Role Of Human Herpesvirus Research Articles

Association between Pityriasis Rosea (PR) and HHV-6/HHV-7 Infection: Importance of Sample Selection and Diagnostic Techniques.

Recent studies have focused on the role of human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) in PR etiology with varying results. In our study, with the approach that the discrepancy between the results may be related to the different samples and techniques used, we aimed to clarify the etiology by examining tissue and plasma samples using molecular methods and evaluating the results together with serological parameters. Skin biopsies and plasma samples of twenty-five PR patients were tested to detect HHV-6 and HHV-7 DNA using calibrated quantitative real-time polymerase chain reaction (CQ RT-PCR). IgG and IgM antibodies against HHV-6 and HHV-7 were tested by enzyme-linked immunosorbent assay and indirect immunofluorescence. Of the patient group, 64% were positive for HHV-6 IgG without IgM positivity. HHV-6 DNA was present in seven tissue and ten plasma samples. HHV-7 positivity was 100% and 12% for IgG and IgM antibodies, respectively. HHV-7 DNA was detected in four tissue samples and one plasma sample. Patients with HHV-7 DNA-positive plasma and tissue samples had also HHV-7 IgM antibodies. In conclusion, our results seem to support the role of HHV-6/HHV-7 in the etiology of PR. To clarify the etiology of PR and avoid confusion, the collection of different biological materials simultaneously and the usage of CQ RT-PCR as a diagnostic technique are recommended.

Human herpesvirus 6-specific T-cell immunity in allogeneic hematopoietic stem cell transplant recipients.

Human herpesvirus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplant (allo-HSCT) and may lead to severe symptoms. HHV-6-specific immune responses after HSCT are largely unexplored. We conducted a prospective observational study on 208 consecutive adult patients who received allo-HSCT to investigate HHV-6 reactivations and specific immune responses. Interferon gamma-producing HHV-6-specific T cells were quantified using enzyme-linked immunospot assay (ELISpot). HHV-6 reactivation occurred in 63% of patients, at a median of 25 days from allo-HSCT. Only 40% of these presented a clinically relevant infection, defined by the presence of classical HHV-6 end-organ diseases (EODs), based on European Conference on Infections in Leukaemia (ECIL) guidelines, and other possible HHV6-related EODs. Using multivariate analysis, we identified risk factors for HHV-6 reactivation: previous allo-HSCT, posttransplant cyclophosphamide (PT-Cy), and time-dependent steroids introduction. The use of PT-Cy and steroids were associated with clinically relevant infections, whereas higher CD3+ cell counts seemed to be protective. Interestingly, circulating HHV-6-specific T cells were significantly higher in patients with reactivated virus. Moreover, HHV-6-specific T-cell responses, quantified at >4 days after the first viremia detection, predicted clinically relevant infections (P< .0001), with higher specificity (93%) and sensitivity (79%) than polyclonal CD3+ cells per μL. Overall survival and transplant-related mortality were not affected by time-dependent HHV-6 reactivation, whereas a significant association was observed between clinically relevant infections and acute graft-versus-host disease. These results shed light on the role of HHV-6 in allo-HSCT and may affect HHV-6 monitoring and treatment.

Human herpesvirus-8 infection in Tunisian adult acute leukemia patients.

Human herpesvirus 8 (HHV-8) has been linked to the development of Kaposi's sarcoma (KS)and multiple other hematologic malignant disorders. However, the role of HHV-8 in acute leukemia patients is unknown. The objective of this study was to determine the prevalence of HHV-8 in Tunisian acute leukemia patients and in healthy blood donors. An indirect immunofluorescence test was used to detect the presence of anti-HHV8 antibodies. Nested PCR was used for the detection of HHV-8 DNAemia in samples of plasma. The seroprevalence of HHV-8 was significantly higher in acute leukemia patients (21,4% ,15/70) than in healthy blood donors (7,1%, 5/70), (p= 0.02). Gender, type of disease, status of disease, prior blood transfusion, and outcome were not associated with HHV-8 seroprevalence. However, among acute leukemia patients, HHV-8 seroprevalence was statistically associated with older age > 40 years of age, (p=0.002). HHV-8 DNAemia was detected (1,4%) in only one patient of acute myeloid leukemia (AML) and none of the healthy blood donors. The seroprevalence of HHV-8 infection in Tunisian adult acute leukemia patients was three times as high compared to healthy blood donors, suggesting that patients with acute leukemia might be at increased risk of HHV-8 infection.

