Association of active human herpesvirus-6 (HHV-6) infection with autoimmune thyroid gland diseases.

OBJECTIVES: Viral infections frequently have been cited as important environmental factors implicated in the onset of autoimmune thyroiditis (AIT). The aim of this study was to determine the involvement of HHV-6 infection in the development of autoimmune thyroiditis. METHODS: This study included 45 patients (42 female and 3 male; median age 47.00 IQR 38.50-57.00) with histologically, laboratory, and clinically confirmed autoimmune thyroiditis, as well as 30 autopsied subjects (26 female and 4 male; median age 58.50, IQR 51.50-67.00) without thyroid pathologies and 30 healthy blood donors (25 female and 5 male; median age 33.50, IQR 27.75-44.25) as controls. Results were obtained by applying molecular virology and immunohistochemistry techniques. RESULTS: The presence of persistent HHV-6 infection in AIT patients was significantly higher (p 0.0058) than in the control group (44/45 (98%) vs. 23/30 (77%), respectively). Also, a significantly higher frequency of HHV-6 activation marker (U79/80 mRNA) was found in patients' thyroid gland tissue samples with AIT in comparison with the control group (18/44 (41%) vs. 1/17 (6%), respectively; p 0.0118). The median HHV-6 load was found to be higher in patients with active viral infection than in patients without it (2147, IQR 971-4188 vs. 551, IQR 145-1589 copies/1×106 cells; p 0.003). The presence of HHV-6 antigen expression was demonstrated in intrafollicular cellular clusters and immunohistochemistry indicated thyrocytes in the follicle wall. CONCLUSIONS: These findings provide evidence of strong HHV-6 infection association with AIT development.

Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development.

AIM: The high incidence of gastrointestinal cancer combined with high mortality from the disease if diagnosed at a late stage, signifies the need for better diagnostic, prognostic and predictive tools. Human beta-herpesviruses have been suggested as possible cofactors in the development of gastrointestinal cancer. METHODS: Sixty five patients with gastrointestinal cancer before surgery and without any treatment were enrolled in this study and divided into two groups depending on lymphocytes' count: I group (n = 35) -- lymphocytes > 1400x10(6)/L and II group (n = 30) -- lymphocytes < 1400x10(6)/L. Nested polymerase chain reaction was used to detect latent and active stage of persistent human herpesvirus-6 and -7 infection, laser flow cytometry with monoclonal antibodies -- to determine immunological parameters. RESULTS: Activation of herpesvirus-6 and -7 was more frequently observed in the patients' group with lymphopenia (HHV-6 1/1 (100%), HHV-7 4/8 (50%) and HHV-6 + HHV-7 6/9 (66%); p < 0.05). Cellular immune parameters were analysed in immunocompromised II group's patients dependently on beta-herpevirus infection. Although number of leukocytes was higher in patients with active HHV-6/-7 infection (p = 0.01), number of lymphocytes CD3(+), CD4(+), CD8(+) and CD38(+) in patients with active HHV-6/-7 infection tended to decrease (p < 0.0001, P = 0.0002, p = 0.0001 and p < 0.0001, respectively). However, number of CD19(+) had tendency to increase (p = 0.03). CONCLUSION: Activation of herpesvirus-6 and -7 may lead to decrease of lymphocytes total count and develop immunosuppression in patients with gastrointestinal cancer.

Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient.

UNLABELLED: Progressive multifocal leukoencephalopathy (PML) is a neurological disease caused by infection of the central nervous system (CNS) with the JC polyomavirus (JCV). JCV is endemic and infects a large proportion (70-90%) of healthy individuals worldwide, but infection is latent. JCV reactivation may occur, if the immune function is compromised. AIM: To present a PML case in a CLL patient after a long course of disease and treatment with fludarabine. JCV virus infection in this patient was proven both in brain biopsy material and blood. METHODS: Patient with a nine-year history of CLL was hospitalized with the weakness in the right leg and left hand, tremors, speech difficulties. An MRI diagnosed infiltrative glial tumor of the left hemisphere, proliferating predominantly in the frontal lobe, more in the gyrus frontalis superior region. CNS tumor biopsy performed. RESULTS: Morphology and immunoprofile of the lesion consistent with progressive multifocal leukoencephalopathy. The material from biopsy was diagnosed as positive for JCV DNA. JCV and HHV-7 genomic sequences were found in patient's PBL DNA sample. In a plasma DNA sample, only genomic sequences were detected. CONCLUSION: The present case draws attention to the fact that the use of fludarabine and its combinations in CLL therapy increases the risk of JCV infection reactivation and development of serious complications like PML.

