Roseola (Human Herpesviruses 6 and 7)

Etiology

HHV-6A, HHV-6B, and HHV-7 are the sole members of the Roseolovirus genus in the Betaherpesvirinae subfamily of human herpesviruses. Human cytomegalovirus, the only other β-herpesvirus, shares limited sequence homology with HHV-6 and HHV-7. Morphologically all human herpesviruses are composed of an icosahedral nucleocapsid, protein-dense tegument, and lipid envelope. Within the nucleocapsid, HHV-6 and HHV-7 both contain large, linear, double-stranded DNA genomes that encode more than 80 unique proteins.

Initially, 2 strain groups of HHV-6 were recognized, HHV-6 variant A and HHV-6 variant B. Despite sharing highly conserved genomes with approximately 90% sequence identity, the 2 variants could be distinguished by restriction fragment length polymorphisms, reactivity with monoclonal antibodies, differential cell tropism, and epidemiology. Because of these differences, the two were reclassified as separate species in the genus Roseolovirus by the International Committee on the Taxonomy of Viruses in 2012.

HHV-6A detection is quite rare, and HHV-6B is the overwhelmingly predominant virus found in both normal and immunocompromised hosts by both culture and polymerase chain reaction (PCR). Previous reports of HHV-6A detection in children in Africa have not been substantiated in a recent large cohort using a more specific PCR target.

Epidemiology

Primary infection with HHV-6B is acquired rapidly by essentially all children following the loss of maternal antibodies in the 1st few mo of infancy, 95% of children being infected with HHV-6 by 2 yr of age. The peak age of primary HHV-6B infection is 6-9 mo of life, with infections occurring sporadically and without seasonal predilection or contact with other ill individuals. Infection with HHV-7 is also widespread but occurs later in childhood and at a slower rate; only 50% of children have evidence of prior infection with HHV-7 by 3 yr of age. Seroprevalence reaches 75% at 3-6 yr of age. In a small study of children with primary HHV-7 infection, the mean age of the patients was 26 mo, significantly older than that of children with primary HHV-6 infection.

Preliminary data suggest that the majority of children acquire primary infection with HHV-6 from the saliva or respiratory droplets of asymptomatic adults or older children. However, congenital infection with HHV-6 occurs in 1% of newborns. Two mechanisms of vertical transmission of HHV-6 have been identified, transplacental infection and chromosomal integration. HHV-6 is unique among the human herpesviruses in that it is integrated at the telomere end of human chromosomes at a frequency of 0.2–2.2% of the population and is passed from parent to child via the germline. Chromosomal integration of HHV-7 has only been suggested in a single case report thus far. Chromosomal integration has been identified as the major mechanism by which HHV-6 is vertically transmitted, accounting for 86% of congenital infections, with one third resulting from HHV-6A, a percentage much higher than in primary infection in the United States. The clinical consequences of chromosomal integration or transplacental infection with HHV-6 have yet to be determined. However, reactivation of chromosomally integrated HHV-6 virus has been demonstrated following hematopoietic stem cell transplantation (HSCT). In one series of infants identified with HHV-6 congenital infection, no evidence of disease was present in the early neonatal period. Primary infection with HHV-7 is presumed to be spread by the saliva of asymptomatic individuals. DNA of both HHV-6 and HHV-7 has been identified in the cervical secretions of pregnant women, suggesting an additional role for sexual or perinatal transmission of these viruses. Breast milk does not appear to play a role in transmission of either HHV-6 or HHV-7.

Pathology/Pathogenesis

Primary HHV-6B infection causes a viremia that can be demonstrated by co-culture of the patient's peripheral blood mononuclear cells with mitogen-stimulated cord blood mononuclear cells. HHV-6 has a recognizable cytopathic effect, consisting of the appearance of large refractile mononucleated or multinucleated cells with intracytoplasmic and/or intranuclear inclusions. Infected cells exhibit a slightly prolonged life span in culture; however, lytic infection predominates. HHV-6 infection also induces apoptosis of T cells. In vitro, HHV-6 can infect a broad range of cell types, including primary T cells, monocytes, natural killer cells, dendritic cells, and astrocytes. HHV-6 has also been documented to infect B-cell, megakaryocytic, endothelial, and epithelial cell lines. Human astrocytes, oligodendrocytes, and microglia have been infected with HHV-6 ex vivo. The broad tropism of HHV-6 is consistent with the recognition that CD46, present on the surface of all nucleated cells, is a cellular receptor for HHV-6, HHV-6A in particular. CD134, a member of the TNFR superfamily, is the main entry receptor for HHV-6B and may explain some of the differences in tissue tropism noted between HHV-6A and HHV-6B. The CD4 molecule has been identified as a receptor for HHV-7. HHV-7 has been demonstrated to reactivate HHV-6 from latency in vitro, but whether this phenomenon occurs in vivo is not clear.

Primary infection with HHV-6 and HHV-7 is followed by lifelong latency or persistence of virus at multiple sites. HHV-6 exists in a true state of viral latency in monocytes and macrophages. The detection of replicating HHV-6 in cultures of primary CD34+ hematopoietic stem cells has also been described, suggesting that cellular differentiation is a trigger of viral reactivation. This observation is clinically significant because HHV-6 may cause either primary or reactivated infection during HSCT. Additionally, HHV-6 and HHV-7 infection may be persistent in salivary glands, and DNA of both HHV-6 and HHV-7 can be routinely detected in the saliva of both adults and children. HHV-7 can also be isolated in tissue culture from saliva, but HHV-6 cannot. HHV-6 DNA has been identified in the cerebrospinal fluid (CSF) of children, both during and subsequent to primary infection, as well as in brain tissue from immunocompetent adults at autopsy, implicating the central nervous system as an additional important site of either viral latency or persistence. HHV-7 DNA has also been found in adult brain tissue but at a significantly lower frequency.