The Human Herpesviruses
Through mechanisms of latency, which are discusses below, herpes viruses are able to establish lifelong infections in their hosts. In exploring herpesvirus replication strategies, clinical presentation, and other manifestations of herpesvirus-associated diseases in humans, it is important to keep in mind this characteristic of lifelong infection. As a result, herpesvirus infections generally do not cause life-threatening disease, although exceptions occur in immunocompromised hosts. Instead, herpesvirus infections cause a range of fairly mild symptoms, often with long periods of latency between reactivations of virus replication. Often referred to as an ancient viral family, the chronic nature of herpesvirus infections and their ability to effectively evade the human immune system are testaments to a centuries-long co-evolution between humans and herpes viruses.
Herpesvirus infections are extremely prevalent in human populations. Herpes simplex virus type 1, for example, has been isolated from individuals in every region of the world, even the most remote, and has found to be present at a prevalence of between 50 to more than 90% of adults. This seroprevalence may be explained by HSV's route of transmission through infectious saliva (explained in detail below), as well as its ability to persist in the host in the host without causing severe disease. Before the advent of an effective vaccine for varicella-zoster virus (VZV), the vast majority of children were infected with chickenpox. In the US alone, for example, there were more than 4 million annual cases of chickenpox before the vaccine was made widely available. Cytomegalovirus (CMV), which rarely results in clinical disease in immunocompetent hosts, has been found to infect between 40-100% of all individuals before they reach puberty. This ubiquity yet again highlights herpes viruses' remarkable ability to effectively thrive in the human host.
Latent infection is a defining characteristic of members of the herpesviridae family: all herpes viruses have the ability to establish latent and lifelong infections in a specific host cell type, wherein viral replication either stops completely for long periods of time, or reduces to a very low rate. Latency is defined not by immediate but slow replication, but rather by the viruses ability to begin active replication after periods of non-replication. Lytic infection occurs in another set of cells from those that support latent infections, and is the mode through which the virus replicates and ultimately transmits to new hosts. Latent virus is able to reactivate to cause lytic infections, leading to onwards transmission of the virus.
The frequency of viral reactivation varies widely between species of herpesviruses – in some, reactivations occur after years of latency; in others, reactivations can be fairly continuous. Due to their proclivity for latent, lifelong infections, herpesviruses are generally fairly mild in nature, and do not generally cause fatal disease in immunocompetent hosts.
Although the specific mechanisms for latency among herpes viruses differ and are still in many aspects not well understood, studies of herpes simplex virus (HSV) in animal models has helped to clarify the mechanisms of latency employed by HSV. As HSV-1 is often considered the prototype of the herpesviridae family, its mechanisms of establishing latency are helpful for conceptualizing latency as an effective viral reproduction strategy. HSV establishes latent infection in neurons by axonal transmission to sensory ganglia. It seems to infect only a very small percentage (approximately 1%) of the neurons in each ganglion. Latent infection can be detected by the presence of a specific viral transcript, known as the latency-associated transcript (LAT), which consists of a set of RNA transcripts which are transcribed but not translated. Thus, LAT is not associated with the synthesis of any viral protein, and is not a precursor of viral replication. While LAT is not thought to be necessary for latent infection to be established, it is the only viral product that is synthesized during latent HSV infection.
Inherent to latent infection is the occurrence of reactivation, during which virus that has established a latent infection reactivates to a productive infection. During reactivation periods, then, the virus is actively replicating. Latent infections and lytic infections occur in different types of cells: during reactivation, previously latent viruses replicate in small quantities in the neurons; newly produced virus can travel down the axons to the epithelial tissues where transmission originally occurred. The frequency of reactivations varies based on a variety of factors, including the length of time since initial infection, the immune status of the host, the specific herpes virus, and a wide range of physical, emotional and other stimuli. Reactivation of HSV, for example, can be precipitated by stimuli such as exposure to sunlight, high stress or other emotional factors, high fever due to influenza virus infection, or by menstruation, to name a few examples. The frequency of reactivations differs from person to person, with some individuals experiencing reactivations months, to other who have reactivations that are separated by years.
Another classic example of reactivation of herpes infection is shingles, or herpes zoster (pictured above). Chickenpox, the once ubiquitous and highly contagious childhood disease that is characterized by itchy, vesicular skin lesions, is the manifestation of primary infection with the herpesvirus varicella-zoster virus (VZV). Individuals who are infected with VZV can fully recover from chickenpox in their childhood, only to experience a reactivation of VZV decades later in the form of shingles. This is due to the fact that VZV can establish long-term latency in the dorsal root ganglia of the spinal cord. Reactivation in a single neuron leads to vesicular lesions that are very painful and usually unilateral (tracing the path of a single sensory ganglion).
Unlike many viral families, which are characterized by a single route of transmission, members of the herpesviridae family are transmitted through a wide range of routes, which variety occuring both within and among individual viral species. Sexual transmission through direct contact may be the most well known route of herpesvirus transmission, and is the route by which HSV, both type 1 and type 2, is spread from person to person. HSV-1 and -2 causes sores or ulcerated vesicles that present at the site of infection, which is either the oral mucosa or facial skin, or in the genital region. Other herpesviruses, however, are transmitted by very different routes: varicella-zoster virus (which causes the highly contagious childhood disease chickenpox) is spread through the respiratory route in aerosolized respiratory secretions. Other herpes viruses, including cytomegalovirus (CMV), are spread parenterally in infectious saliva, in urogenital secretions, and through vertical transmission from mother to child.