Association of HHV-6 and HHV-7 reactivation with the development of chronic allograft nephropathy.

BACKGROUND: The long-term effect of HHV-6 and HHV-7 infections on chronic allograft nephropathy (CAN) development after renal transplantation is uncertain. OBJECTIVES: To determine HHV-6 and HHV-7 reactivation during the post-transplantation period and to evaluate its effect on CAN development in renal transplant patients. STUDY DESIGN: Eighty-one renal allograft recipients (28 with CAN, 53 with normal transplant function) were studied to determine the frequency of HHV-6 and HHV-7 reactivation during 36.4+/-7.8 months after renal transplantation using nested PCR. HHV-6 variants were identified using restriction endonuclease analysis. Patients were monitored for the development of CAN. RESULTS: The frequency of HHV-6 and/or HHV-7 plasma DNA was significantly higher in CAN patients (25/28, 89.3%) compared to control patients (15/50, 30.0%, p=0.0001). CAN patients also had an increased incidence of dual active infections (20/25, 80% and 2/15, 13.3%, p=0.007, respectively). In all 34 HHV-6 positive cases, the HHV-6B variant was identified. The presence of HHV-7 DNA in plasma preceded the presence of HHV-6 DNA. Early development of CAN and graft loss was detected only in patients with simultaneous HHV-6 and HHV-7 plasma DNA. CONCLUSIONS: Reactivation of HHV-6 and HHV-7 in renal graft recipients is a risk factor for CAN development. The presence of concurrent HHV-6 and HHV-7 DNA in the plasma is an unfavorable prognostic factor.

Reactivation of BK Virus in the Early Period After Kidney Transplantation.

BACKGROUND: Typically, polyoma BK virus (BKV) remains latent in the urogenital tract after primary infection. Reactivation of BKV in recipients of kidney allografts can cause progressive graft dysfunction known as BK virus nephropathy (BKVN). The cornerstone of treatment for BKVN is prevention; therefore, it is important to detect BKV reactivation early and reduce immunosuppression. We sought to identify the BKV reactivation rate and associated factors in a prospective study. MATERIALS AND METHODS: We studied 37 consecutive unselected adult recipients who underwent deceased donor kidney transplantation in 2007 and completed at least 3 months of observation. Qualitative nested polymerase chain reaction (PCR) testing was performed to detect BKV DNA in urine and plasma specimens. RESULTS: In all cases, BK viremia or viruria was not detected on the postoperative day or 2 weeks thereafter. At 3 months, BKV reactivation developed in 6 (16%) of 37 recipients. Simultaneous viremia and viruria were present on 5 patients and viremia only in 1 patient. Significant risk factors for BK viremia were body mass index >30 kg/m(2) (P = .02), retransplantation (P =.04), and use of tacrolimus (P = .02). Serum creatinine values at 3 months after transplantation were significantly higher among patients with active BKV infection (P = .008). CONCLUSIONS: Early BKV reactivation is associated with worse graft function as early as 3 months after transplantation. Obesity, retransplantation, and use of tacrolimus were factors promoting early development of BKV viremia.

Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome.