Human Herpesvirus 6A Is a Risk Factor for Multiple Sclerosis

The role for human herpesvirus (HHV)-6A or HHV-6B in multiple sclerosis (MS) pathogenesis has been controversial. Possibly because the damage of the virus infection may occur before onset of clinical symptoms and because it has been difficult to detect active infection and separate serological responses to HHV-6A or 6B. Recent studies report that in MS patients the serological response against HHV-6A is increased whereas it is decreased against HHV-6B. This effect seems to be even more pronounced in MS patients prior to diagnosis and supports previous studies postulating a predomination for HHV-6A in MS disease and suggests that the infection is important at early stages of the disease. Furthermore, HHV-6A infection interacts with other factors suspected of modulating MS susceptibility and progression such as infection with Epstein-Barr virus (EBV) and Cytomegalovirus (CMV), tobacco smoking, HLA alleles, UV irradiation and vitamin D levels. The multifactorial nature of MS and pathophysiological role for HHV-6A in inflammation and autoimmunity are discussed.

Overwhelming Evidence for a Major Role for Herpes Simplex Virus Type 1 (HSV1) in Alzheimer's Disease (AD); Underwhelming Evidence against.

This review describes investigations of specific topics that lie within the general subject of HSV1’s role in AD/dementia, published in the last couple of years. They include studies on the following: relationship of HSV1 to AD using neural stem cells; the apparent protective effects of treatment of HSV1 infection or of VZV infection with antivirals prior to the onset of dementia; the putative involvement of VZV in AD/dementia; the possible role of human herpes virus 6 (HHV6) in AD; the seemingly reduced risk of dementia after vaccination with diverse types of vaccine, and the association shown in some vaccine studies with reduced frequency of HSV1 reactivation; anti-HSV serum antibodies supporting the linkage of HSV1 in brain with AD in APOE-ε4 carriers, and the association between APOE and cognition, and association of APOE and infection with AD/dementia. The conclusions are that there is now overwhelming evidence for HSV1’s role—probably causal—in AD, when it is present in brain of APOE-ε4 carriers, and that further investigations should be made on possible prevention of the disease by vaccination, or by prolonged antiviral treatment of HSV1 infection in APOE-ε4 carriers, before disease onset.

Detection of human herpes virus 6&amp;7 in pityriasis rosea and the efficacy of acyclovir

The exact aetiology of pityriasis rosea (PR) is still unknown as various researches exist aiming to explain the exact cause. The role of Human Herpes Virus(HHV)-6 & HHV-7 DNA in PR patients has been evaluated in many studies with variable results. The rationale behind the use of antiviral in PR is that the course of the disease follows that of a viral exanthem and also probable involvement of HHV 6 and 7 in its etiopathogenesis. The current case-control study aimed at evaluation of the possible relation between HHV-6 & HHV-7 and PR through detection of HHV-6 & HHV-7 DNA in PR patients in comparison to controls and also illumination the therapeutic efficacy of Acyclovir in PR treatment.Based on the number of positive cases for HHV-6 and HHV-7 in the results of the present study on 30 PR patients, we can conclude that HHV-6 and HHV-7 may play a part in the pathogenesis of PR in some patients. Although PR is a self-limited disease which resolves within three weeks to three months, this study revealed that the difference between the treatment groups regarding the course of the disease was statistically significant and oral Acyclovir is helpful in rapid decreasing the severity and shortening the course of the disease in some patients, making those patients satisfied with the rapid cure. This clinical trial, although small, suggest a therapeutic benefit from oral Acyclovir in shortening the course of the disease.