While members of the herpesviridae family share many characteristics of genomic organization, replication strategies and immune system evasion, their clinical presentation varies widely between viral species. From the characteristic cold sores, or fever blisters, caused by herpes simplex virus to chickenpox, caused by varicella zoster virus, and from blotchy, mild rashes caused by human herpesvirus 6 to a variety of cancers, including Burkitt's Lymphoma caused by Epstein-Barr virus and Kaposi's Sarcoma caused by human herpes virus 8, herpesvirus infections vary in their characteristic signs and symptoms, routes of transmission, and severity.
Such range of clinical manifestations within a single viral family, however, is not incredibly unusual. What makes the herpes viruses particularly unusual is the variety of clincial manifestations associated with each individual species of herpes virus. A perfect example is Epstein-Barr virus (EBV), a gammaherpesvirus. EBV, which is associated with multiple human cancers (described in more detail below), is also the leading cause of infectious mononucleois (IM). Of EBV infections that occur in adolescents and young adults, more than one-fourth result in symtomatic IM. The symptoms of IM can vary from mild fever to protracted illness with pharyngititis, extreme malaise and fatigue, and lymphodenopathy. Symptoms of IM are generally caused not by the virus itself, but by the proinflammatory cytokines produced by the host immune response. This example of EBV-associated diseases highlights the wide variety of clinical manifestations, even in a single herpesvirus species.
Many members of the herpesviridae family are characterized by mild or asymptomatic disease in the immunocompetent host. Disease outcomes associated with herpesvirus infection have a tendency to be much more clinically apparent and significant in the immuno-compromised host. This tendency of severe disease in the immunocompromised has significant implications for people living with HIV/AIDS. In the case of EBV and KSHV infections, for example, immunocompromised host are at exponentially higher risks for development of lymphomas than are immunocompetent hosts. CMV infection can also be extremely severe in AIDS patients and other immunocompromised individuals, resulting in systemic disease that can lead to retinitis (observed in over 20% of AIDS patients), as well as life-threatening disease of the central nervous system, lungs and gastrointestinal tract.
The gammaherpesviruses Epstein-Barr virus and human herpesvirus 8 (HHV-8), also known as Kaposi's Sarcoma-Associated Herpesvirus (KSHV), both have well-documented oncogenic potential. Gammaherpesviruses are members of the herpesviridae family that are characterized by their ability to establish latent infection in B cells, causing them to immortalize and proliferate indefinitely. Their ability to stimulate B lymphocyte activation and replication gives the human gammaherpesviruses EBV and KSHV the ability to cause cancer.
Epstein-Barr virus, most commonly recognized as the leading cause of infectious mononucleosis (more generally referred to as mono, or the "kissing disease), is associated with a number of human cancers. Burkitt's lymphoma (pictured above) is one such cancer, and is characterized by the development of tumors in the lymph nodes. It is particularly prevalent in children who live in malaria-endemic regions of Africa and New Guinea. This association of Burkitt's lymphoma (BL) with malaria long remained a topic of research and speculation. The association, however, has been recently been linked to inhibition and mutation of the host oncogene c-myc in BL cells. Translocation of mutated sequences to regions near the immunoglobulin locus can lead to further mutation of c-myc and the subsequent development of tumors. This process is facilitated by infection with the malaria parasite, which causes expansion of germinal centers. These expansions, which are associated with lymphoma development, facilitate translocations and other events that can lead to BL oncogenesis. EBV is associated with a variety of other human cancers, including T-cell lymphomas, nasopharyngeal carcinoma, and Hodgkin's disease. For more information on EBV, visit Epstein-Barr Virus and Associated Diseases.
Kaposi's Sarcoma-Associated Herpesvirus (KSHV), the herpes virus that was most recently identified, is also associated with the development of human cancer. Kaposi's sarcoma is characterized by inflamed, angioproliferative lesions that until recently were strongly associated with elderly men of Mediterranean origin. In the early 1980s, however, outbreaks of KS began to occur in clusters of young, gay men. The connection between HIV and Kaposi's sarcoma led many to believe that KS was actually directly caused by HIV. This has been proven untrue, however, due to DNA sequencing of KS lesions that have shown KSHV, rather than HIV, to be necessary for the development of the lesions. KSHV preferentially infects a type of endothelial cells called spindle cells, from which KS develops. KS cells often have reactive hyperplasia or inflammatory angioproliferative features, and can spread both locally and systemically. Typical KS lesions are pictured below.
Although many species of herpesviruses exist, infecting a wide range of vertebrates, the majority of herpesviruses are extremely specialized. This narrow specificity of host range reflects centuries of virus-host co-evolution, resulting in viruses that are extremely specific to a single host, and are thus better able to evade that host's immune defenses and establish latent, lifelong infection. Varicella-zoster virus (VZV), the etiologic agent of both chickenpox and shingles, is so highly specialized that it can only infect human cells. Herpes simplex virus is the exception to the rule, due to the fact that HSV-1 enters the host cell using cell surface receptors that are widely present on both human and non-human cells. Thus, unlike many other herpes viruses, HSV-1 has a wide host range. It is in part due to this ability to readily infect nonhuman cells that has led HSV-1 to be widely studied.
There are two vaccines currently licensed in the US to prevent diseases caused by herpesviruses. These vaccines both target varicella-zoster virus (VZV).
Created by Claire Watt
for Dr. Robert Siegel's Humans and Viruses course,
Stanford University, 2008