Management of oral herpes simplex virus infections: The problem of resistance. A narrative review.

Herpes Simplex Virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) are among the most common human viral pathogens, affecting several billion people worldwide. Although in healthy patients clinical signs and symptoms of HSV infection are usually mild and self-limiting, HSV-infections in immunocompromised patients are frequently more aggressive, persistent, and even life-threatening. Acyclovir and its derivatives are the gold standard antiviral drugs for the prevention and treatment of HSV infections. Although the development of acyclovir resistance is a rather uncommon condition, it may be associated with serious complications, especially in immunocompromised patients. In this review, we aim to address the problem of drug resistant HSV infection and discuss the available alternative therapeutic interventions. All relative studies concerning alternative treatment modalities of acyclovir resistant HSV infection published in PubMed between 1989 to 2022 were reviewed. Long-term treatment and prophylaxis with antiviral agents predisposes to drug resistance, especially in immunocompromised patients. Cidofovir and foscarnet could serve as alternative treatments in these cases. Although rare, acyclovir resistance may be associated with severe complications. Hopefully, in the future, novel antiviral drugs and vaccines will be available in order to avoid the existing drug resistance.

Relationship Between Pemphigus Vulgaris Severity and PCR-positive Herpes Simplex Virus.

Pemphigus vulgaris is a rare autoimmune skin disease. Although herpes simplex virus has been associated with autoimmune diseases, evidence regarding its association with pemphigus vulgaris exacerbations is scarce. This retrospective cohort study aimed to characterize the epidemiological and clinical features of patients with pemphigus vulgaris who were herpes simplex-positive, compared with those who were herpes simplex-negative, during disease onset. Of 62 patients with pemphigus vulgaris who underwent PCR testing for herpes simplex virus, 25 (40.3%) were positive, with a mean age of 56.1 ± 15.5 years; 35.5% were male. The herpes-positive group had significantly elevated levels of C-reactive protein, Pemphigus Disease Activity Index score, and shorter time to relapse. The time to remission, number of exacerbations per year, and remission status were non-significantly elevated in the herpes-positive group. Thus, routine testing lesions from patients with pemphigus for herpes simplex virus should be performed. If positive, antiviral treatment should be initiated; and preventive antiviral treatment should be considered in severe cases.

The Solution Is a Solution.

BACKGROUND: Infections in neonates with herpes simplex virus 1 (HSV-1) following circumcision due to Metzitzah Be'Peh (MBP) performed by a Mohel occur each year in small numbers. One solution to this problem is the use of a mucus extractor device instead of MBP, which has been authorized by some rabbis. Yet, using a mucus extractor remains controversial among ultra-Orthodox Jews; thus, creating a need for additional solutions. OBJECTIVES: To seek to reduce HSV-1 infection of neonates due to MBP. METHODS: We tested several oral rinse solutions for their ability to destroy virus infectivity following incubation for 30 seconds and using plaque reduction assays. RESULTS: Corsodyl, Decapinol, and Listerine® all destroyed plaques formation of spiked virus, while Gengigel and Tantum Verde were found to be less effective. We focused specifically on Listerine® due to its efficacy in eliminating contagious HSV-1 from saliva after a 30-second oral rinse. Five different products of Listerine® reduced the infectivity of a spiked virus by more than 4 orders of magnitude in 30 seconds. We also showed that Listerine (up to 7% v/v) can stay in the mouth but did not harm living cells and therefore will not cause any damage to the injured tissue. CONCLUSIONS: Significant reduction in cases of infection with HSV-1 due to MBP can be achieved if Mohalim consistently adopt the practice of careful mouth washing with Listerine® just before performing MBP.

Primary infection with human herpes virus type 6, post-pediatric liver transplantation-A pathogen to remember.

BACKGROUND: In recent years, liver transplantation (LT) has become a well-accepted therapeutic modality for children with end-stage liver disease, with transplantation surgery being performed at a younger age. Human herpes virus 6 (HHV-6) infection occurs in most children within the first 2 years of life, therefore, data on primary HHV-6 infection in pediatric liver transplant recipients is scarce. OBJECTIVE: To describe the course of primary HHV-6 infection after pediatric LT. METHODS: Medical files, between the years 2015-2016, of post-LT pediatric patients with suspected primary HHV-6 infection were reviewed. Clinical and laboratory data for enrolled cases were evaluated. Primary infection was defined as DNAemia in children who were seronegative prior to transplantation or seroconversion from negative to positive IgG posttransplantation. RESULTS: Four cases of primary HHV-6 (type B) infection were identified among the 26 children who had undergone LT at our center during the study period. All patients were <1 year old and presented with fever, hepatitis, and elevated inflammatory markers, most (75%) within a short-period posttransplantation. All were initially treated with empiric antibiotics for a suspected bacterial infection and three underwent liver biopsy, one showing signs of rejection. Three were treated with antiviral therapy with a gradual resolution of symptoms. DISCUSSION: Primary HHV-6 should be taken into account in young children shortly after LT, especially when presenting with fever and elevated liver enzymes. Treatment with antiviral therapy should be considered. CONCLUSIONS: In young infants post-LT, a high index of suspicion may promote early detection of HHV-6 primary infection and prevent serious complications.

