to identify possible associations between HHV-8 subtypes, HHV-8 loads and clinical manifestations of HIV infected patients diagnosed with different malignancies associated with HHV-8 infection. Forty six HIV-1 infected individuals diagnosed with different HHV-8 associated diseases were studied [37 epidemic Kaposi’s sarcoma (KS), 3 pleural effusion lymphoma (PEL);5 peripheral lymphadenopathies (PL);1 Hodgkin’s lymphoma (HL);1 non Hodgkin’s lymphoma (NHL)]. HHV-8 loads were determined by quantitative real time PCR (qRT-PCR) whilst HHV-8 subtypes were determined by open-reading frame (ORF)-K1 gen genotyping. HHV-8 subtypes B, A, C, A5 and E were exhibited by 31.8%, 23.4%, 19.1%, 17% and 8.5% of the studied patients, respectively. The median HHV-8 viral load did not differ between subtypes (p > 0.05) but HHV-8 viral loads were significantly higher in PEL than in epidemic KS lesion or lymph nodes (p = 0.04). Subtype B was detected in 60% of patients with B cell lymphoma (NHL, PEL and HL) whereas subtype E was only detected in patients with epidemic KS diagnosis. Our data suggest that HHV-8 DNA quantification instead of subtype identification could be used as a surrogate marker for monitoring its infection, not only in epidemic KS patients but also in HIV infected individuals with lymphoproliferative disorders.

Stimulation of Phagocytosis and Production of Antibodies against Canine Herpesvirus Type 1 by Pidotimod (Adimod^TM)

Neutrophils are the most important circulating phagocytes. Circulating mono-cytes and precursors of tissue macrophages also have the ability to phagocytize. Pidotimod (ADIMODTM) exerts immunostimulatory and immunoregulatory effects through the stimulation and regulation of cellular immune responses by lymphocytes Canine herpesvirus (CHV) mainly affect puppies between the first and second weeks of age, causing high morbidity in the litter. To date, there is only one commercial vaccine in Europe to prevent disease. In this work, inactivated CHV cultures were inoculated in rabbits, adsorbed and not adsorbed to chitosan nanoparticles. Phagocytosis in the presence or absence of specific antibodies was measured. Response of virus neutralizing antibodies was also evaluated. AdimodTM enhanced the nonspecific and specific phagocytotic response. The association of the virus to the nanoparticles increased the phagocytic ability of blood cells;however, AdimodTM alone had a greater effect on phagocytic activity and generated a stronger immune response that corresponded to the increased phagocytosis (p TM was used.

Investigation of DNA Sequences Related to Latency-Associated Transcripts in the Genome of Canine Herpesvirus Type 1 (CHV-1) by Means of Bioinformatics Tools

A characteristic common to herpesviruses is the ability to establish a latent infection in the hosts, a transcriptionally active region has detected during latency as well as a set of RNA that are known as Latency Associated Transcripts (LATs), their functions have been clarified in recent work. The present work was carried using different bioinformatics method in order to determine if Herpesvirus Canine 1 (CHV-1) has a region associated with latency. Our result was the selection of nine sequences candidate of micro RNA (miRNA) (MIREval 2.0 software), and 26 miRNA (miRNAFold v.1.0 software), of them, were selected 14 with real precursors of miRNA, two were found between the RL2 and RS1 genes, one in the RL2 gene and 11 in the RS1 gene. The results showed that the similarities of these regions are very low among the herpesviruses analyzed, so it was not possible to deduce the presence of the LAT gene in canine herpesvirus type 1 with bioinformatics. On the other hand, the comparison showed that the miRNA predicted: chv1-mir-mirnafold-8 has similarity with the ebv-mir-BART7-3p of Epstein-Barr Virus (EBV), in this way, the microRNAs predicted by means of bioinformatic programs met the theoretical requirements of these molecules, however at not having a degree of preservation in other herpesviruses, the expression by CHV-1 in latency cannot be confirmed and it is necessary to identify through experimental tests.

Canine Herpesvirus Latent Infection in Experimentally Infected Rabbits

An experimental inoculation of canine Herpesvirus (HVC), strain H17, was performed in rabbits previously and simultaneously treated with dexamethasone, the behavior of the leukocyte count was followed prior and during the experimental phase. Upon death or euthanasia of the animals, a necropsy and evaluation of various organs was performed by histopathology and by nested PCR against the Herpesvirus Polymerase gene. All animals inoculated with dexamethasone showed leukopenia (p < 0.05), animals inoculated with HVC and treated with dexamethasone did not show significant histological lesions, but showed amplification of the Herpesvirus Polymerase gene in various organs despite not showing clinical signs of the illness. A dolphin Herpesvirus isolate was used as a positive control as rabbits developed fatal systemic disease and lesions typical of active (lytic) infection in various organs within 72 hours post-inoculation. The absence of clinical signs, significant histological lesions, and the presence of viral DNA in some organs suggested a state of latency due to canine Herpesvirus. Dexamethasone allowed HVC infection, but did not promote viral reactivation in rabbits contrary to that observed in canines experimentally induced to the lytic cycle by HVC.

Canine Herpesvirus Seroprevalence and Associated Factors in Dogs of Mexico

Canine herpesvirus (CHV-1) causes disease associated with high mortality in infect-ed puppies, which represents large financial losses for dog breeders. Since CHV-1 at the time of the study he had not been reported in Mexico, the main objective of this study was to determine the prevalence of antibodies against CHV-1 in canine kennels in the metropolitan area of Mexico City. A commercial enzyme-linked immuno-sorbent assay (ELISA) was used, and the results were compared to those of a viral neutralization test. The ELISA kit uses the complete viral particle as the antigen. The plaque reduction neutralization test was combined with the immunoperoxidase technique because of the low cytopathic effect of CHV-1. Neutralizing antibodies were also detected in 20 randomly selected samples. The prevalence of CHV-1 with ELISA was 87%. The concordance between ELISA and serum neutralization (SN) was 0.1129, the sensitivity of the ELISA against SN was 1.0 (100%), the positive predic-tive value was 0.39 (39%), and the negative predictive value was 1 (100%). These results show that ELISA is useful for monitoring the dog population for CHV-1;a positive test result requires confirmation with an SN test, and a negative ELISA result indicates a high probability of being SN-negative. The only variables that were sta-tistically associated with CHV-1 prevalence were breed and kennel. A statistically significant relationship between the degree of ELISA and SN titer was obtained, with a confidence level of 95%. None of the clinical presentation factors was statistically significant. These results suggest that most of the canine population studied in Mex-ico is in a herpesvirus latency state.