Reactivation Of Herpesvirus Research Articles

RIG-I Detects Kaposi's Sarcoma-Associated Herpesvirus Transcripts in a RNA Polymerase III-Independent Manner.

ABSTRACTRetinoic acid-inducible gene I (RIG-I) is a cytosolic pathogen recognition receptor that initiates the innate immune response against many RNA viruses. We previously showed that RIG-I restricts Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation (J. A. West et al., J Virol 88:5778–5787, 2014, https://doi.org/10.1128/JVI.03226-13). In this study, we report that KSHV stimulates the RIG-I signaling pathway in a RNA polymerase (Pol) III-independent manner and subsequently induces type I interferon (IFN) responses. Knockdown or inhibition of RNA Pol III had no effect on beta interferon (IFN-β) induction by KSHV. By using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) approach, we identified multiple KSHV regions that give rise to RNA fragments binding to RIG-I, such as ORF810420-10496, Repeat region (LIR1)119059-119204, and ORF2543561-43650. The sequence dissimilarity between these fragments suggests that RIG-I detects a particular structure rather than a specific sequence motif. Synthesized ORF810420-10496 RNA stimulated RIG-I-dependent but RNA Pol III-independent IFN-β signaling. In summary, several KSHV RNAs are sensed by RIG-I in a RNA Pol III-independent manner.

Abstract 603: Immune response to the influenza vaccination and heart rate variability in breast cancer survivors

Abstract Background: Cancer treatment dysregulates immune function. These effects can persist long after the cessation of therapy and may diminish the immune system's ability to effectively mount an adequate immune response. Latent herpesvirus reactivation may mark a poor immune response to the influenza vaccination. Cancer treatment can also cause adverse effects on cardiac autonomic function as assessed by heart-rate variability (HRV), which is associated with higher morbidity and decreased survival in patients with cancer. Objective: To determine immune response to seasonal influenza vaccination as measured by human cytomegalovirus (CMV) IgG antibody titers and HRV in breast cancer survivors treated with radiation relative to healthy aged-matched controls. Methods: Serum samples for 13 breast cancer survivors within the first year of post-treatment and 13 healthy age-matched controls (mean age 44.7 years) were assayed for CMV IgG antibody titers and heart-rate variability was assessed using MindWare technologies. Group differences between cancer survivors versus healthy individuals were estimated using analysis of covariance (ANCOVA), with adjustment for age, body mass index (BMI) and race. Results: One-way ANCOVA modeling showed that breast cancer survivors treated with radiation had significantly higher antibody titers to CMV relative to age-matched healthy controls (F = 9.15 ; p <.01). While heart rate did not differ among the two groups (F = .36 ; p = .56), high frequency values were significantly lower in breast cancer survivors relative to the healthy controls (HF: F = 10.40 ; p <. 01). Conclusion: Breast cancer survivors manifested a dampened immune response to influenza vaccination and cardiovascular imbalance compared to healthy age-matched controls. These findings have important implications for long-term treatment outcomes. Citation Format: Annina Seiler, Angie S. LeRoy, Christopher P. Fagundes. Immune response to the influenza vaccination and heart rate variability in breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 603.

Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions.

Recent studies have established that dysregulation of the human immune system and the reactivation of latent herpesviruses persists for the duration of a 6-month orbital spaceflight. It appears certain aspects of adaptive immunity are dysregulated during flight, yet some aspects of innate immunity are heightened. Interaction between adaptive and innate immunity also seems to be altered. Some crews experience persistent hypersensitivity reactions during flight. This phenomenon may, in synergy with extended duration and galactic radiation exposure, increase specific crew clinical risks during deep space exploration missions. The clinical challenge is based upon both the frequency of these phenomena in multiple crewmembers during low earth orbit missions and the inability to predict which specific individual crewmembers will experience these changes. Thus, a general countermeasure approach that offers the broadest possible coverage is needed. The vehicles, architecture, and mission profiles to enable such voyages are now under development. These include deployment and use of a cis-Lunar station (mid 2020s) with possible Moon surface operations, to be followed by multiple Mars flyby missions, and eventual human Mars surface exploration. Current ISS studies will continue to characterize physiological dysregulation associated with prolonged orbital spaceflight. However, sufficient information exists to begin consideration of both the need for, and nature of, specific immune countermeasures to ensure astronaut health. This article will review relevant in-place operational countermeasures onboard ISS and discuss a myriad of potential immune countermeasures for exploration missions. Discussion points include nutritional supplementation and functional foods, exercise and immunity, pharmacological options, the relationship between bone and immune countermeasures, and vaccination to mitigate herpes (and possibly other) virus risks. As the immune system has sentinel connectivity within every other physiological system, translational effects must be considered for all potential immune countermeasures. Finally, we shall discuss immune countermeasures in the context of their individualized implementation or precision medicine, based on crewmember specific immunological biases.

