Human Herpesvirus 6 (HHV-6) is a member of the Herpesviridae family that has infected nearly the entire global population by adulthood. HHV-6 is classified as a Beta-herpesvirus and includes two closely related, yet distinct, species known as HHV-6A and HHV-6B. Understanding the virus involves examining its physical makeup, the specific ways it moves between people, and the laboratory techniques used to identify its presence in the body.
Viral Architecture and Classification
Human Herpesvirus 6 possesses the characteristic physical structure of all herpesviruses, known as a virion. At its core is a double-stranded linear DNA genome housed within a protective protein shell called an icosahedral capsid. Surrounding the capsid is a layer of proteins known as the tegument, which helps mediate the initial steps of infection once the virus enters a cell.
The virion is encased in an outer lipid envelope, studded with viral glycoproteins that facilitate entry into new target cells. The virus specifically targets immune cells, primarily CD4+ T-lymphocytes, by binding to a widely expressed cell surface marker called CD46.
The virus is formally classified within the Betaherpesvirinae subfamily, alongside cytomegalovirus (CMV), and belongs to the genus Roseolovirus. Although HHV-6A and HHV-6B share approximately 95% of their DNA sequence, they are recognized as two distinct species. HHV-6B is the variant responsible for the vast majority of primary infections and associated childhood disease globally.
Routes of Transmission
The high seroprevalence of HHV-6 in adults is largely explained by its primary mode of spread through saliva. The virus establishes a persistent infection within the salivary glands and is shed in high concentrations in oral secretions. Transmission commonly occurs through contact with respiratory droplets, such as during kissing, sharing utensils, or other close contact between adults and infants.
Vertical transmission, or the passage of the virus from mother to child, can also occur during pregnancy or birth. In these instances, the virus is chromosomally integrated into the host germline cells, a condition known as inherited chromosomally integrated HHV-6 (iciHHV-6).
A different route of transmission is observed in clinical settings, particularly following solid organ or hematopoietic stem cell transplantation. In transplant recipients, the virus can be transmitted through the transplanted tissue or reactivate from latency due to the immunosuppressive drug regimen. Reactivation in this patient population is a significant medical concern, as the virus can cause severe complications.
Primary Infection and Latency
Primary HHV-6B infection typically manifests as Roseola Infantum, also known as Exanthem Subitum. This self-limiting childhood illness affects infants between six months and two years of age. The classic presentation begins with an abrupt onset of a high fever that lasts for three to five days.
During the febrile phase, the child usually appears well despite the high temperature, but the fever can occasionally lead to febrile seizures in up to 15% of patients. The fever then subsides rapidly, and a non-itchy, pink, maculopapular rash appears, primarily on the trunk before spreading. This rash usually fades within one to two days and marks the end of the acute illness.
Following the resolution of the primary infection, HHV-6 establishes a lifelong latent state. The viral DNA persists within host cells, most notably T-lymphocytes and monocytes. The virus can also integrate its genome directly into the host cell’s chromosomes, particularly at the telomeres.
This latent virus can reactivate, especially when the host’s immune system is suppressed, such as in transplant recipients or those with advanced immune deficiencies. Reactivation can range from asymptomatic shedding to serious clinical disease. In immunocompromised individuals, HHV-6 reactivation is a known cause of complications, including hepatitis, pneumonitis, and encephalitis.
Methods for Diagnosis
Diagnosing HHV-6 infection requires careful consideration of the patient’s immune status and clinical context, as the virus exists in both active and latent states. The most reliable method for detecting active viral replication is the use of quantitative Polymerase Chain Reaction (PCR) testing. Quantitative PCR measures the amount of viral DNA present in a given sample, such as whole blood, plasma, or cerebrospinal fluid.
A rising or high viral load in plasma or cerebrospinal fluid generally indicates active viral replication and is used to monitor disease progression or response to treatment. The presence of viral DNA alone in whole blood is often insufficient for diagnosis, as it may only reflect the latent virus present in circulating immune cells. In individuals with chromosomally integrated HHV-6, high levels of viral DNA will consistently show in all nucleated cells, even without active disease.
Serology, which involves testing for antibodies against HHV-6, can also be utilized, primarily to confirm a primary infection. The detection of Immunoglobulin M (IgM) antibodies or a four-fold increase in Immunoglobulin G (IgG) antibodies between acute and convalescent samples indicates a recent infection. However, serology is rarely useful for diagnosing reactivation in older children and adults because nearly everyone has detectable IgG antibodies from a prior childhood infection.