BACKGROUND: Human herpesvirus 6 (HHV-6) and 7 (HHV-7) have been suggested as possible triggering agents for chronic fatigue syndrome (CFS). OBJECTIVES: To determine the possible association of HHV-6 and HHV-7 infections with CFS. STUDY DESIGN: The prevalence of latent/persistent and active viral infections by nPCR, characteristic of HHV-6 variants using restriction endonuclease analysis and changes of lymphocyte subsets in peripheral blood by laser flow-cytometry in 17 CFS patients was examined. In addition, 12 patients with unexplained chronic fatigue and 20 blood donors (BD) were studied. RESULTS: No difference in prevalence of latent/persistent single viral infections between the patients and BD was found but dual infection rate was significantly higher in CFS patients. Active HHV-6 and dual (HHV-6 + HHV-7) infections were detected in CFS patients only and frequency of HHV-7 reactivation was also significantly higher in these patients. HHV-6 variant B was predominant in CFS patients (12/13). The changes of immunological parameters in CFS patients with active dual infection were characterized by significant decrease of CD3+ and CD4+ T cells, significant increase of CD95+ cells and decrease of CD4+/CD8+ ratio. CONCLUSIONS: HHV-6 and HHV-7 may be involved in the pathogenesis of CFS and reactivation of both viruses may provoke changes in the phenotype of circulating lymphocytes.

Association of human herpesvirus 6 and human herpesvirus 7 with demyelinating diseases of the nervous system.

Peripheral blood mononuclear cells and plasma of 113 patients with neurological disorders and 150 blood donors were analyzed for HHV-6 and HHV-7 sequences by PCR. The prevalence of HHV-6 was significantly higher in patients with multiple sclerosis (P < 0.01) than in cases of nondemyelinating diseases of the central and demyelinating diseases of the peripheral nervous systems and blood donors. HHV-6 viremia was found only in patients with multiple sclerosis, predominantly in the active phase of the disease. A significantly higher frequency of HHV-7 reactivation in patients with demyelinating diseases of the peripheral nervous system suggests also its association with demyelinating processes.

Co-infection of two beta-herpesviruses (CMV and HHV-7) as an increased risk factor for 'CMV disease' in patients undergoing renal transplantation.

The ubiquity of human cytomegalovirus (CMV) and human herpesvirus-7 (HHV-7), as well as activation of these viruses during immunosuppression, allows the suggestion that both viruses could participate in the development of 'CMV disease' in patients after renal transplantation (RT). The aim of our research was to study the prevalence of latent CMV and HHV-7 infections in patients before RT, to determine interaction between these viruses in dual infection and possible association of their reactivation with the progression of 'CMV disease' after RT. Peripheral blood samples were collected from 49 patients before and up to 10-12 wk after RT. The methods used for diagnostics of viral infections were: serology, nested polymerase chain reaction (nPCR) analysis of peripheral blood leukocytes (PBL) and plasma, and virus isolation in cell cultures (morphological changes, nPCR analysis of cellular and cell-free samples, indirect immunofluorescence analysis). Before RT, CMV and HHV-7 DNAs were detected in PBL but not in the plasma samples, which indicates the presence of latent viral infection in patients. Latent dual (CMV + HHV-7) infection was prevalent (51.0%) in 49 patients, while CMV and HHV-7 infections alone were detected in 26.5 and 12.2% of patients, respectively. Risk of viral disease after RT, for recipients with latent dual infection before RT, was 12- and 2.2-fold higher in comparison with CMV and HHV-7 infections alone, respectively. Frequency of dual infection in 18 recipients with 'viral syndrome' or 'CMV disease' after RT was reliably higher (13/18, 81.3%) than CMV (1/18, 6.2%) (p < 0.025) and HHV-7 (2/18, 12.5%) (p < 0.025) infections alone. HHV-7 reactivation preceded CMV reactivation in 77.0% of the cases of dual infection in the recipients with viral disease and reactivation of both viruses preceded the development of viral disease. Severe 'CMV disease' developed in 2 out of 2 recipients with CMV primary infection and 'viral syndrome' in 1 recipient with CMV reinfection. The reactivation of CMV was detected in all recipients prior to onset of the disease. Correlation was shown between reactivation of latent HHV-7 infection and development of febrile syndrome in 2 out of 2 recipients with HHV-7 infection alone. Taking into account that dual infection is an increased risk factor for 'viral syndrome' and 'CMV disease' development, screening diagnostic should include testing for both viral infections in transplant donors as well as in recipients before and after RT.