Herpesvirus and inflammatory bowel disease

Aim. Conduct a review of studies characterizing the role of herpesvirus infections in the pathogenesis of inflammatory bowel disease (IBD).Introduction. The study of the role of herpes virus infections in the pathogenesis of inflammatory bowel disease (IBD) is currently of considerable interest to researchers from different countries.Result. The results of studies on the significance of human herpes viruses (HHV) in inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD), their effect on the course of these diseases, and refractory treatment of UC and CD in the presence of HHV are presented.It is shown that most researchers unanimously conclude that the main attention should be paid to Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpes simplex virus type 6 (HHV-6), which are found in the mucous membrane of the colon in patients with IBD and affect both the course of the disease and the effectiveness of the treatment. Attention is focused on the fact that it is necessary to differentiate colitis due to HHV and IBD, proceeding against the background of HHV reactivation, since approaches to the treatment of these conditions are different.Conclusion. Requires targeted research on the role of human herpes viruses in the pathogenesis of IBD.

The role of human herpesvirus-6 and inflammatory markers in the pathogenesis of multiple sclerosis

Multiple sclerosis (MS) is a destructive autoimmune neuroinflammatory and neurodegenerative disorder of the central nervous system (CNS) with unknown etiology and mechanism of pathogenesis. Pathogens, especially human herpes viruses, have been suggested as environmental factors of the MS and other neuroinflammatory disorders. This study aimed to determine the prevalence of HHV-6 antibody response in MS patients and investigate the levels of pro/anti-inflammatory cytokine and chemokines in MS patients in comparison with healthy subjects. Two hundred sixty-three patients with clinically defined MS (140 females and 123 males), along with 263 healthy subjects (140 females and 123 males), were recruited for this study. After the analysis of HHV-6 seropositivity/seronegativity, the levels of some pro/anti-inflammatory cytokines, including TNF-α, IFN-γ, IL-1β, IL-6, and IL-12 as well as two chemokines, namely CCL-2 and CCL-5 were determined by the enzyme-linked immunosorbent assay (ELISA) method in HHV-6 seropositive/seronegative MS patients and healthy subjects. Our results showed that the serum concentrations of TNF-α, IFN-γ, IL-1β, IL-6, and CCL-5 elevated in HHV-6 seropositive compared with seronegative MS patients (P < .05). Moreover, the levels of IL-12, IL-10, and CCL-2 levels were significantly lower in seropositive MS patients when compared with seronegative MS patients (P < .05). Also, our results revealed that the mean values of the expanded disability status scale (EDSS) were significantly higher in HHV-6 seropositive versus seronegative MS patients (P < .05). In conclusion, we proposed that HHV-6 infection may play a role in MS pathogenesis by changing cytokine signaling in MS patients that may lead to peripheral inflammation.

The Potential Role of Human Herpes Virus-6 in Idiopathic Facial Nerve Paralysis

Background:Bell’s palsy (BP) is an acute, generally unilateral, paralysis or weakness of facial musculature consistent with peripheral facial nerve dysfunction; different factors suspected to contribute to the development of BP including herpesviruses. Objective:To detect human herpes virus 6 (HHV-6) in the saliva samples of patients in the early presentation of BP. Methods: A case-control study included saliva samples taken from 50 patients with BP and 50 apparently healthy controls without any neurological deficit, viral DNA was extracted from the saliva and then subjected for quantitative real time polymerase chain reaction (PCR) for detection of HHV-6 viral load (VL) in saliva. Results: HHV-6 DNA was positive in 22 (44%) out of the 50 patients, and in 12 (24%) of the controls (p=0.028), with a significantly higher mean viral load in patients than control (p=0.002), in addition, 70% of HHV-6 positive patients had severe grades with a significantly higher VL (p=0.007) and (0.015), respectively. Conclusion: HHV-6 could play an important role in the development of BP and HHV-6 might have a neuro-pathological effect in severe cases of BP. Keywords: HHV-6, Bell's palsy, Saliva, real time PCR Citation: Rhaif RH, Al-Obaidi AB, Al-Khazrajee AK. The potential role of Human Herpes Virus-6 in idiopathic facial nerve paralysis. Iraqi JMS. 2020; 18(1): 47-51. doi: 10.22578/IJMS.18.1.7

HHV-6 Infection and Chemokine RANTES Signaling Pathway Disturbance in Patients with Autoimmune Thyroiditis.