Superiority of West Nile Virus RNA Detection in Whole Blood for Diagnosis of Acute Infection.

The current diagnosis of West Nile virus (WNV) infection is primarily based on serology, since molecular identification of WNV RNA is unreliable due to the short viremia and absence of detectable virus in cerebrospinal fluid (CSF). Recent studies have shown that WNV RNA can be detected in urine for a longer period and at higher concentrations than in plasma. In this study, we examined the presence of WNV RNA in serum, plasma, whole-blood, CSF, and urine samples obtained from patients diagnosed with acute WNV infection during an outbreak which occurred in Israel in 2015. Our results demonstrate that 33 of 38 WNV patients had detectable WNV RNA in whole blood at the time of diagnosis, a higher rate than in any of the other sample types tested. Overall, whole blood was superior to all other samples, with 86.8% sensitivity, 100% specificity, 100% positive predictive value, and 83.9% negative predictive value. Interestingly, WNV viral load in urine was higher than in whole blood, CSF, serum, and plasma despite the lower sensitivity than that of whole blood. This study establishes the utility of whole blood in the routine diagnosis of acute WNV infection and suggests that it may provide the highest sensitivity for WNV RNA detection in suspected cases.

Analysis of HSV1/2 Infection Reveals an Association between HSV-2 Reactivation and Pregnancy.

The herpes simplex viruses consist of the strains, HSV-1 and HSV-2, which are prevalent worldwide and lack a definitive cure. We aimed to explore the specific characteristics of HSV 1 and 2 infections, such as differences between gender assigned at birth, age at infection, site of infection, comorbidities, and effect of pregnancy, through a data analysis. Between 2011 and 2018, the Israeli Central Virology Laboratory diagnosed 9189 samples using multiplexed real-time PCR. In addition, we extracted all of the medical data for 287 females hospitalized at the Sheba Medical Center with HSV-1 (161) or HSV-2 (126) genital infections. HSV-2 was almost absent in the orofacial samples from both genders, while in other lesion sites, HSV-2 was significantly more abundant in females than in males (p < 0.05,). HSV-2 was initially detected at puberty. In the hospitalized females' malignancies, both HSV-1 and HSV-2 were found with a non-significant difference. Simultaneously, pregnancies were more common in females who were HSV-2-positive compared with those who were HSV-1-positive (27.8% vs. 12.4%, respectively, p < 0.01). Primary infections occur more with HSV-1 than with HSV-2 (15.6% vs. 3.2%, respectively). Our findings demonstrate that genital HSV-2 infection episodes are more frequent during pregnancy, suggesting that pregnancy may serve as a risk factor for HSV-2 reactivation or infection.

The Outbreak of Unexplained Acute Hepatitis in Children: The Role of Viral Infections in View of the COVID-19 Pandemic.

BACKGROUND AND AIMS: An increase in the number of cases of acute hepatitis of unknown origin (HUO) in children was observed in 2021. Adenovirus and adeno-associated virus 2 (AAV2) infections have been suggested as possible triggers. However, the potential etiology is still unclear. We aimed to characterize a cohort of children with HUO in Israel in view of the COVID-19 pandemic. METHOD: Demographics, clinical data, and laboratory results on the children compatible with the CDC criteria for HUO were collected by the established registry of the Ministry of Health. Available specimens were sent to the Central Virology Laboratory. RESULTS: A total of 39 children were included in the registry. A total of 20 were enrolled prospectively, in which human herpes virus 6 (HHV6) infection or reactivation was identified in 11/19, adenovirus was found in 4/19 of the cases, and AAV2 was detected in 2/16. Past COVID-19 exposure was recorded for 24/39 of the children. A total of 10 children underwent liver biopsy, and 8 were successfully treated with steroids and 2 underwent liver transplantation. CONCLUSIONS: The COVID-19 pandemic and the related containment measures combined with reactivation or active infection with other viruses could have been a trigger for the HUO outbreak. In our cohort, HHV6 was the most abundant finding.

Polymerase-chain-reaction-based diagnosis of viral pulmonary infections in immunocompromised children.

