Age-Related Patterns of DNA Detection and Specific IgG Subclasses in Healthy HHV-6- and HHV-7-Infected Individuals.

Human herpesvirus 6A (HHV-6A), Human herpesvirus 6B (HHV-6B), and Human herpesvirus 7 (HHV-7) can persist by establishing a lifelong infection which could have implications on the immunocompetent host. The aim of this work is to contribute with some knowledge about the HHV-6 A/B and HHV-7 infection in healthy individuals. We have carried out a longitudinal study in seropositive healthy individuals for the detection of viral DNA in saliva and plasma samples, and for determining a specific IgG isotype immune response, which enabled the performance of these viruses to be observed over time. Furthermore, an elderly population was transversely studied to provide data of the activity of these viruses in the older population. In the longitudinal study, HHV-6 DNA was occasionally detected and an isotype immune response with a specific IgG1 profile, while in the older group HHV-6 DNA was frequently detected and an isotype immune response with specific IgG1, IgG3, and IgG4. HHV-7 DNA was frequently detected in both groups and isotype patterns of specific IgG1, IgG3, and IgG4. The results of this study highlight that the long-lasting relationship in healthy HHV-6 A/B-infected individuals have the imprint of age groups.

Detection of cytomegalovirus and human herpesvirus-6 DNA in liver biopsy specimens and their correlation with rejection after liver transplantation.

Cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6) reactivation after transplantation put patients at an increased risk of graft rejection mainly among those who receive organs that are positive in their donor biopsies. The aim of this study was to investigate the presence of CMV and HHV-6 DNA in liver biopsy specimens from the donors and from their grafts for correlation with rejection after transplantation. We followed 41 liver transplantation patients whose samples were evaluated using nested-polymerase chain reactions (N-PCR). Twenty-one (51%) of the 41 studied patients experienced rejection; 4/21 (19%) were CMV positive in the donor biopsy specimens and remained positive; another 5 subjects became positive. The patients who received organs from donors with biopsies positive for CMV demonstrated a trend to develop graft rejection after transplantation (Fisher's exact test [P = .0591] with significant results on univariate and multivariate analysis [P = .042]). Eight of the 21 who experienced rejection episodes were HHV-6 positive in the donor biopsy but there was no statistical significance CMV DNA diagnosed in liver donor biopsies remained positive posttransplantation in liver biopsy recipients; it was considered a tendency to develop acute cellular rejection after transplantation.

Co-infection and clinical impact of human herpesvirus 5 and 6 in liver transplantation.

BACKGROUND: Human herpesvirus (HHV) 5 and 6 remain latent after primary infection and can be reactivated after immunosuppression for organ transplantation. An association between HHV-5 and HHV-6 has been reported in liver transplant patients. The coinfection is associated with clinical manifestations and graft dysfunction. OBJECTIVE: The aim of this study was to monitor herpesviruses in liver transplant recipients to better understand issues involving coinfection with HHV-5/6 and correlations with acute cellular rejection episodes and bacterial infections. METHODS: Forty-five adult liver transplant patients of median age 47 years (range, 18-66), gave blood samples and liver biopsies in the first 6 months after their surgeries. Viremia was detected with the use of nested PCR and antigenemia; the Banff classification was used to detect allograft rejection. RESULTS: IgG positive for HHV-5 was observed in 94% of subjects whose main indication (67%) for transplantation was hepatitis C. Twenty-three (51.1%) displayed cytomeg virus (CMV) infections and 12 (26.7%) HHV-6 infection. There were 6 patients (13.3%) with HHV-5/6 coinfections. Eighteen of the 23 patients had CMV disease, showing a strong correlation between a positive test and CMV disease; 6 displayed an acute cellular rejection episode in the same period (χ(2) = 6.62; P < .03). Four out of 6 patients who displayed coinfections (HHV-5/6) had concomitant bacterial infections; 3/6 experienced graft rejection episodes. During follow-up, 1 patient had HHV-6 infection diagnosed as encephalitis followed by fever on the 24th day after surgery. The median 32 days for HHV-6 detection by nested PCR positivity was shorter than 38 days for HHV-5. CONCLUSIONS: HHV-5/6-infected patients displayed more allograft rejection episodes, coinfections, and concomitant bacterial infections, besides an higher risk for CMV disease.

Cytomegalovirus, human herpesvirus-6, and human herpesvirus-7 in adult liver transplant recipients: diagnosis based on antigenemia.