A nuclear receptor involved in cholesterol metabolism regulates herpesvirus latency and reactivation

Abstract Herpesviruses are a component of our virome, and infect virtually everyone. They establish chronic latent infection that is punctuated with periods of viral reactivation. Reactivation is thought to drive herpesvirus pathologies, including lymphomas and tumors. However, the signals that promote herpesvirus reactivation are poorly understood. We previously showed that parasite co-infection could induce herpesvirus reactivation through the induction of the cytokines IL-4 and IL-13, and activation of Stat6. Stat6 directly binds to a viral promoter and induces virus reactivation, suggesting that the virus has evolved to sense immune signals from the host to modulate reactivation. We sought to identify other factors that induce herpesvirus reactivation through the modulation of inflammation. We found that peroxisome proliferator-activated receptor (PPAR)-a, a ligand-activated nuclear receptor, is upregulated during g-herpesvirus infection. PPAR-a is activated by endogenous fatty acids to regulate cholesterol metabolism. PPARs also regulate inflammation, although these functions are less well understood. We found that agonist activation of PPAR-a induces herpesvirus reactivation. PPAR-a activation dampens type I interferon signaling, by inhibiting genes that modulate the DNA sensing pathway. These data suggest that in addition to evolving cytokine-sensitive promoters, herpesviruses induce cellular machinery that sense fatty acids as a means of regulating viral reactivation.

Increased reactivation of murine gammaherpesvirus-68 during Heligmosomoides polygyrus infection

Abstract A vast majority of people are infected with a herpesvirus. These viruses are double stranded DNA viruses that avoid eradication by the immune system by becoming latent. Certain signals, such as immune repression, can lead to reactivation of the virus. Reactivation of gamma herpesviruses is associated with pathologies, such as lymphomas and tumors. Past studies have shown that infection with helminths, extracellular parasitic worms, during gamma herpesvirus latency can cause reactivation. Helminths are known to secrete immunomodulatory factors that suppress host inflammation. The aim of the current study is to determine how prior helminth infection leads to increased reactivation of murine gammaherpesvirus-68 (MHV68). In this study, mice were or were not infected with Heligmosomoides polygyrus (HP), and then infected with MHV68. We found that infection with HP increased the reactivation of virus and the number of infected cells. However, there was no difference in acute replication of the virus between HP infected mice and HP uninfected mice. This suggests that the helminth infection specifically alters viral reactivation. The increased reactivation was only seen in a conventional mouse facility, but not in a barrier mouse facility, suggesting dependence on a microbiota component. Further work is required to determine how HP infection alters immune signals, such as IL-4 and STAT6 signaling, to cause increased MHV68 reactivation. Whether HP alters the permissiveness of cells to MHV68 infection should also be explored.

Herpes reactivation after Fingolimod in MS patients: What happens after drug use in real world? (P5.373)

Herpes reactivation after Fingolimod in MS patients: What happens after drug use in real world? (P5.373)

The Assessment of the Association Between Herpesviruses and Subgingival Bacterial Plaque by Real-time PCR Analysis

