Human Herpesvirus 6 (HHV-6) and Human Herpesvirus 7 (HHV-7) are members of the betaherpesvirus subfamily. Nearly all humans are infected with these viruses, typically during early childhood, making them among the most prevalent infectious agents worldwide. Once the initial infection resolves, the viruses establish a lifelong, dormant presence within the body. This article focuses on how this viral persistence is maintained in adulthood and the consequences of periodic viral reactivation.
Viral Persistence and Latency
Following the primary childhood infection, often manifesting as the rash illness roseola, the viruses enter a state of latency. The viral genome remains inside host cells, but gene expression is limited to avoid immune detection. HHV-6 and HHV-7 establish this latent reservoir primarily within immune cells, specifically T-cells and monocytes or macrophages. The virus also shows a neurotropic tendency, as its DNA can be detected in the central nervous system of healthy adults.
A unique mechanism of persistence for HHV-6 is its ability to integrate its entire genome into the telomere region of a host chromosome. This condition, known as chromosomally integrated HHV-6 (CI-HHV-6), occurs in about one percent of the global population. If this integration happens in germline cells, the virus is inherited in a Mendelian fashion, meaning every cell carries the viral DNA. This inherited form results in persistently high viral DNA levels in the blood, which complicates diagnostic testing for active infection later in life.
Reactivation in Healthy Adults
The latent virus frequently reactivates, though this is usually a silent process in individuals with a robust immune system. Reactivation involves the virus exiting its dormant state and beginning to replicate, often triggered by stress, other illnesses, or hormonal changes. When symptoms occur in healthy adults, they are typically non-specific and transient, resolving without medical intervention.
Symptomatic reactivation may present as a mononucleosis-like syndrome, characterized by fever, swollen lymph nodes, and sometimes mild hepatitis. Viral replication leads to the shedding of infectious particles, most notably in the saliva. Saliva is considered the primary vehicle for transmission of both HHV-6 and HHV-7. This frequent, often asymptomatic, shedding highlights that viral latency is a dynamic process.
Severe Disease in Immunocompromised Patients
The clinical significance of HHV-6 and HHV-7 becomes pronounced when the host immune system is suppressed, particularly in transplant recipients. Reactivation rates are high, affecting 30 to 70 percent of hematopoietic stem cell transplant (HSCT) recipients within the first few weeks following the procedure. In this setting, the virus can lead to serious organ-specific diseases, including pneumonitis, bone marrow suppression, and graft rejection.
A particularly serious complication is HHV-6 encephalitis, which involves inflammation of the brain and occurs most commonly in allogeneic HSCT recipients. Symptoms include delirium, confusion, and memory problems, and the condition is associated with high mortality and significant long-term neurological damage.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Another severe manifestation is DRESS syndrome, a life-threatening drug hypersensitivity reaction. HHV-6 reactivation is a defining feature of DRESS, typically occurring two to three weeks after the initial rash and preceding a secondary worsening of the patient’s condition. The virus’s ability to infect T-cells is key, as the drug reaction upregulates the CD134 receptor, which HHV-6 uses to enter and spread.
Investigation of Chronic Health Links
Ongoing research explores the potential role of HHV-6 and HHV-7 reactivation in chronic health conditions. The viruses exhibit neurotropism, leading to investigation into their association with neuroinflammatory disorders like Multiple Sclerosis (MS). Studies suggest that the less common HHV-6A variant may be more frequently associated with MS risk than HHV-6B, possibly by influencing immune regulation within the central nervous system.
HHV-6 and HHV-7 have also been implicated in myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Researchers often detect higher viral loads or signs of active replication in the blood or saliva of ME/CFS patients compared to healthy individuals. The main challenge is determining whether viral activity causes the chronic condition or is merely a consequence of underlying immune dysregulation. Current diagnostic tools struggle to differentiate between true active replication and the persistent, low-level latent virus, making a definitive causal link difficult to establish.