Protection against bovine leukemia virus infection in two breeds of cattle.

Calves of two breeds--Brown Latvian and Black and White, were immunized against bovine leukemia virus with an immunogen produced from short-term cultured blood lymphocytes of BLV-positive Brown Latvian cows. The immunogen contained the viral proteins gp51 and p24 as well as some cellular proteins. As determined by bioassay in sheep, it did not contain infective bovine leukemia virus. The calves were challenged by BLV-producing lymphocytes 2 weeks after the immunization procedure. Effective protection against BLV infection was induced by the tested immunogen in all Brown Latvian calves for 6 months and in 70% of the Black and White calves.

[Effect of allogeneic tumor extracts on the development in calves of an experimental infection by the bovine leukemia virus]. / Izuchenie vliianiia ékstraktov allogennykh opukholei na razvitie u teliat éksperimental'noi infektsii virusom leikoza krupnogo rogatogo skota.

The allogenic tumour extracts were studied as immunogens for the prevention of cattle infection with BLV. Immunization did not induce both the production of antibodies against the virus and spontaneous viral infection. Experimental infection of immunized animals with living leukocytes of a leukemic donor caused a BLV infection in 100% of cases.

[Role of the expression of the bovine leukemia virus in the pathogenesis of hemoblastoses]. / Rol' ékspressii virusa leikoza krupnogo rogatogo skota v patogeneze gemoblastozov.

The role of bovine leukemia virus (BLV) expression was demonstrated in normal, BLV-infected and leukemic cattle. The studies established the changeable character of viremia on the basis of BLV p24 expression in blood plasma and native leukocyte lysates. The experiment revealed a marked regularity: a decrease of antibody titer in blood serum--the appearance of the virus in the body--lymphocytosis. The development of lympholeukemia shortly after experimental infection was detected in animals with an antigen regularly detectable in the plasma.

[Experimental induction of lympholeukemia in calves by a purified preparation of bovine leukemia virus]. / Eksperimental'noe vosproizvedenie limfoleikoza u teliat preparatom ochishchennogo virusa leikoza krupnogo rogatogo skota.

The leukemogenic properties of bovine leukemia virus (BLV), isolated from blood plasma, milk and short-term cultures of blood-circulating leukocytes were studied. A complex life-time examination of 14 calves inoculated with a preparation of BLV established leukemia in 4 animals; it was suspected in 3 calves. By the present time leukemia has been morphologically established in 6 out of 13 calves and one was a suspect. Positive results point directly to the viral etiology of bovine leukemia.

BLV-LB virus-specific sequences in cattle with spontaneous and experimentally induced leukemia.

Poly(A)-containing RNAs were extracted directly from the culture fluid of BLV-producing continuous and short-term lymphocyte cultures. The abovesaid poly(A)-RNAs were used as a template to synthesize complementary [3H]DNA (BLV cDNA). BLV cDNA possessed a high degree of homology to poly(A)-RNA isolated directly from the blood plasma of a leukemic animal. In contrast of leukemic cattle BLV-related sequences in white blood cells of normal animals were absent. Leukemic cells of cattle with both, spontaneous and experimentally induced leukemia contained bovine leukemia virus sequences in their genomes.

Induction of bovine leukemia C-type oncornaviruses.

The data are presented concerning the induction of bovine leukemia with purified and concentrated C-type oncornaviruses isolated from cattle of Latvian Brown breed with persistent lympholeukemia. The calves induced with C-type oncornaviruses were found to have early signs of persistent lympholeukemia. Pathohistological changes suggesting persistent lympholeukemia were observed to precede early clinical and hematological signs of the disease. C-type oncornaviruses were reisolated from blood plasma of calves with experimentally induced lympholeukemia.