The aim of this study was to investigate the role of human herpesvirus-6 (HHV-6) in autoimmune thyroiditis (AIT) development. We examined the possible involvement of HHV-6 gene expression encoding immunomodulating proteins U12 and U51 in AIT development and their role in the modulation of chemokine signaling. One hundred patients with autoimmune thyroiditis following thyroidectomy were enrolled in this study. Nested polymerase chain reaction (nPCR) was used to detect the HHV-6 sequence in DNA samples. Reverse transcription PCR (RT-PCR) with three different HHV-6 gene targets (U79/80, U51 and U12) was to detect active infection markers. HHV-6 load was identified using a commercial real-time PCR kit. Immunohistochemistry was performed to investigate the expression of the HHV-6 antigen and RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) in thyroid gland tissue. Different commercial immunosorbent assay kits were used for the detection of RANTES, IFNγ, IL-6, and TNFα levels in the AIT patient group and controls. We detected 98% presence of the HHV-6 genomic sequence in AIT patients’ thyroid gland tissues. Markers of active HHV-6 infection (HHV-6 U79/80, U12 and/or U51 mRNA) were predominant in AIT patients’ thyroid tissue samples in comparison with the control group (56% vs. 6%). Evidence from immunofluorescence microscopy showed that HHV-6 can persist in thyrocytes and can interact with RANTES. Visual confirmation of the intense immunofluorescence signal of RANTES detected in thyroid tissues could indicate high expression of this chemokine in the thyroid gland. On the other hand, immunosorbent assays showed very low RANTES levels in AIT patients’ peripheral plasma. These results indicate that RANTES level in AIT patients could be influenced by HHV-6 activation, which in turn may aid AIT development.

Serum levels of matrix metalloproteinase-2, -9, and vitamin D in patients with multiple sclerosis with or without herpesvirus-6 seropositivity

In recent years, extreme attention has been focused on the role of human herpesvirus-6 (HHV-6) in multiple sclerosis (MS) pathogenesis. However, the pathogenesis of MS associated with HHV-6 infection remains unknown. In this study, we measured the serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and vitamin D levels in MS patients with HHV-6 infection and MS patients without HHV-6 infection. Five hundred sixty (including 300 females and 260 males) MS patients along with 560 healthy subjects were analyzed for HHV-6 seropositivity using enzyme-linked immunosorbent assay (ELISA). Subsequently, we measured the serum levels of MMP-2, MMP-9, and vitamin D levels in MS patients with HHV-6 infection and MS patients without HHV-6 infection by ELISA. About 90.7% of MS patients (508/560) were seropositive for HHV-6, while 82.3% (461/560) of healthy subjects were seropositive for this virus (p = 0.001). Moreover, there was a significant increase in the levels of MMP-2, MMP-9, and lower vitamin D in the serum samples of MS patients when compared with healthy subjects. Additionally, we demonstrated that the MMP-9 levels in seropositive MS patients were significantly higher than seronegative MS patients (p = 0.001). Finally, our results demonstrated that the mean of expanded disability status scale (EDSS) in seropositive MS patients was significantly higher in comparison to seronegative MS patients (p < 0.05). In conclusion, we suggest that the HHV-6 infection may play a role in MS pathogenesis.