Human herpesvirus (HHV)-6, HHV-7, and cytomegalovirus (CMV) that remain latent after primary infection can be reactivated during immunosuppression following organ transplantation in liver transplant recipients. The aim of this study was to monitor active infections for HHV-6, HHV-7, and CMV among adult liver transplantation recipients using antigenemia detected by an immunoperoxidase staining. Twenty-eight adult liver transplant patients were monitored using antigenemia in blood samples obtained at the time of transplantation, as well as weekly in the first month and once a month for 6 months. Of these patients, 28.5% showed positive CMV antigenemia; 39.2%, HHV-6 antigenemia; and 14.2%, HHV-7 antigenemia. The detection of the three viruses was considered to be independent of one another (P>.05). The results described above showed that few patients remain free of beta herpesviruses after liver transplantation. Most patients were infected sequentially and not concurrently. Antigenemia has been considered useful to detect active HHV-6 and HHV-7 infections. Antigenemia can be more efficiently interpreted when compared with polymerase chain reaction results, although other studies are necessary to establish the reference of HHV-6 and HHV-7 antigenemia.

Herpesvirus type 7 infection may play an important role in individuals with a genetic profile of susceptibility to Graves' disease.

OBJECTIVE: An inherited profile of genes related to the response to aggressive environmental factors such as viruses and chemicals may be related to an increased susceptibility to Graves' disease (GD). DESIGN AND METHODS: This prospective case-control study was designed to examine the relationship between human herpesviruses (HHV) infection, determined by circulating DNA; tumour protein p53 (TP53) apoptotic ability; and detoxification system genes, and GD. We studied 280 confirmed GD patients paired to 284 controls with respect to environmental exposure. Exclusion criteria included medications that could interfere with thyroid function evaluation and a recent history of viral and bacterial infections. RESULTS: A stepwise regression analysis adjusted for age, gender, and ethnicity established the inheritance of glutathione S-transferase pi 1 (GSTP1) (odds ratio (OR)=3.423; 95% confidence interval (CI)=2.120-5.527; P<0.001) and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) variants (OR=1.649; 95% CI=1.012-2.686; P=0.0445) as significant risk factors for the disease. HHV-7 infection was much more common in GD patients (64.64%) than in controls (38.73%; chi(2), P<0.0001), and it increased the risk for GD more than three times (OR=3.133; 95% CI=1.959-5.011; P<0.0001). The inheritance of less efficient Pro/Pro TP53 gene variants significantly increased the risk of GD development (OR=5.196; 95% CI=2.112-12.783; P<0.0001) and also favored HHV-7 infection (OR=2.835; 95% CI=1.100-7.310; P=0.0275). In addition, 72TP53 variants augmented the risk of GD relapse (OR=1.860; 95% CI=1.015-3.410; P=0.0446). CONCLUSIONS: We suggest that an inherited genetic profile involving TP53 may favor HHV-7 infection and maintenance, which, in turn, may initiate and perpetuate GD autoimmune process.

Human herpesvirus-7 in Brazilian liver transplant recipients: a follow-up comparison between molecular and immunological assays.

Human herpesvirus-6 and -7 (HHV-6, HHV-7) remain latent after primary infection and can reactivate after transplantation. HHV-6 active infection has been related to some clinical manifestation, but the role of HHV-7 remains unclear. The clinical significance of HHV-7 DNAemia is not completely known and the immune response against HHV-7 has been poorly studied in transplantation. In this study, we investigated HHV-7 DNAemia in liver transplant recipients and evaluated the immunoglobulin (Ig) G and IgM response against HHV-7. A total of 22 adult liver transplant recipients were followed up for 90 days. HHV-7 DNAemia was detected by nested polymerase chain reaction (PCR) in DNA extracted from sera. IgG and IgM detection was performed by immunofluorescent assay using HHV-7-infected cord blood mononuclear cells. A significant virus antibody response was defined as either a positive IgM or a > or =4-fold rise in the virus IgG antibody. All patients had pre-transplant HHV-7-positive serostatus. Nine of 22 (40.9%) patients presented HHV-7 DNAemia during follow-up. All these patients had anti-HHV-7-positive IgM and/or significant increase in IgG titers with concurrent or subsequent DNAemia. In patients without DNAemia and low persistent IgG antibody titers, IgM was not detected. Correlation between nested PCR and IgM detection was statistically significant (P=0.01). Our study indicates that nested PCR in DNA extraction from serum can be useful to detect and monitor HHV-7 active infection in liver transplant recipients. IgM antibody detection also can be useful as a first immunological technique to detect active infection, especially if combined with PCR.

The accuracy of anti-human herpesvirus 6 IgM detection in children with recent primary infection.

Human herpesvirus 6 (HHV-6) has been shown to infect almost all children by 4 years of age. Even with a typical clinical presentation, HHV-6 infection is misdiagnosed frequently as measles or rubella. The aim of this study was to assess the accuracy of the IgM test for detection of recent primary HHV-6 infection. The study was conducted between January, 1998 and December, 2006 at primary health care units in Niterói, Rio de Janeiro, Brazil. Sera from 185 children, in whom measles, rubella, dengue fever and parvovirus B19 infections were excluded, were studied for anti-HHV-6 IgG and IgM antibodies using an indirect immunofluorescence test. Seventy-one (38.4%) of the children had evidence of primary HHV-6 infection. Taking the IgG avidity test as the "gold standard", the following results for IgM were obtained-sensitivity: 76.1%; specificity: 87.5%; accuracy: 82.4%. This study confirmed the low accuracy of IgM detection for the diagnosis of primary HHV-6 infection.