This study used a real-time PCR analysis to determine possible correlations between periodontal presence of human cytomegalovirus, Epstein-Barr virus and various putative parodontopathogenic bacteria. The study included 18 patients (aged 18-38 years) with aggressive periodontitis, 12 patients (ages 37 to 62) with chronic periodontitis and 30 periodontally healthy subjects (aged 21-54 years). Clinical periodontal evaluation included plaque index, gingival index, percentage of bleeding on probing sites, and probing depth. In each patient, a subgingival bacterial plaque sample was obtained from the deepest periodontal pocket. The real-time fluorogenic PCR detection system was used to determine the number of infectious agents. Human cytomegalovirus was detected in 17 sites with periodontal lesions and in two healthy periodontal sites, and the Epstein-Barr virus was detected in 19 sites with periodontal lesions and in 3 normal periodontal sites. Positive correlations were found between human cytomegalovirus and P. gingivalis, T. forsythia and C. rectus. The Epstein-Barr virus positively correlated with P. gingivalis and T. forsythia. Unfavorable changes in environmental exposure or alteration of the immune system genes can periodically suppress the host�s defence against periodontal aggression, which can then result in reactivation of resident herpesviruses and increased pro-inflammatory mediators followed by an increase in pathogenic bacteria.

Latent viral reactivation is associated with changes in plasma antimicrobial protein concentrations during long-duration spaceflight

Long duration spaceflights are associated with profound dysregulation of the immune system and latent viral reactivations. However, little is known on the impact of long duration spaceflight on innate immunity which raises concerns on crewmembers' ability to fight infections during a mission. The aim of this study was to determine the effects of spaceflight on plasma antimicrobial proteins (AMPs) and how these changes impact latent herpesvirus reactivations. Plasma, saliva and urine samples were obtained from 23 crewmembers before, during and after a 6-month mission on the International Space Station (ISS). Plasma AMP concentrations were determined by ELISA, and saliva Epstein-Barr virus (EBV) and varicella zoster virus (VZV) and urine cytomegalovirus (CMV) DNA levels were quantified by Real-Time PCR. There was a non-significant increase in plasma HNP1-3 and LL-37 during the early and middle stages of the missions, which was significantly associated with changes in viral DNA during and after spaceflight. Plasma HNP1-3 and Lysozyme increased at the late mission stages in astronauts who had exhibited EBV and VZV reactivations during the early flight stages. Following return to Earth and during recovery, HNP1-3 and lysozyme concentrations were associated with EBV and VZV viral DNA levels, reducing the magnitude of viral reactivation. Reductions in plasma LL-37 upon return were associated with greater CMV reactivation. This study shows that biomarkers of innate immunity appeared to be partially restored after 6-months in space and suggests that following adaptation to the space environment, plasma HNP1-3 and lysozyme facilitate the control of EBV and VZV reactivation rate and magnitude in space and upon return on earth. However, the landing-associated decline in plasma LL-37 may enhance the rate of CMV reactivation in astronauts following spaceflight, potentially compromising crewmember health after landing.

558 - Reactivation of Human Herpesvirus 6 (HHV6) in Pediatric Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients

558 - Reactivation of Human Herpesvirus 6 (HHV6) in Pediatric Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients

Recent Advances in Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms.

Drug-induced hypersensitivity syndrome (DIHS), also termed as drug reaction with eosinophilia and systemic symptoms (DRESS), is a multiorgan systemic reaction characterized by a close relationship with the reactivation of herpes virus. Published data has demonstrated that among patients with DIHS/DRESS, 75–95% have leukocytosis, 18.2–90% show atypical lymphocytes, 52–95% have eosinophilia, and 75–100% have hepatic abnormalities. Histologically, eosinophils were observed less frequently than we expected (20%). The mainstay of DIHS/DRESS treatment is a moderate dose of systemic corticosteroids, followed by gradual dose reduction. In this review, we will emphasize that elevations in the levels of several cytokines/chemokines, including tumor necrosis factor- (TNF-) α and the thymus and activation-regulated chemokine (TARC/CCL17), during the early stage of disease, are good markers allowing the early recognition of HHV-6 reactivation. TNF-α and TARC levels also reflect therapeutic responses and may be useful markers of the DIHS disease process. Recently, the pathogenic mechanism of T-cell activation triggered by human leukocyte antigen- (HLA-) restricted presentation of a drug or metabolites was elucidated. Additionally, we recently reported that dapsone would fit within the unique subpocket of the antigen-recognition site of HLA-B∗13:01. Further studies will render it possible to choose better strategies for DIHS prevention and therapy.

New Insights into Drug Reaction with Eosinophilia and Systemic Symptoms Pathophysiology.