Human herpesvirus-6 is present at higher levels in the pancreatic tissues of donors with type 1 diabetes

Human herpesvirus-6 (HHV-6) is a ubiquitous pathogen associated with nervous and endocrine autoimmune disorders. The aim of this study was to investigate the presence of HHV-6 in pancreatic tissue sections from non-diabetic, auto-antibody positive (AAB+), and donors with type 1 diabetes (T1D) and explore whether there is any association between HHV-6 and MHC class I hyperexpression and CD8 T cell infiltration.HHV-6 DNA was detected by PCR and its protein was examined by indirect immunofluorescence assay followed by imaging using high-resolution confocal microscopy. Viral DNA (U67) was found in most pancreata of non-diabetic (3 out of 4), AAB+ (3 out of 5) and T1D donors (6 out of 7). Interestingly, HHV-6 glycoprotein B (gB) was more expressed in islets and exocrine pancreas of donors with T1D. However, gB expression was not directly associated with other pathologies. Out of 20 islets with high gB expression, only 3 islets (15%) showed MHC class I hyperexpression. Furthermore, no correlation was found between gB expression and CD8 T cell infiltration on a per-islet basis in any of the groups.Our observations indicate that HHV-6 DNA and protein are present in the pancreas of non-diabetic subjects but gB expression is higher in the pancreas of donors with T1D. The possible role of HHV-6 as a contributory factor for T1D should therefore be further investigated.

Non-Destructive Post-Transplant Lymphoproliferative Disorder Shows Distinct Clinical Features with HHV-6 Reactivation in a Subset

Background: Post-transplant lymphoproliferative disorders (PTLD) are a diverse group of lymphoid neoplasms arising after solid organ (SOT) or hematopoietic stem cell transplant (HSCT). They may resemble lymphomas in immunocompetent patients (monomorphic); present as destructive, heterogeneous lesions (polymorphic); or be non-destructive but mass-forming (non-destructive, previously known as 'early lesions'). PTLDs are often associated with Epstein-Barr virus (EBV) infection or reactivation, which likely functions as a driver in these cases. Non-destructive lesions may be challenging to diagnose in the absence of EBV. However, a significant fraction of PTLDs are EBV(-), including a subset of non-destructive lesions. The pathogenesis of these remains to be fully elucidated. Human herpesvirus 6 (HHV-6) reactivation is common during transplantation, occurring in up to 70% of HSCT and 80% of SOT patients. While it has been hypothesized that HHV-6 may play a role in PTLD, particularly in EBV(-) cases, the role of HHV-6 in the pathogenesis of PTLD remains underexplored. Methods: Following IRB approval, pathology archives at Weill Cornell/New York Presbyterian Hospital were searched to identify patients with a tissue diagnosis of PTLD and correlated with clinical information. A tissue microarray was constructed from blocks with sufficient tissue. Standard immunohistochemistry (IHC) and in situ hybridization for EBV-encoded RNA (EBER) were performed, and IHC conditions were optimized for antibodies against HHV-6 gp60/110 (Millipore Sigma, MAB853) and p41 (Santa Cruz Biotechnologies, 9A5D12). Statistical comparisons utilized Student's t-test and Fisher's exact test. Results: We identified 79 patients from 6/23/94-6/6/19 with a tissue diagnosis of PTLD. Morphologic subtype could be determined in 74, including 8 patients with non-destructive lesions. Compared to monomorphic or polymorphic, patients with non-destructive PTLDs were significantly younger (median age 9, p&lt;0.01) and more likely status post heart transplant (5/8 cases, p&lt;0.001, Table 1). By contrast, polymorphic PTLDs occurred relatively more frequently in HSCT patients (25/33 cases, p&lt;0.01). All morphologic subtypes were frequently EBV+ (63-88%) but EBV positivity was greater in polymorphic than monomorphic lesions (p&lt;0.05). While tissue testing failed on blocks &gt; 20 years old, 13 PTLD cases from 12 patients had sufficient evaluable material for HHV-6 testing (Table 2). 9/12 patients had a SOT (8 renal, 1 heart) and 3 had HSCT. HHV-6 was identified in 5/13 lesions (38%), all of which were in SOT patients (Figure 1). EBER was detected in 8/13 lesions (62%). When stratified by PTLD subtype, 3/3 non-destructive PTLDs were HHV-6+ (100%). Two were EBER(-) and the remaining case only showed scattered EBER+ cells. Unfortunately, material was not available for testing the EBER+ non-destructive lesions. 2/9 of the monomorphic lesions tested (22%) were positive for both HHV-6 and EBER. While the series is limited, the association between HHV-6 and non-destructive lesions, compared to other types of PTLD, appears significant (p&lt;0.05). EBV did not appear to be associated with HHV-6 status (p = 0.29). Conclusions: Non-destructive, monomorphic and polymorphic PTLDs show significant differences in timing, patient demographics and transplant type, suggesting that they may differ in associated risk factors affecting their pathogenesis. Confirming prior studies, we find non-destructive lesions tend to occur in younger patients, often following SOT as compared to HSCT and with a median time from transplantation of ~50 months. In addition, the presence of HHV-6 in the absence of (or with limited) EBV in the 3 non-destructive lesions tested raises the possibility that HHV-6 may play a role in the pathogenesis of this PTLD subtype that has yet to be defined. These findings are intriguing given the frequent reactivation of HHV-6 seen in transplant populations. HHV-6 has been variably associated with post-transplant complications including pneumonitis, delayed hematopoietic engraftment and graft versus host disease and thus received relatively more attention in the HSCT population. A causative role for HHV-6 in PTLD remains speculative, but these findings raise the possibility that clinicians treating the SOT population should also consider aggressively identifying and treating HHV-6 reactivation. Disclosures Rutherford: AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Janssen Scientific Affairs: Consultancy, Honoraria; Juno Therapeutics Inc: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Time for Well-Powered Controlled Prospective Studies to Test a Causal Role for Herpes Viruses in Alzheimer's Disease Using Antiherpetic Drugs.

