Transplacental Congenital Human Herpesvirus 6 Infection Caused by Maternal Chromosomally Integrated Virus

Hall, Caroline Breese; Caserta, Mary T.; Schnabel, Kenneth C.; Shelley, Lynne; Carnahan, Jennifer; Mariño, Andrea; Yoo, Christina; Lofthus, Geraldine

doi:10.1086/650495

Cited by 81 publications

(65 citation statements)

References 12 publications

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“…Congenital infection results from either the germ line transmission of ciHHV-6 (i.e., congenital ciHHV-6) or transplacental passage of the virus following endogenous reactivation (or putative exogenous reinfection) in the mother. Unexpectedly, in view of its low frequency in adults, ciHHV-6 has been found to be the predominant context associated with congenital HHV-6 infection (162,163). In addition, HHV-6A was detected significantly more frequently in congenital infection than in postnatally acquired infection, and in a study limited to 6 children with transplacentally acquired infection, all the mothers had ciHHV-6.…”

Section: Clinical Impacts Of Hhv-6 Infections Primary Infectionsmentioning

confidence: 96%

“…In addition, HHV-6A was detected significantly more frequently in congenital infection than in postnatally acquired infection, and in a study limited to 6 children with transplacentally acquired infection, all the mothers had ciHHV-6. These data have led to a picture of congenital infection which appears to be far more complex than that of HCMV and in which ciHHV-6 plays a prominent role (162,163). These results also raise numerous questions, which mainly refer to the capability of ciHHV-6 to feed virus reactivation, tolerate exogenous HHV-6 reinfection, induce protective immunity, and enhance potential developmental deficits, particularly in the CNS.…”

Section: Clinical Impacts Of Hhv-6 Infections Primary Infectionsmentioning

confidence: 99%

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Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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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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Section: Clinical Impacts Of Hhv-6 Infections Primary Infectionsmentioning

confidence: 96%

Section: Clinical Impacts Of Hhv-6 Infections Primary Infectionsmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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“…Evidence suggests the integrated HHV-6 is primarily in a latent state, but there are reports of reactivation giving placental infection (Hall et al, 2010). Moreover, in the absence of other virus gene expression both HHV-6A and HHV-6B U83N, can be expressed, encoding the spliced-truncated version which includes the U83B-NT peptide (French et al, 1999).…”

Section: U83b-nt Stimulation Of Ccr2+cd14+cd16+ Monocytic Cellsmentioning

confidence: 99%

Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide

Clark

Catusse

Stacey

et al. 2013

Journal of General Virology

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Human monocytes expressing CCR2 with CD14 and CD16 can mediate antigen presentation, and promote inflammation, brain infiltration and immunosenescence. Recently identified roles are in human immunodeficiency virus infection, tuberculosis and parasitic disease. Human herpesvirus 6B (HHV-6B) encodes a chemokine, U83B, which is monospecific for CCR2, and is distinct from the related HHV-6A U83A, which activates CCR1, CCR4, CCR5, CCR6 and CCR8 on immune effector cells and dendritic cells. These differences could alter leukocyte-subset recruitment for latent/lytic replication and associated neuroinflammatory pathology. Therefore, cellular interactions between U83A and U83B could help dictate potential tropism differences between these viruses. U83A specificity is maintained in the 38-residue N-terminal spliced-truncated form. Here, we sought to determine the basis for the chemokine receptor specificity differences and identify possible applications. To do this we first analysed variation in a natural host population in sub-Saharan Africa where both viruses are equally prevalent and compared these to global strains. Analyses of U83 N-terminal variation in 112 HHV-6A and HHV-6B infections identified 6/ 38 U83A or U83B-specific residues. We also identified a unique single U83A-specific substitution in one U83B sequence, 'U83BA'. Next, the variation effects were tested by deriving N-terminal (NT) 17-mer peptides and assaying activation of ex vivo human leukocytes, the natural host and cellular target. Chemotaxis of CCR2+ leukocytes was potently induced by U83B-NT, but not U83BA-NT or U83A-NT. Analyses of the U83B-NT activated population identified migrated CCR2+, but not CCR5+, leukocytes. The U83BA-NT asparagine-lysine14 substitution disrupted activity, thus defining CCR2 specificity and acting as a main determinant for HHV-6A/B differences in cellular interactions. A flow-cytometry-based shape-change assay was designed, and used to provide further evidence that U83B-NT could activate CCR2+CD14+CD16+ monocytes. This defines a potential antiviral target for HHV-6A/B disease and novel peptide immunomodulator for proinflammatory monocytes.

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“…Indeed, HHV-6 and HHV-7 may be present in the organism under different status with (i) an active infection that occurs in mainly T lymphocytes during primary infection or reactivation and can lead to symptoms, (ii) a latent infection as episome in monocytes/macrophages for which there is probably no pathology associated. Finally, HHV-6 has been identified in another form of latency, as chromosomally integrated/inherited genome (ciHHV-6), with perhaps pathologies associated and probably possible reactivation [4][5][6]. The distinction between these three modes of infection is required in order to propose or exclude an antiviral therapy that may be toxic.…”

Section: Introductionmentioning

confidence: 99%