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome, is a severe type of cutaneous drug-induced eruption. DRESS may be a difficult disease to diagnose since the symptoms mimic those of cutaneous and systemic infectious pathologies and can appear up to 3 months after the initial culprit drug exposure. The symptoms of DRESS syndrome include rash development after a minimum of 3 weeks after the onset of a new medication, associated with facial edema, lymphadenopathy, and fever. Biological findings include liver abnormalities, leukocytosis, eosinophilia, atypical lymphocytosis, and reactivation of certain human herpes viruses. In DRESS, liver, kidneys, and lungs are frequently involved in disease evolution. Patients with serious systemic involvement are treated with oral corticosteroids, and full recovery is achieved in the majority of cases. DRESS is a rare disease, and little is known about factors that predict its occurrence. The key features of this reaction are eosinophil involvement, the role of the culprit drug, and virus reactivation that trigger an inappropriate systemic immune response in DRESS patients. Interestingly, it was evidenced that at-risk individuals within a genetically restricted population shared a particular HLA loci. In this respect, a limited number of well-known drugs were able to induce DRESS. This review describes the up-to-date advances in our understanding of the pathogenesis of DRESS.

Herpesvirus and Autophagy: "All Right, Everybody Be Cool, This Is a Robbery!"

Autophagy is an essential vacuolar process of the cell, leading to lysosomal degradation and recycling of proteins and organelles, which is extremely important in maintaining homeostasis. Multiple roles have been now associated with autophagy, in particular a pro-survival role in nutrient starvation or in stressful environments, a role in life span extension, in development, or in innate and adaptive immunity. This cellular process can also take over microorganisms or viral proteins inside autophagosomes and degrade them directly in autolysosomes and is then called xenophagy and virophagy, respectively. Several Herpesviruses have developed strategies to escape this degradation, by expression of specific anti-autophagic proteins. However, we are increasingly discovering that Herpesviruses hijack autophagy, rather than just fight it. This beneficial effect is obvious since inhibition of autophagy will lead to decreased viral titers for human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) or Varicella-Zoster virus (VZV), for example. Conversely, autophagy stimulation will improve viral multiplication. The autophagic machinery can be used in whole or in part, and can optimize viral propagation or persistence. Some viruses block maturation of autophagosomes to avoid the degradation step, then autophagosomal membranes are used to contribute to the envelopment and/or the egress of viral particles. On the other hand, VZV stimulates the whole process of autophagy to subvert it in order to use vesicles containing ATG (autophagy-related) proteins and resembling amphisomes for their transport in the cytoplasm. During latency, autophagy can also be activated by latent proteins encoded by different oncogenic Herpesviruses to promote cell survival and achieve long term viral persistence in vivo. Finally, reactivation of gammaherpesvirus Murid Herpesvirus 68 (MHV68) in mice appears to be positively modulated by autophagy, in order to control the level of inflammation. Therefore, Herpesviruses appear to behave more like thieves than fugitives.

Localization of Double-Strand Break Repair Proteins to Viral Replication Compartments following Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus.

ABSTRACTDouble-strand breaks (DSBs) in DNA are recognized by the Ku70/80 heterodimer and the MRE11-RAD50-NBS1 (MRN) complex and result in activation of the DNA-PK and ATM kinases, which play key roles in regulating the cellular DNA damage response (DDR). DNA tumor viruses such as Kaposi's sarcoma-associated herpesvirus (KSHV) are known to interact extensively with the DDR during the course of their replicative cycles. Here we show that during lytic amplification of KSHV DNA, the Ku70/80 heterodimer and the MRN complex consistently colocalize with viral genomes in replication compartments (RCs), whereas other DSB repair proteins form foci outside RCs. Depletion of MRE11 and abrogation of its exonuclease activity negatively impact viral replication, while in contrast, knockdown of Ku80 and inhibition of the DNA-PK enzyme, which are involved in nonhomologous end joining (NHEJ) repair, enhance amplification of viral DNA. Although the recruitment of DSB-sensing proteins to KSHV RCs is a consistent occurrence across multiple cell types, activation of the ATM-CHK2 pathway during viral replication is a cell line-specific event, indicating that recognition of viral DNA by the DDR does not necessarily result in activation of downstream signaling pathways. We have also observed that newly replicated viral DNA is not associated with cellular histones. Since the presence and modification of these DNA-packaging proteins provide a scaffold for docking of multiple DNA repair factors, the absence of histone deposition may allow the virus to evade localization of DSB repair proteins that would otherwise have a detrimental effect on viral replication.IMPORTANCE Tumor viruses are known to interact with machinery responsible for detection and repair of double-strand breaks (DSBs) in DNA, although detail concerning how Kaposi's sarcoma-associated herpesvirus (KSHV) modulates these cellular pathways during its lytic replication phase was previously lacking. By undertaking a comprehensive assessment of the localization of DSB repair proteins during KSHV replication, we have determined that a DNA damage response (DDR) is directed to viral genomes but is distinct from the response to cellular DNA damage. We also demonstrate that although recruitment of the MRE11-RAD50-NBS1 (MRN) DSB-sensing complex to viral genomes and activation of the ATM kinase can promote KSHV replication, proteins involved in nonhomologous end joining (NHEJ) repair restrict amplification of viral DNA. Overall, this study extends our understanding of the virus-host interactions that occur during lytic replication of KSHV and provides a deeper insight into how the DDR is manipulated during viral infection.