Twenty-six phase III studies on Alzheimer's disease are ongoing or have been completed in 2018. Most of these studies are targeting amyloid-beta, its production, polymerization, and/or multiple interactions. None of the amyloid-beta studies seem to affect positively the clinical outcome of patients with Alzheimer's disease thus far, no matter the advancement of disease. It is time to consider other hypotheses for the pathogenesis of Alzheimer's disease, including the potential role of human herpes viruses (HHV), and especially HHV1 (herpes simplex virus type 1), HHV3 (varicella zoster virus), HHV6A, and HHV7. With this perspective, we review the scientific evidence and make the case for appropriately powered, prospective, randomized, and controlled studies using an anti-HHV drug, to establish a causal role for HHV in Alzheimer's disease.

The role of HHV-6 and HHV-7 infections in the development of fibromyalgia

Human herpes virus-6 (HHV-6) and human herpes virus-7 (HHV-7) are immunomodulating viruses potentially affecting the nervous system. We evaluated the influence of HHV-6 and HHV-7 infections on fibromyalgia (FM) clinical course. Forty-three FM patients and 50 control group participants were enrolled. 39.50% (n = 17) FM patients had light A delta and C nerve fiber damage, 27.91% (n = 12) had severe A delta and C nerve fiber damage. 67.44% (n = 29) FM patients had loss of warm sensation in feet, loss of heat pain sensation, and increased cold pain sensation (34.90%, n = 15 in both findings). HHV-6 and HHV-7 genomic sequences in peripheral blood DNA in 23/43 (51.00%) and 34/43 (75.50%) of samples from FM patients and in 3/50 (6.00%) and 26/50 (52.00%) of samples from the control group individuals were detected. Active HHV-6 (plasma viremia) or HHV-7 infection was revealed only in FM patients (4/23, 17.40% and 4/34, 11.80%, respectively). A statistically significant moderate positive correlation was found between A delta and C nerve fiber damage severity and HHV-6 infection (p < 0.01, r = 0.410). 23/43 patients from the FM group and control group participants HHV-6 and 34/45 HHV-7 did have infection markers. A statistically significant moderate positive correlation was found between A delta and C nerve fiber damage severity and HHV-6 infection (p < 0.01, r = 0.410). No difference was found between detection frequency of persistent HHV-6 and HHV-7 infection between FM patients and the control group. Statistically significant correlation was observed between quantitation of changes in QST thermal modalities and HHV-6 infection. There was no correlation between A delta and C nerve fiber damage and HHV-7 infection.

