Prevalence of Human Herpesvirus-6 Chromosomal Integration (CIHHV-6) in Italian Solid Organ and Allogeneic Stem Cell Transplant Patients

Potenza, Leonardo; Barozzi, Patrizia; Masetti, Michele; Pecorari, Monica; Bresciani, Pablo Diego; Gautheret‐Dejean, Agnès; Riva, Giovanni; Vallerini, Daniela; Tagliazucchi, Sara; Codeluppi, Mauro; Benedetto, Fabrizio Di; Gerunda, G.E.; Narni, Franco; Torelli, Giuseppe; Luppi, Mario

doi:10.1111/j.1600-6143.2009.02685.x

Cited by 41 publications

(40 citation statements)

References 25 publications

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“…The results obtained here indicate that the prevalence of iciHHV-6 in Quebec falls within the 0.2-2.9% prevalence previously reported for other region of the globe (40)(41)(42)(43)(44). The main finding of the current study is that prevalence of angina pectoris is found elevated 3.3 times in iciHHV-6+ subjects relative to iciHHV-6− subjects (P = 0.017).…”

Section: Discussionsupporting

confidence: 69%

“…One potential caveat of the previous study lies in the fact that such assumption was made by pooling data from several small independent studies from various geographical regions where iciHHV-6 incidence and environmental factors may differ, which is likely to affect analysis outcome. The worldwide prevalence of iciHHV6+ individuals is estimated to be ∼1% with variations observed (0.2-2.9%) depending on the geographical regions and population sampled (healthy vs. diseased) (40)(41)(42)(43)(44). A relatively large sample size is therefore needed to have a sufficient number of subjects with iciHHV-6 to determine potential disease associations.…”

Section: Discussionmentioning

confidence: 99%

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Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris

Gravel

Dubuc

Morissette

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inherited chromosomally integrated human herpesvirus-6 (iciHHV-6) results in the germ-line transmission of the HHV-6 genome. Every somatic cell of iciHHV-6+ individuals contains the HHV-6 genome integrated in the telomere of chromosomes. Whether having iciHHV-6 predisposes humans to diseases remains undefined. DNA from 19,597 participants between 40 and 69 years of age were analyzed by quantitative PCR (qPCR) for the presence of iciHHV-6. Telomere lengths were determined by qPCR. Medical records, hematological, biochemical, and anthropometric measurements and telomere lengths were compared between iciHHV-6+ and iciHHV-6− subjects. The prevalence of iciHHV-6 was 0.58%. Two-way ANOVA with a Holm-Bonferroni correction was used to determine the effects of iciHHV6, sex, and their interaction on continuous outcomes. Two-way logistic regression with a Holm-Bonferroni correction was used to determine the effects of iciHHV6, sex, and their interaction on disease prevalence. Of 50 diseases monitored, a single one, angina pectoris, is significantly elevated (3.3×) in iciHHV-6+ individuals relative to iciHHV-6− subjects (P = 0.017; 95% CI, 1.73-6.35). When adjusted for potential confounding factors (age, body mass index, percent body fat, and systolic blood pressure), the prevalence of angina remained three times greater in iciHHV-6+ subjects (P = 0.015; 95%CI, 1.23-7.15). Analyses of telomere lengths between iciHHV-6− without angina, iciHHV-6− with angina, and iciHHV-6+ with angina indicate that iciHHV-6+ with angina have shorter telomeres than age-matched iciHHV-6− subjects (P = 0.006). Our study represents, to our knowledge, the first largescale analysis of disease association with iciHHV-6. Our results are consistent with iciHHV-6 representing a risk factor for the development of angina.HHV-6 | telomere | angina | chromosomal integration | ciHHV-6

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris

Gravel

Dubuc

Morissette

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…By extrapolation, considering that HHV-6 infects close to 100% of the human population, this suggests that nearly 70 million individuals carry CIHHV-6. Not only is the prevalence of integration much higher than for any other human herpesvirus, but a major difference lies in the observation that CIHHV-6 is present in every nucleated cell of the body, from hair follicles to PBMCs (37,78,101). Because the medical consequences of CIHHV-6 are not known, there is a lot of concern as to whether cells, tissues, and organs from individuals with CIHHV-6 are to be considered acceptable and "medically safe" for transplant purposes.…”