Pain in the elderly and its association with latent Epstein-Barr virus reactivation

Background Stress promotes immune dysregulation, including reactivation of latent viral infections and inflammation. Immune dysregulation can have severe health consequences, including delayed wound healing, impaired responses to vaccination, development and progression of cancer, and onset of mood disorders. Little is known about how pain is associated with reactivation of herpesviruses. Objective To evaluate the effects of pain on reactivation of latent Epstein-Barr virus (EBV), c-reactive protein (CRP), and interleukin-6 (IL-6) after controlling for age, gender, body mass index (BMI), race and income. Methods 51 bereaved and 64 controls were examined for pain (SF-36_Pain_Subscale) and immune dysregulation (EBV antibody titers, CRP, and IL-6). Linear regression models, adjusted for age, gender, BMI, race, and income were used to examine the association between pain and immune dysregulation. Results Results showed that greater pain was associated with higher reactivation of EBV ( β = −0.30; p β = −0.22; p β = −0.14; p = 0.16). Moreover, being older was associated with reactivation of EBV ( β = 0.32; p β = 0.27; p β = 0.34; p Conclusion Our results add to growing evidence of how pain can promote immune dysregulation. To our knowledge, this study is the first to demonstrate an association between pain and reactivation of a latent herpesvirus, which provides important implications for health outcomes.

Cardiorespiratory fitness is associated with better control of latent herpesvirus infections in a large ethnically diverse community sample: Evidence from the Texas City Stress and Health Study

Regular exercise has been purported to improve immune function and prevent latent herpesvirus reactivation, which may help delay the onset of immunosenescence with advancing age. We determined the relationship between cardiorespiratory fitness (VO2max) and latent viral load in respondents of the Texas City Stress and Healthy Study (n = 1,455, 58.4 percent female; age 25–91 years). VO2max was estimated using non-exercise equations that incorporate physical activity rating, body-mass index, age and sex. VO2max was inversely associated with high serum antibody titers against the Epstein-Barr virus capsid antigen and cytomegalovirus (CMV) optical density (surrogate measure of viral load), withstanding adjustment for demographic variables (age, sex, race, education, income, smoking) and inflammation (IL-1; C-reactive protein). The VO2max and EBV relationship was strongest in Whites and Hispanics compared to Blacks, in women compared to men, and in those aged 65 years compared to those of younger age, but similar between men and women. VO2max was also inversely associated with high herpes simplex virus-1 antibody titers, but did not withstand adjustment for inflammation. We conclude that high levels of cardiorespiratory fitness are associated with better control of latent herpesvirus infections, advocating exercise as a viable behavioral intervention to offset age- related declines in immune function.

Commentary: High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus

Commentary: High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus

Effects of the NEDD8-Activating Enzyme Inhibitor MLN4924 on Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus.

