The Herpesviridae family comprises a large group of DNA viruses that are highly successful pathogens, establishing lifelong infections in their hosts. These viruses are widespread, with a majority of the human population being infected with at least one type. This viral family is notable for its complex structure and its ability to lie dormant within the body, a characteristic known as latency.
Defining Characteristics of Herpesviruses
Herpesviruses are structurally defined by a unique four-layered architecture. At the core is a large, linear, double-stranded DNA genome, protected by an icosahedral protein shell called the capsid. Surrounding the capsid is the tegument, a proteinaceous layer containing viral enzymes and regulatory proteins essential for the initial stages of infection. The outermost layer is a lipid bilayer envelope, acquired from the host cell membrane. This envelope is studded with viral glycoproteins that facilitate entry into new host cells.
The active phase of a herpesvirus infection is called the lytic cycle, where the virus takes over the host cell’s machinery to produce new viral particles. After the virus enters the cell and uncoats its DNA, the genome travels to the host cell nucleus where it begins a cascade of gene expression. This process involves the sequential transcription of immediate-early, early, and late genes, ultimately leading to the assembly of new virions and the destruction of the host cell.
The Biological Mechanism of Latency
A defining feature of all herpesviruses is their capacity to establish latency, a dormant phase that allows the viral genome to persist within the host without actively replicating. During latency, the virus sharply curtails the expression of most of its genes, making it virtually invisible to the host’s immune system. The viral DNA remains as an episome, a circular DNA molecule, within the nucleus of specific cell types, rather than integrating into the host’s chromosomes.
Latency Locations
The specific cell type where latency is established varies depending on the herpesvirus subfamily:
- Alpha-herpesviruses, such as Herpes Simplex Virus and Varicella-Zoster Virus, typically hide in the sensory neurons of the peripheral nervous system.
- Beta-herpesviruses, including Cytomegalovirus, often establish latency in mononuclear cells like macrophages and lymphocytes.
- Gamma-herpesviruses, such as Epstein-Barr Virus, favor B-lymphocytes.
Latency is not a permanent state and can be interrupted by reactivation, which allows the virus to re-enter the lytic cycle and produce infectious particles. This shift is often triggered by various forms of stress or changes in the host’s internal environment. Common triggers include psychological or physical stress, fever, hormonal fluctuations, or exposure to ultraviolet (UV) light. Reactivation is initiated by host cell signaling pathways that activate viral gene expression, leading to the migration of the virus back to the epithelial tissue and often causing recurrent lesions.
Overview of Major Human Herpesvirus Types
There are eight distinct human herpesviruses (HHVs) that infect people, classified as HHV-1 through HHV-8. These viruses are categorized into three subfamilies—alpha, beta, and gamma—based on their replication speed and the cell type they favor for latency.
The alpha-herpesviruses include Herpes Simplex Virus Type 1 (HSV-1) and Type 2 (HSV-2). HSV-1 is primarily associated with oral herpes, causing cold sores, though it is increasingly a cause of genital herpes. HSV-2 is the main cause of genital herpes, characterized by painful blisters. Varicella-Zoster Virus (VZV), or HHV-3, is also an alpha-herpesvirus, causing chickenpox upon primary infection and shingles (herpes zoster) when it reactivates later in life.
The beta-herpesviruses have a slower replication cycle and a more restricted host range. Cytomegalovirus (CMV), or HHV-5, is highly prevalent and often causes asymptomatic infection in healthy individuals. However, CMV can lead to severe disease in newborns or those with compromised immune systems. Human Herpesvirus 6 (HHV-6) and Human Herpesvirus 7 (HHV-7) are responsible for roseola infantum, a common childhood illness characterized by a high fever followed by a rash.
The gamma-herpesviruses include Epstein-Barr Virus (EBV) and Kaposi’s Sarcoma-Associated Herpesvirus (KSHV), which are often associated with lymphoproliferative disorders. EBV (HHV-4) is the cause of infectious mononucleosis, commonly known as “mono,” and is also linked to certain cancers like Burkitt’s lymphoma and Hodgkin’s lymphoma. KSHV (HHV-8) causes Kaposi’s sarcoma, a type of cancer that forms in the lining of blood and lymph vessels and is most often seen in individuals with immune deficiencies.
Strategies for Managing Herpesvirus Infections
The medical management of herpesvirus infections primarily focuses on treating active outbreaks and suppressing viral replication, as current treatments cannot eliminate the latent virus from the body. The mainstay of therapy involves antiviral medications that specifically target the virus’s ability to copy its DNA.
Drugs such as acyclovir, valacyclovir, and famciclovir are nucleoside analogs that inhibit the viral DNA polymerase, the enzyme necessary for genome replication. These medications are converted into an active form only by a viral enzyme, making them selectively toxic to infected cells and minimizing harm to host cells. For these antivirals to be most effective, they are administered early in an outbreak, ideally within 72 hours of symptom onset.
These antivirals can be used in short-term courses to treat acute episodes or as long-term suppressive therapy to reduce the frequency of recurrent outbreaks and decrease viral shedding. In cases of severe or resistant infections, particularly in immunocompromised patients, alternative agents like foscarnet or cidofovir may be used. Prevention is also a strategy, most notably with the Varicella-Zoster Virus, for which vaccines are available to prevent both chickenpox and shingles.