A Possible Role of Human Herpes Viruses Belonging to the Subfamily Alphaherpesvirinae in the Development of Some Cancers.

Seroepidemiological studies suggest that human herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) are linked with several types of cancer; however, they do not appear to play a direct role and are considered to be cofactors. The abilities of HSV-1 and -2 to transform cells in vitro can be demonstrated by suppressing their lytic ability via irradiation with a specific dose of ultraviolet light, photoinactivation in the presence of photosensitizers (e.g., neutral red or methylene blue), and culture under specific conditions. Several mechanisms have been proposed to explain the actions of these viruses. According to the hit-and-run mechanism, viral DNA initiates transformation by interacting with cellular DNA and thereby inducing mutations and epigenetic changes, but is not involved in other stages of neoplastic progression. By contrast, according to the hijacking mechanism, viral products in infected cells can activate signaling pathways and thereby cause uncontrolled proliferation. Such products include RR1PK, an oncoprotein that activates the Ras pathway and is encoded by the HSV-2 gene ICP10. Virus-encoded microRNAs may act as cofactors in tumorigenesis of serous ovarian carcinoma and some prostate tumors. Herpes virus-associated growth factors that facilitate or suppress transformation may play important roles in tumor formation. Finally, there is much evidence that HSV-2 increases the risk of cervical cancer after infection of human papilloma viruses. Key words: HSV-1 - HSV-2 - cancer - mechanisms of transformation This work was supported by APVV 0621-12. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 29. 11. 2016 Accepted: 20. 3. 2018.

Laboratory Diagnosis of Pediatric Herpesvirus Infections of the Central Nervous System by a Multiplex Polymerase Chain Reaction Assay and Intrathecal Antibodies

Abstract Introduction Central nervous system (CNS) viral infections are a serious problem requiring accurate diagnosis and treatment. Human herpesviruses (HHVs) are an important cause of these infections. Recent research has focused on new diagnostic methods allowing accurate and rapid identification of viral infections because there are still diagnostic difficulties for these infections. This study was done to determine the etiologic role of human herpes viruses and to obtain information that will contribute to the diagnostic algorithm in suspected cases of viral encephalitis or aseptic meningitis. Materials and Methods In our study, herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), and HHV-6 DNA was detected in the cerebrospinal fluid (CSF) by multiplex polymerase chain reaction (PCR) and virus-specific immunoglobulin G (IgG) antibodies in CSF and serum by EIA in pediatric encephalitis/meningitis cases. Results HSV-1 and VZV were detected in 5 and 3.3% of aseptic meningitis cases, respectively, but no encephalitis cases. Other viruses were not identified as etiologic agents. The seroprevalences were determined as 72.4, 34.3, 81.9, 93.3, 88.6, and 80.9%, respectively for HSV-1, HSV-2, VZV, CMV, EBV, and HHV-6. The performance of specific IgG CSF/serum antibody index (AI) was not satisfactory. Conclusion Our study indicates that the multiplex PCR method is the most suitable for the diagnosis of CNS infections caused by HHVs. However, due to the high cost of the PCR method, the positive results of the specific AI may be significant, but the negative results are unreliable, especially in limited health care facilities.

Correction for Cousins and Nicholas, "Role of Human Herpesvirus 8 Interleukin-6-Activated gp130 Signal Transducer in Primary Effusion Lymphoma Cell Growth and Viability".

Correction for Cousins and Nicholas, "Role of Human Herpesvirus 8 Interleukin-6-Activated gp130 Signal Transducer in Primary Effusion Lymphoma Cell Growth and Viability".

