Human Herpesviruses 6 and 7 (Roseola, Exanthem Subitum)

Description of the Pathogens

HHV-6A, HHV-6B, and HHV-7 comprise the Roseolovirus genus of the subfamily β-Herpesvirinae. They have the characteristic human herpesvirus family morphology and structure: an electron-dense nucleic acid core encased in an icosahedral capsid surrounded by proteins collectively known as the tegument and an outer envelope containing proteins and glycoproteins in a lipid bilayer. The linear, double-stranded deoxyribonucleic acid (DNA) genome of HHV-6 is 160–170 kilobases (kb) and has a unique central region (U), which contains open reading frames (ORFs) U1–U100 bounded on each end by terminal direct repeats (tDR). HHV-6A, HHV-6B, and HHV-7 all share limited homology with human cytomegalovirus (CMV), the only other human β-herpesvirus. ^, The overall nucleotide sequence identity between HHV-6A and HHV-6B is approximately 90%, but less in the direct repeats (85%) and U86–U100 (72%). ^, HHV-6A and HHV-6B are colinear with minimal (<1%) intragroup variation. Although HHV-6A and HHV-6B initially were classified as separate subgroups of HHV-6, in 2012, the two were recognized officially as distinct species based on differences in biology, immunology, epidemiology, and disease associations.

HHV-6B causes almost all primary infections in infants and is the predominant virus associated with reactivated infection in immunocompetent and immunocompromised individuals. ^, However, in a previous report from an African population, most of the infant infections were associated with HHV-6A. More recent data have not confirmed this finding. HHV-6 infects mature T lymphocytes in vitro, especially activated CD4 ⁺ cells. However, in contrast to the findings of the in vitro studies, HHV-6B replicates more efficiently in monocytes and macrophages during acute infection than in CD4 ⁺ cells. HHV-6 also can infect multiple other cell types, including B lymphocytes, fibroblasts, natural killer (NK) cells, and neuronal, epithelial, and endothelial cells. ^{, ,} Growth is characterized by cellular ballooning, lysis, and cell death.

HHV-6A uses CD46 as a cellular receptor. This receptor is expressed on the surface of all human nucleated cells, which may partly explain the wide in vitro cellular tropism and tissue distribution of HHV-6A. Viral binding occurs through the interaction of CD46 with the glycoprotein complex HHV-6A gHgLgQ1gQ2. The same complex is responsible for the binding of HHV-6B to the newly identified receptor CD134 (OX40), a member of the tumor necrosis factor (TNF) superfamily present on the surface of activated T lymphocytes. For both viruses, the interaction between the cellular gp96 and HHV-6 gQ1 proteins has an important role in establishing infection. Differences in the gQ1 and gQ2 nucleotide sequences between HHV-6A and HHV-6B are thought to play a role in defining receptor specificity and tissue tropism.

After primary infection, HHV-6A and HHV-6B establish latency in monocytes and macrophages and possibly in other sites, such as hematopoietic stem cells (HCT; CD34 ⁺ ) and the central nervous system (CNS). ^, Persistent infection can occur in the salivary glands. ^, The structure of the HHV-6 genome during latency appears to be maintained by chromosomal integration and/or by closed circular molecules, similar to episomes of other herpesviruses, with only a few viral genes expressed. ^{, ,}

Reactivation occurs with multiple but poorly defined stimuli and can be asymptomatic or result in organ-specific diseases. Usually, reactivation in a healthy person is clinically occult. Occasionally, primary infection with a closely related virus (e.g., HHV-7) can result in HHV-6 reactivation associated with viremia and a febrile illness.

Neutralizing antibodies to multiple HHV-6 proteins, especially to linear and conformational epitopes of the glycoproteins, develop after primary HHV-6B infection. Immunoglobulin M (IgM) antibody usually appears in the first week of illness and disappears within 1–2 months. IgG antibody appears during the second week after the onset of illness, and concentrations and avidity peak within 1–2 months. ^{, ,} The antibody response to primary infection occurs despite the presence of maternal antibody but can be dampened by high levels of passive antibody. Humoral antibody appears to be protective because illness is uncommon during the first few months of life when maternal antibody is present in high concentration ( Fig. 207.1 ). As transplacental antibody concentrations decline, infants rapidly acquire HHV-6B infection. HHV-6 IgG antibody titers subsequently fluctuate and can be boosted by infection with other closely related herpesviruses. The immunologic response after primary infection usually protects against subsequent episodes of viremia and clinical illness. HHV-6 antibody is detectable throughout life, as evidenced by its almost universal presence in the cord blood of neonates.

Clinical observations suggest that cellular immunity is critical in the control, persistence, and reactivation of HHV-6B infection. Patients with compromised cellular immunity, especially HCT and solid-organ transplant (SOT) recipients, are most prone to developing disease with HHV-6B reactivation. The effects of HHV-6 on the innate and adaptive cellular responses are incompletely defined but appear to be complex. Multiple observations indicate that HHV-6 can modulate and circumvent the body’s immune response, enhancing the pathogenesis of primary infection and favoring lifetime survival of the virus. ^,

Epidemiology

HHV-6B infection has a worldwide distribution and no seasonal or gender predilection. ^{, ,} Primary infection usually occurs between 6 months and 3 years of age, ^, which matches the typical age distribution of roseola. ^, Studies of HHV-6B primary illness in Japan and the US show similar age distributions, with relatively few cases before 6 months or after 2–3 years of age. ^{, ,} The peak period of acquisition is between 6 and 12 months; the median is about 8 months of age. ^{, , ,}

HHV-6B is a significant cause of acute febrile illness in infants 6–18 months of age, and it is responsible for about 20% of visits to emergency departments for acute illness in infants 6–12 months of age ( Fig. 207.1 ). ^, Infection is ubiquitous, and in most areas studied, essentially all adults are seropositive. ^, Some geographic differences may exist, and in some countries, the age of acquisition of initial infection is later than in the US. HHV-6A has not been associated clearly with a distinct disease, and significant cross-reactivity between HHV-6A and HHV-6B in standard serologic assays has limited epidemiologic investigations.

Mode of Transmission

Clinical Manifestations