AIM: Viral pneumonia is a serious complication in immunocompromised children. Its aetiology is difficult to identify owing to the limitations of conventional microbiological tests. The aim of this study was to determine whether polymerase chain reaction (PCR) assays for respiratory viruses increase the diagnostic yield of bronchoalveolar lavage (BAL) in immunocompromised children. METHODS: BAL samples obtained from immunocompromised children hospitalized with pneumonia were processed for respiratory viruses by viral culture, rapid antigen test and PCR (for CMV, adenovirus, influenza, parainfluenza, herpesvirus, RSV and hMPV). RESULTS: The study group included 42 patients (mean age 7.2 ± 5.1 years) with 50 episodes of clinical pneumonia (50 BAL samples). Forty viral pathogens were identified in 30 episodes (60%). PCR increased the diagnostic rate by fourfold (75% identified by PCR alone, p < 0.0001). When viral culture and rapid antigen test were used as the gold standard, PCR was found to have high sensitivity (86-100% when assessed) and specificity (80-96%). The PCR results prompted the initiation of specific antiviral therapy and the avoidance of unnecessary antibiotic treatment in 17 (34%) episodes. CONCLUSION: PCR-based diagnosis from BAL may increase the rate of pathogen detection in immunocompromised children, decrease the time to diagnosis and spare patients unnecessary antimicrobial treatment.

Varicella vaccine strain infection in a non-immunocompromised patient. A case report and review of literature.

Varicella live attenuated vaccine led to a significant reduction in morbidity and mortality from varicella zoster disease. Vaccine adverse effects are mostly mild. Immunosuppression is the main risk factor for severe varicella. Risk factors for disease following vaccination are less studied. We report a 12-month-old infant with no T-cell immunodeficiency who developed severe varicella infection by vaccine strain.

Human herpes virus 6 reactivation following autologous hematopoietic cell transplantation - a single-center experience.

Data regarding presentation and management of human herpes virus 6 (HHV-6) reactivation among autologous hematopoietic cell transplantation (HCT) recipients are limited. We retrospectively reviewed medical charts of all autologous HCT patients tested for HHV-6 reactivation due to suspected clinical presentation between 1/2012 and 8/2017. Among 328 autologous HCT recipients, 44 patients were tested for HHV-6 reactivation. Thirty patients tested positive; 29 (97%) had sustained fever, six (20%) had rash and four (13%) had pneumonia. Median C-reactive protein was significantly lower in HHV-6 positive patients compared to negative patients (3.6 (range, 0.4-11) vs. 9.6 (range, 3.2-30) mg/dL, respectively, p = .004). Ganciclovir formulations were administrated in 29 (97%) patients with median time to fever resolution of one (range, 1-2) day. HHV-6 should be considered as an important cause of post engraftment fever in autologous HCT. Larger studies are warranted to evaluate incidence of HHV-6 reactivation and optimal treatment regimen.

Induction of G2/M arrest and apoptosis by sesquiterpene lactones in human melanoma cell lines.

Malignant melanoma is a highly aggressive tumor which frequently resists chemotherapy, therefore, the search for new agents for its treatment is of great importance. In this study, we purified the sesquiterpene lactones (SLs), Tomentosin and Inuviscolide from Inula viscosa (Compositae) leaves and studied their anti-cancer potency against human melanoma cell lines in order to develop new agents for melanoma treatment. SLs inhibited the proliferation of three human melanoma cell lines: SK-28, 624 mel and 1363 mel in a dose-dependent manner. We further investigated SLs mechanism of action using SK-28 as a representative cell line model. SLs caused cell-cycle arrest at G(2)/M, accompanied by the appearance of a sub-G0 fraction, indicative of apoptotic cell death. Induction of apoptosis was further confirmed by changes in membrane phospholipids, changes in mitochondrial membrane potential (DeltaPsi) and by detection of Caspase-3 activity. Rapid inhibitory phosphorylation of Cdc2 (Thr14 and Tyr15) was seen early after treatment, followed by a later decrease in the expression level of both Cyclin b1 and Cdc2. Induction of p53 and p21(waf1) proteins and phosphorylation of p53 at Ser15 were also detected early after treatment. The anti-apoptotic proteins, p65 subunit of nuclear factor kappaB (NF-kappaB), and Survivin were reduced in a dose-dependent manner. Taken together, these changes partially explain the ability of the SLs to induce G(2)/M arrest and apoptosis. Induction of apoptosis by Tomentosin and Inuviscolide in human aggressive melanoma cell lines has high pharmacological value and implies that SLs might be developed as new agents for melanoma treatment.

Growth inhibitory activity of cucurbitacin glucosides isolated from Citrullus colocynthis on human breast cancer cells.