Loss of maternally-derived human herpesvirus-7 immunity and natural infection in Argentinian infants.

BACKGROUND: Human herpes virus-7 (HHV-7) infection is widespread throughout the world. No data are available in Argentina about loss of maternally-derived HHV-7 immunity and natural infection. OBJECTIVES: The objective of this study was to characterize the time when children lose maternal antibodies and become susceptible to natural infection. METHODS: Sera from 39 pregnant women and 207 infants between 2 and 29 months of age were tested. Determination of IgG antibodies was made by indirect immunofluorescence. RESULTS: The seropositive ratio fell in the 2-4 month group (15% seropositive) and increased between 5 months (47% seropositive) and 23 months (67%). Geometric mean titers (GMT) of the infants aged 2-4 months (GMT = 60) were statistically different (p < 0.0001, Student's t-test) to those from the group of pregnant women (GMT = 83) and those from the other infant groups (p < 0.001, least significant difference (LSD) test). The GMT of the groups between 5 and 23 months did not show significant differences whereas those of infants between 24 and 29 months (GMT = 179, 79% seropositive) were different from all the groups studied (p < 0.0001, LSD test). CONCLUSIONS: This study shows a significant association between the loss of passive HHV-7 antibody and age. HHV-7 enters the susceptible population at 5 months, leading to the high prevalence of antibodies between 24 and 29 months of age. This study also shows that natural infection by HHV-7 in children during their first years of life follows the infection pattern found in developing countries.

Isotype immune response of IgG antibodies at the persistence and reactivation stages of human herpes virus 6 infection.

BACKGROUND: Infections with human herpes virus 6 (HHV-6) are very common. After primary infection, the virus remains latent and persists at low level in cells and tissues. Not usually associated with disease in the immunocompetent host, HHV-6 infection is a major cause of opportunistic viral infections in the immunosuppressed. The different stages of HHV-6 infection are difficult to characterize in the laboratory. OBJECTIVES: The aim of this paper was to assess the isotype patterns of IgG antibodies against HHV-6 in seropositive subjects during different stages of the virus activity. STUDY DESIGN: From a total of 190 human serum samples from 43 healthy children, 24 pregnant women and 24 patients with bone marrow transplants, 111 sera were processed by indirect immunofluorescence assay for the detection of IgG1, IgG2, IgG3 and IgG4 specific antibodies. The mean geometrical title (MGT) of the antibodies was calculated. RESULTS: All pregnant women had IgG1 (24/24; 100%; MGT 46). A 95% (41/43) of healthy infants had IgG1 (MGT 57). In bone marrow transplants, 58% (14/24) of the patients showed seroconversion (MGT 529) with an isotype response of IgG1 and IgG4 during the observation period. Remaining bone marrow transplant patients, who had the IgG without any variations (MGT 184), had isotype IgG1. CONCLUSIONS: These results revealed two different immune isotype response patterns. One of them is restrictive to IgG1 in the latent phase of HHV-6 infection in healthy children, pregnant women and transplant patients with stable levels of antibodies whereas IgG1 and IgG4 are detected in the reactivation of HHV-6 in transplant patients. The IgG isotype immune responses may contribute to the existing set of serological markers in characterizing the different stages of natural infection of HHV-6.

Loss of maternally derived human herpesvirus-6 immunity and natural infection in Argentinian infants.

BACKGROUND: Human herpesvirus-6 (HHV-6) infection is widespread throughout the world. No data are available in Argentina about the loss of maternally derived HHV-6 immunity and natural infection in infants. METHODS: A population of 100 pregnant women and 407 children between 1 and 15 months of age were assayed by indirect immunofluorescence to detect and quantify specific IgG anti-human herpesvirus-6 (anti-HHV-6) antibodies in Córdoba City, Argentina. RESULTS: There was no significant difference in the positive rate between infants aged 1 to 9 months (range, 43.6 35.5%) and pregnant women (37%). Seropositive ratio dropped in the 10-month group (23.33% seropositive) and rose sharply in the 11-month group (38.89%), 12-month (60.61%), and 13- to 15-month group (63.46%). The geometric mean titer (GMT) for infants in the 12 to 15 months age group (23.4 41.64) was significantly higher than the GMT for infants 10 months of age (11.04) (P < 0.05 with the Tukey-HSD test). CONCLUSIONS: This study shows a significant association between loss of passive HHV-6 antibody and age among infants. The results support evidence that HHV-6 enters the susceptible population at 11 months, leading to a high prevalence of antibodies in children between 13 and 15 months of age.