SUMMARYChromosomally integrated human herpesvirus 6 (ciHHV-6) is a condition in which the complete HHV-6 genome is integrated into the host germ line genome and is vertically transmitted in a Mendelian manner. The condition is found in less than 1% of controls in the USA and UK, but has been found at a somewhat higher prevalence in transplant recipients and other patient populations in several small studies. HHV-6 levels in whole blood that exceed 5.5 log10 copies/ml are strongly suggestive of ciHHV-6. Monitoring DNA load in plasma and serum is unreliable, both for identifying and for monitoring subjects with ciHHV-6 due to cell lysis and release of cellular DNA. High HHV-6 DNA loads associated with ciHHV-6 can lead to erroneous diagnosis of active infection. Transplant recipients with ciHHV-6 may be at increased risk for bacterial infection and graft rejection. ciHHV-6 can be induced to a state of active viral replication in vitro. It is not known whether ciHHV-6 individuals are put at clinical risk by the use of drugs that have been associated with HHV-6 reactivation in vivo or in vitro. Nonetheless, we urge careful observation when use of such drugs is indicated in individuals known to have ciHHV-6. Little is known about whether individuals with ciHHV-6 develop immune tolerance for viral proteins. Further research is needed to determine the role of ciHHV-6 in disease. Copyright © 2011 John Wiley & Sons, Ltd.

SUMMARY Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus.

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Human herpesvirus (HHV)-6 and HHV-7 loads were evaluated retrospectively in peripheral blood mononuclear cells (PBMC) from 78 recipients of stem cell transplantation (SCT) by real-time polymerase chain reaction. The median HHV-6 load in patients was 1357 genome equivalent copies (EqCop)/10(6) PBMC but was below the quantitation threshold in 31 immunocompetent individuals, which strongly suggests that HHV-6 reactivation occurred after SCT. The HHV-6 load was higher in patients with delayed neutrophil engraftment (P=.002) or severe graft-versus-host disease (P=.009). Moreover, the occurrence of at least 1 HHV-6-related manifestation (fever, cutaneous rash, pneumonitis, or partial myelosuppression) was statistically associated with a concomitant virus load >10(3) EqCop/10(6) PBMC (P=.007). Conversely, HHV-7 reactivation was not favored, because median HHV-7 loads were similar in patients and healthy control subjects (1053 vs. 1216 EqCop/10(6) PBMC). The kinetics of Roseolovirus loads during the posttransplantation period suggested that HHV-7 may act as a cofactor of HHV-6 reactivation.

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Human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, HHV-7) are genetically related to cytomegalovirus. They belong to the Roseolovirus genus and to the Betaherpesvirinae subfamily. They infect T cells, monocytes-macrophages, epithelial cells, and central nervous system cells. These viruses are ubiquitous and are responsible for lifelong chronic infections, most often asymptomatic, in the vast majority of the general adult population. HHV-6B is responsible for exanthema subitum, which is a benign disease of infants. HHV-6A and HHV-6B also cause opportunistic infections in immunocompromised patients: encephalitis, hepatitis, bone marrow suppression, colitis, and pneumonitis. Their etiological role in chronic diseases such as multiple sclerosis, cardiomyopathy, and thyroiditis is still controversial. The pathogenicity of HHV-7 is less clear and seems to be much more restricted. Chromosomal integration of HHV-6A and HHV-6B is transmissible from parents to offspring and observed in about 1% of the general population. This integration raises the question of potential associated diseases and can be a confounding factor for the diagnosis of active infections by both viruses. The diagnosis of HHV-6A, HHV-6B, and HHV-7 infections is rather based on gene amplification (PCR), which allows for the detection and quantification of the viral genome, than on serology, which is mainly indicated in case of primary infection. Ganciclovir, foscarnet, and cidofovir inhibit the replication of HHV-6A, HHV-6B, and HHV-7. Severe infections may thus be treated but these therapeutic indications are still poorly defined.