Our aim was to study the effects of cucurbitacin glucosides extracted from Citrullus colocynthis leaves on human breast cancer cell growth. Leaves were extracted, resulting in the identification of cucurbitacin B/E glucosides. The cucurbitacin glucoside combination (1:1) inhibited growth of ER(+) MCF-7 and ER(-) MDA-MB-231 human breast cancer cell lines. Cell-cycle analysis showed that treatment with isolated cucurbitacin glucoside combination resulted in accumulation of cells at the G(2)/M phase of the cell cycle. Treated cells showed rapid reduction in the level of the key protein complex necessary to the regulation of G(2) exit and initiation of mitosis, namely the p34(CDC2)/cyclin B1 complex. cucurbitacin glucoside treatment also caused changes in the overall cell morphology from an elongated form to a round-shaped cell, which indicates that cucurbitacin treatment caused impairment of actin filament organization. This profound morphological change might also influence intracellular signaling by molecules such as PKB, resulting in inhibition in the transmission of survival signals. Reduction in PKB phosphorylation and inhibition of survivin, an anti-apoptosis family member, was observed. The treatment caused elevation in p-STAT3 and in p21(WAF), proven to be a STAT3 positive target in absence of survival signals. Cucurbitacin glucoside treatment also induced apoptosis, as measured by Annexin V/propidium iodide staining and by changes in mitochondrial membrane potential (DeltaPsi) using a fluorescent dye, JC-1. We suggest that cucurbitacin glucosides exhibit pleiotropic effects on cells, causing both cell cycle arrest and apoptosis. These results suggest that cucurbitacin glucosides might have therapeutic value against breast cancer cells.

JAK-STAT signaling involved in phorbol 12-myristate 13-acetate- and dimethyl sulfoxide-induced 2'-5' oligoadenylate synthetase expression in human HL-60 leukemia cells.

The JAK-STAT signal transduction cascade participates in various cellular processes, including immune response, cell replication, differentiation and oncogenesis. Here, we report that this cascade is induced in two human myeloid HL-60 leukemia cell variants by the granulocyte differentiation inducer dimethyl sulfoxide (DMSO) and macrophage differentiation inducer phorbol 12-myristate 13-acetate (PMA). DMSO and PMA also induced the expression and catalytic activity of 2'-5' oligoadenylate synthetase (2-5A synthetase), a known interferon (IFN) inducible enzyme. The HL-60 cell variants included HL-205, which is susceptible to DMSO- and PMA-induced differentiation, and HL-525, which is susceptible to DMSO- but not to PMA-induced differentiation. Treatment of HL-205 and HL-525 cells with DMSO and HL-205 cells with PMA-induced JAK1 phosphorylation, JAK1/STAT1 association, formation of STAT1-STAT2 heterodimers, and the binding of the active IFN stimulating growth factor 3 (ISGF3) to the IFN-stimulated response element (ISRE) fragment isolated from the 2-5A synthetase promoter. These events were either reduced or absent in the resistant HL-525 cells treated with PMA. Taken together, our data implicate the above signaling cascade in DMSO- and PMA-induced 2-5A synthetase expression and catalytic activity in the HL-60 cell system.

Unique natural antioxidants (NAOs) and derived purified components inhibit cell cycle progression by downregulation of ppRb and E2F in human PC3 prostate cancer cells.

Prostate cancer (PCA) is the leading cause of cancer mortality among older men in Western countries. Epidemiological studies have shown correlation between a lower risk of PCA and a higher consumption of antioxidants. However, the mechanism by which antioxidants exert their effects is still unknown. In the present study, we explored the signaling mechanism through which unique natural antioxidant derived from spinach extract (NAO) exerts their beneficial effects in the chemoprevention of PCA using human PC3 cells. Probing into the effect of NAO and its derived polyphenols on cell-cycle G1 arrest, we found that they cause cell-cycle prolongation. NAO and its two derived purified components exhibited a significant increase in the level of p21cip1 expression after 36 h of starvation, followed by 18 h of treatment with NAO in the presence of serum. In addition, under similar conditions, the expressed level of Cyclin A and CDK-2 in the PC3 cells was significantly reduced after treatment with NAO or its purified components. Immunoblot analysis demonstrated a significant increase in the hypophosphorylated form of pRb and a decrease in ppRb. NAO and its purified derived components were found to downregulate the protein expression of another member of the pRb family, p107, as well as that of E2F-1. These results suggest that NAO-induced G1 delay and cell cycle prolongation are caused by downregulation of the protein expression of ppRb and E2F in the human PCA cell line PC3.

Role of protein kinase C delta in reactivation of Kaposi's sarcoma-associated herpesvirus.

TPA (12-O-tetradecanoylphorbol-13-acetate), a well-known activator of protein kinase C (PKC), can experimentally induce reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) in certain latently infected cells. We selectively blocked the activity of PKC isoforms by using GF 109203X or rottlerin and demonstrated that this inhibition largely decreased lytic KSHV reactivation by TPA. Translocation of the PKCdelta isoform was evident shortly after TPA stimulation. Overexpression of the dominant-negative PKCdelta mutant supported an essential role for the PKCdelta isoform in virus reactivation, yet overexpression of PKCdelta alone was not sufficient to induce lytic reactivation of KSHV, suggesting that additional signaling molecules participate in this pathway.