HIV/Human herpesvirus co-infections: Impact on tryptophan-kynurenine pathway and immune reconstitution.

BackgroundCo-infections with human herpesvirus (HHV) have been associated with residual chronic inflammation in antiretroviral (ART)-treated human immunodeficiency virus (HIV)-infected individuals. However, the role of HHV in modulating the tryptophan-kynurenine pathway and clinical outcomes in HIV-infected individuals is poorly understood. Thus, we investigated the seroprevalence of four common HHVs among treated HIV-infected participants and their impact on kynurenine/tryptophan (K/T) ratio and long-term CD4 T-cell recovery in HIV/HHV co-infected participants.MethodIn this cross-sectional study, HIV-infected participants receiving suppressive ART for a minimum of 12 months were recruited from the University Malaya Medical Centre (UMMC), Malaysia. Stored plasma was analyzed for CMV, VZV, HSV-1 and HSV-2 IgG antibody levels, immune activation markers (interleukin-6, interferon-γ, neopterin and sCD14), kynurenine and tryptophan concentrations. The influence of the number of HHV co-infection and K/T ratio on CD4 T-cell recovery was assessed using multivariate Poisson regression.ResultsA total of 232 HIV-infected participants were recruited and all participants were seropositive for at least one HHV; 96.1% with CMV, 86.6% with VZV, 70.7% with HSV-1 and 53.9% with HSV-2. K/T ratio had a significant positive correlation with CMV (rho = 0.205, p = 0.002), VZV (rho = 0.173, p = 0.009) and a tendency with HSV-2 (rho = 0.120, p = 0.070), with CMV antibody titer demonstrating the strongest modulating effect on K/T ratio among the four HHVs assessed in SOM analysis. In multivariate analysis, higher K/T ratio (p = 0.03) and increasing number of HHV co-infections (p<0.001) were independently associated with poorer CD4 T-cell recovery following 12 months of ART initiation.ConclusionMultiple HHV co-infections are common among ART-treated HIV-infected participants in the developing country setting and associated with persistent immune activation and poorer CD4 T-cell recovery.

HHV8-related lymphoid proliferations: a broad spectrum of lesions from reactive lymphoid hyperplasia to overt lymphoma

Human herpesvirus 8 (HHV8)-associated lymphoid proliferations are uncommon and poorly characterized disorders mainly affecting immunosuppressed patients, especially with HIV infection. They encompass different diseases with overlapping features that complicate their classification. In addition, the role of HHV8 in reactive lymphoid hyperplasia is not well known. To analyze the clinicopathological spectrum of these lesions, we have reviewed 66 biopsies of 61 patients with HHV8 infection. All cases were also investigated for Epstein-Barr virus (EBV) and HIV infection. We identified 13 (20%) cases of HHV8-related reactive lymphoid hyperplasia, 2 (3%) HHV8 plasmablastic proliferations of the splenic red pulp, 28 (42%) multicentric Castleman disease, 6 (9%) germinotropic lymphoproliferative disorders, and 17 (26%) HHV8-related lymphomas. As expected, the pathologic subtype was predictive of overall survival (P<0.05). Forty-seven of our cases were HIV positive (77%). In addition to the classical presentation of the different entities, we identified novel and overlapping features. Reactive HHV8 proliferations were frequently associated with systemic symptoms but never progressed to overt HHV8-positive lymphoma. Two cases had a plasmablastic proliferation limited to spleen. Eight cases of multicentric Castleman disease had a previously unrecognized presentation shortly after the diagnosis of HIV infection, six cases had cavity effusions, and three showed plasmablast enriched proliferations. One germinotropic lymphoproliferative disorder was EBV negative and three occurred in HIV-positive patients, who had distinctive clinical and morphological features. Two of the HHV8-related lymphomas did not fulfill the criteria for previously recognized entities. All these findings expand the clinical and pathological spectrum of HHV8-related lymphoid proliferations, which is broader than current recognized.