ABSTRACTThe switch of Kaposi's sarcoma-associated herpesvirus (KSHV) from latency to lytic replication is a key event for viral dissemination and pathogenesis. MLN4924, a novel neddylation inhibitor, reportedly causes the onset of KSHV reactivation but impairs later phases of the viral lytic program in infected cells. Thus far, the molecular mechanism involved in the modulation of the KSHV lytic cycle by MLN4924 is not yet fully understood. Here, we confirmed that treatment of different KSHV-infected primary effusion lymphoma (PEL) cell lines with MLN4924 substantially induces viral lytic protein expression. Due to the key role of the virally encoded ORF50 protein in the latent-to-lytic switch, we investigated its transcriptional regulation by MLN4924. We found that MLN4924 activates the ORF50 promoter (ORF50p) in KSHV-positive cells (but not in KSHV-negative cells), and the RBP-Jκ-binding elements within the promoter are critically required for MLN4924 responsiveness. In KSHV-negative cells, reactivation of the ORF50 promoter by MLN4924 requires the presence of the latency-associated nuclear antigen (LANA). Under such a condition, LANA acts as a repressor to block the ORF50p activity, whereas MLN4924 treatment relieves LANA-mediated repression. Importantly, we showed that LANA is a neddylated protein and can be deneddylated by MLN4924. On the other hand, we revealed that MLN4924 exhibits concentration-dependent biphasic effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)- or sodium butyrate (SB)-induced viral reactivation in PEL cell lines. In other words, low concentrations of MLN4924 promote activation of TPA- or SB-mediated viral reactivation, whereas high concentrations of MLN4924, conversely, inhibit the progression of TPA- or SB-mediated viral lytic program.IMPORTANCE MLN4924 is a neddylation (NEDD8 modification) inhibitor, which currently acts as an anti-cancer drug in clinical trials. Although MLN4924 has been reported to trigger KSHV reactivation, many aspects regarding the action of MLN4924 in regulating the KSHV lytic cycle are not fully understood. Since the KSHV ORF50 protein is the key regulator of viral lytic reactivation, we focus on its transcriptional regulation by MLN4924. We here show that activation of the ORF50 gene by MLN4924 involves the relief of LANA-mediated transcriptional repression. Importantly, we find that LANA is a neddylated protein. To our knowledge, this is the first report showing that neddylation occurs in viral proteins. Additionally, we provide evidence that different concentrations of MLN4924 have opposite effects on TPA-mediated or SB-mediated KSHV lytic cycle activation. Therefore, in clinical application, we propose that MLN4924 needs to be used with caution in combination therapy to treat KSHV-positive subjects.

Drug rash with eosinophilia and systemic symptoms (DRESS) caused by phenytoin

Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare but potentially life-threatening condition with high mortality. Diagnosis is challenging due to variable clinical presentation and a protracted latency...

Diabetes and risk of Kaposi's sarcoma: effects of high glucose on reactivation and infection of Kaposi's sarcoma-associated herpesvirus.

Patients with diabetes are generally prone to pathogen infection and tumor progression. Here, we investigated the potential association between diabetes and Kaposi's sarcoma (KS), a tumor linked to infection with Kaposi's sarcoma-associated herpesvirus (KSHV). By using Taiwan's National Health Insurance Research Database, we found that diabetes is statistically associated with increased risk of KS in a case-control study. Since a high level of blood sugar is the hallmark of diabetes, we determined whether high glucose promotes both KSHV reactivation and infection, which are crucial for KS pathogenesis. Our results showed that high glucose significantly increases lytic reactivation of KSHV but not Epstein-Barr virus, another related human oncogenic gammaherpesvirus, in latently infected cells. Activation of the transcription factor AP1 by high glucose is critically required for the onset of KSHV lytic reactivation. We also demonstrated that high glucose enhances susceptibility of various target cells to KSHV infection. Particularly, in endothelial and epithelial cells, levels of specific cellular receptors for KSHV entry, including integrin α3β1 and xCT/CD98, are elevated under high glucose conditions, which correlate with the enhanced cell susceptibility to infection. Taken together, our studies implicate that the high-glucose microenvironment may be an important predisposing factor for KS development.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. Reactivation of human herpesviruses (HHV), especially HHV-6, is the hallmark of the disease. Anti-viral immune responses intertwined with drug hypersensitivity make the disease more complicated and protracted. In recent years, emerging studies have outlined the disease more clearly, though several important questions remain unresolved. In this review, we provide an overview of DRESS syndrome, including clinical presentations, histopathological features, pathomechanisms, and treatments.