Human herpesvirus-6 (HHV-6) was isolated in tissue culture in 1986 from peripheral blood leukocytes of patients with both lymphoproliferative disorders and human immunodeficiency virus (HIV) infection. It is the major etiologic agent of exanthem subitum (roseola) and has also been implicated in other clinical syndromes. HHV-6 is a prototypical member of the betaherpesvirus family of herpesviruses, which also includes human herpesvirus-7 (HHV-7) and human cytomegalovirus (HCMV). The virus has a double-stranded DNA genome contained within an icosahedral capsid, surrounded by an outer envelope. HHV-6 is subclassified as either variant A or B, based on differences in nucleotide sequence, restriction enzyme profile, and reactivity with monoclonal antibodies. Some experts have suggested that HHV-6A and -6B are sufficiently different from one another that they should be considered distinct, unique herpesviruses. HHV-6B is the subtype associated with exanthem subitum.
PATHOGENESIS AND EPIDEMIOLOGY
HHV-6 has a tropism for T cells and neuronal cells (particularly oligodendrocytes and microglia). Recent evidence suggests that HHV-6 can be maintained in the host cell in a chromosomally integrated form. The site of integration of the viral genome is the telomere. Approximately 1% of individuals have inherited integrated viral sequences in their genomes, transmitted vertically through the germline, and these individuals characteristically have very high “viral loads” (representing germline inheritance, and not active viral replication) in blood and other sample types when interrogated by PCR. It is unclear whether HHV-6A and HHV-6B chromosomal integration produces any disease phenotype or long-term adverse health consequences, although the integrated viral genome appears capable of becoming excised from the telomeric integration site under some circumstances, potentially allowing for the initiation of viral replication. The clinical consequences of inherited chromosomally integrated HHV-6 have yet to be fully elucidated.
Infection with HHV-6 is ubiquitous, and virtually all children are infected by 2 to 3 years of age. Infection is seldom seen before 6 months of age, presumably due to the protective effect of transplacental antibody. The incidence of infection peaks between 6 and 12 months of age. A recent study in Ugandan infants demonstrated that over 75% of infants acquire HHV-6 infection in the first year of life. HHV-6 can be found in the salivary gland and is shed in saliva of seropositive individuals, suggesting that saliva is the source of virus that leads to person-to-person transmission. Primary infection in children most likely occurs via contact with HHV-6 shed in the secretions of older children or caregivers.
The spectrum of disease associated with primary HHV-6 infection is broad, ranging from asymptomatic infection to (rarely) fatal disseminated disease. Most commonly, primary infection occurs early in life and is manifested as either exanthem subitum or an undifferentiated febrile illness. Reports of HHV-6 infection linked to other clinical syndromes must be interpreted cautiously. Because infection is ubiquitous and persistent in ...