Section: Chromosomal Integration Of Hhv-6mentioning

confidence: 99%

Herpesviruses and Chromosomal Integration

Morissette

Flamand

2010

J Virol

205

164

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Herpesviruses are members of a diverse family of viruses that colonize all vertebrates from fish to mammals. Although more than one hundred herpesviruses exist, all are nearly identical architecturally, with a genome consisting of a linear double-stranded DNA molecule (100 to 225 kbp) protected by an icosahedral capsid made up of 162 hollow-centered capsomeres, a tegument surrounding the nucleocapsid, and a viral envelope derived from host membranes. Upon infection, the linear viral DNA is delivered to the nucleus, where it circularizes to form the viral episome. Depending on several factors, the viral cycle can proceed either to a productive infection or to a state of latency. In either case, the viral genetic information is maintained as extrachromosomal circular DNA. Interestingly, however, certain oncogenic herpesviruses such as Marek's disease virus and Epstein-Barr virus can be found integrated at low frequencies in the host's chromosomes. These findings have mostly been viewed as anecdotal and considered exceptions rather than properties of herpesviruses. In recent years, the consistent and rather frequent detection (in approximately 1% of the human population) of human herpesvirus 6 (HHV-6) viral DNA integrated into human chromosomes has spurred renewed interest in our understanding of how these viruses infect, replicate, and propagate themselves. In this review, we provide a historical perspective on chromosomal integration by herpesviruses and present the current state of knowledge on integration by HHV-6 with the possible clinical implications associated with viral integration.

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“…A highly conserved region of the U94 gene in HHV-6A and HHV-6B was amplified and used to distinguish species. Testing for chromosomally integrated HHV-6 was considered for patients with suggestive test results (viral load >3.5 log 10 copies/mL or persistent levels >100 copies/mL in >80% of plasma samples) (26). CMV PCR test results from our original publication were used for this study, and testing was performed as previously described (27).…”

Section: Methodsmentioning

confidence: 99%

Coreactivation of Human Herpesvirus 6 and Cytomegalovirus Is Associated With Worse Clinical Outcome in Critically Ill Adults*

López-Roa

Hill

Kirby

et al. 2015

Critical Care Medicine

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OBJECTIVE Human herpesvirus 6 (HHV-6) is associated with a variety of complications in immunocompromised patients, but no studies have systematically and comprehensively assessed the impact of HHV-6 reactivation, and its interaction with cytomegalovirus (CMV), in intensive care unit (ICU) patients. DESIGN We prospectively assessed HHV-6 and CMV viremia by twice-weekly plasma PCR in a longitudinal cohort study of 115 adult, immunocompetent ICU patients. The association of HHV-6 and CMV reactivation with death or continued hospitalization by day 30 (primary endpoint) was assessed by multivariable logistic regression analyses. SETTING This study was performed in trauma, medical, surgical, and cardiac ICU’s at two separate hospitals of a large tertiary care academic medical center. PATIENTS A total of 115 CMV seropositive, immunocompetent adults with critical illness were enrolled in this study. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS HHV-6 viremia occurred in 23% of patients at a median of 10 days. HHV-6B was the species detected in eight samples available for testing. Most patients with HHV-6 reactivation also reactivated CMV (70%). Severity of illness was not associated with viral reactivation. Mechanical ventilation, burn ICU, major infection, HHV-6 reactivation, and CMV reactivation were associated with the primary endpoint in unadjusted analyses. In a multivariable model adjusting for mechanical ventilation and ICU type, only co-reactivation of HHV-6 and CMV was significantly associated with the primary endpoint (adjusted odds ratio, 7.5; 95% CI, 1.9-29.9; p=0.005) compared to patients with only HHV-6, only CMV, or no viral reactivation. CONCLUSIONS Co-reactivation of both HHV-6 and CMV in ICU patients is associated with worse outcome than reactivation of either virus alone. Future studies should define the underlying mechanism(s) and determine whether prevention or treatment of viral reactivation improves clinical outcome.

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Prevalence of Human Herpesvirus-6 Chromosomal Integration (CIHHV-6) in Italian Solid Organ and Allogeneic Stem Cell Transplant Patients

Cited by 41 publications

References 25 publications

Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris

Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris

Herpesviruses and Chromosomal Integration

Coreactivation of Human Herpesvirus 6 and Cytomegalovirus Is Associated With Worse Clinical Outcome in Critically Ill Adults*

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