After serial passage in the presence of increasing concentrations of ganciclovir (GCV) in vitro, a human herpesvirus-6 (HHV-6) mutant exhibiting a decreased sensitivity to the drug was isolated. Analysis of drug susceptibility showed that the IC 50 of this mutant was 24-, 52-and 3-fold higher than that of the wild-type (wt) IC 50 in the case of GCV, cidofovir and foscarnet, respectively. Genotypic analysis showed two single nucleotide changes as compared to the wild-type : an A G substitution of the U69 protein kinase (PK) gene resulted in an M 318 V amino acid substitution and the other change, located in the C-terminal part of the U38 gene, resulted in an A 961 V amino acid substitution within the DNA polymerase. The M 318 V change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the M 460 V and M 460 I changes that had been reported previously within the consensus sequence DITPMN of the human cytomegalovirus (HCMV) UL97 PK and associated with the resistance of HCMV to GCV. The M 318 V change was also detected by PCR in HHV-6-infected PBMCs from an AIDS patient who had been treated with GCV for a long period of time and exhibited a clinically GCVresistant HCMV infection. These findings provide strong circumstantial evidence that the M 318 V change of the PK gene is associated with resistance to GCV and raise the question of cross resistance to this drug among different betaherpesviruses.

The herpes simplex virus type 1 (HSV-1) genome is a linear double-stranded DNA of 152 kpb. It is divided into long and short regions of unique sequences termed U L and U S , respectively, and these are flanked by regions of inverted internal and terminal repeats. Microsatellites are short tandem repeats of 1-to 6-nucleotide motifs; they are often highly variable and polymorphic within the genome, which raises the question of whether they may be used as molecular markers for the precise differentiation of HSV-1 strains. In this study, 79 different microsatellites (mono-, di-, and trinucleotide repeats) in the HSV-1 complete genome were identified by in silico analysis. Among those microsatellites, 45 were found to be distributed in intergenic or noncoding inverted repeat regions, while 34 were in open reading frames. Length polymorphism analysis of the PCR products was used to investigate a set of 12 distinct HSV-1 strains and allowed the identification of 23 polymorphic and 6 monomorphic microsatellites, including two polymorphic trinucleotide repeats (CGT and GGA) within the UL46 and US4 genes, respectively. A multiplex PCR method that amplified 10 polymorphic microsatellites was then developed for the rapid and accurate genetic characterization of HSV-1 strains. Each HSV-1 strain was characterized by its own microsatellite haplotype, which proved to be stable over time in cell culture. This relevant innovative tool was successfully applied both to confirm the close relationship between sequential HSV-1 isolates collected from patients with multiple recurrent infections and to investigate putative nosocomial infections.Herpes simplex virus type 1 (HSV-1) is a member of the subfamily Alphaherpesvirinae. The seroprevalence of HSV-1 infection increases progressively from childhood and is inversely proportional to an individual's socioeconomic background (35). Primary HSV-1 infections in children are typically asymptomatic but can give rise to herpetic gingivostomatitis. After primary infection of the orofacial region, HSV-1 is transported in a retrograde manner to the nuclei of the trigeminal sensory neurons through their axons, which innervate the infected area. HSV-1 then establishes a life-long latent infection in the nuclei of sensory neurons, where the genome lies in a nonreplicating chromatin-associated state. Recurrent HSV-1 lesions occur following the reactivation of latent HSV-1, axonal transport of the reactivated virus, and HSV-1 replication on the skin and mucous membranes. Recurrent infections typically give rise to herpes labialis or may be responsible for more severe clinical manifestations, including keratitis, meningoencephalitis, bronchopneumonitis (22), chronic or disseminated infections in immunosuppressed patients, or eczema herpeticum. Eczema herpeticum, or Kaposi-Juliusberg disease, is an uncommon herpes simplex virus superinfection that occurs in patients with atopic dermatitis. Additionally, HSV-1 accounts for about half of the new cases of genital herpes in developed countries (14).The HS...