Herpes: The Virus, The Disease

From crispyneurons

28 May 2005
Jason Wells

[edit] Introduction

Herpes is a big and growing problem. The statistics are striking. Workowski and Levine (2002) claim that by 2002, just a single type of herpes simplex virus, HSV-2, had infected at least 50 million people in the United States alone (Genital Herpes Simplex Virus Infections section, ¶ 1). Roe (2004) claims that an estimated that 1.6 million new cases are added annually (Introduction section, ¶ 2), that 20-25% of Americans are infected (Introduction section, ¶ 1), that 20% of infected individuals may shed HSV with no outward symptoms, and perhaps most disturbing, that 90% of infected individuals are not aware of their infection (Introduction section, ¶ 3). According to the American Herpes Foundation ("Herpesvirus clinician FAQ," 2005), herpes "is the most common ulcerative sexually transmitted disease in North America," generating an estimated $208 million in direct medical costs (Impact section, ¶ 1). Oral herpes is even more prevalent. Sedano (1998) claims that it is carried by around 90% of adults in the United States, and that 99% of infected individuals display no symptoms at all (Primary Infection section, ¶ 1).

Given these sobering statistics and their widespread relevance, the value of awareness and understanding of herpes would seem clear. However, discussion of both the virus and the disease can be inhibited or distorted by the stigma it carries as an STD. The impact herpes has is vast and rapidly increasing, yet accurate information about the disease can often be difficult to distinguish from alarmist fantasies or wishful thinking.

To examine this complex phenomenon, this paper begins with a basic characterization of HSV as an example of a virus. From there it proceeds into detailing the many facets of herpes: the biological classification, structure and physical architecture of HSV; how it can infect human cells; descriptions of the various disease forms; diagnosis and testing methods; and a survey of existing therapies and preventative strategies.

[edit] Virus Basics

HSV is a virus, an entity described by the McGraw-Hill Encyclopedia of Science and Technology ("Virus," 2002) as a small particle that infects a biological host organism, such as an animal, parasitically. A virus, when it is independent of a host cell, exists as an discrete, potentially infectious package known as a virion (p. 286). Though viruses are infectious agents, Audeskirk (2005) claims that they are not generally considered to be a form of life because essential mechanisms needed for survival are not contained within the virion. For example, a virus contains no internal source of energy and must successfully penetrate and take over a host cell in order to reproduce itself (p. 360). Though it is a biological entity, a virus is not actually alive, and HSV is no exception.

[edit] Classification

As biological entities that can reproduce and pass genetic traits, viruses are subject to natural and artificial selection, and therefore can evolve, as Roe (2004) implies in her discussion of resistance to antiviral therapies (Pharmacological Management of Genital HSV Infection section, ¶ 3). Viruses are therefore classified taxonomically in a manner similar to that of living organisms. HSV happens to be a member of the highly successful herpesviridae family ("Herpesvirus overview", 2005, ¶ 1). This family is in turn part of the much larger dsDNA group of viruses, ones that feature a double strand of DNA (Roe, 2004, Natural History of Genital Herpes section, ¶ 1).

The herpesviridae family includes over 100 viruses (Roizman and Baines, 1991, p. 63) capable of infecting a wide variety of vertebrate animals. Only eight strains, known collectively as human herpesviruses, or HHV, are known to infect humans (Sander, 1999, ¶ 1). The first two, HSV-1 and HSV-2, cause herpes, and are also known as HHV-1 and HHV-2 (Herpes Simplex section, ¶ 2). HHV-3, or varicella-zoster virus, causes chickenpox and shingles (Varicella Zoster Virus section, ¶ 2). HHV-4, or Epstein-Barr virus, causes infectious mononucleosis (Epstein-Barr Virus section, ¶ 1). HHV-5, or cytomegalovirus, causes no detectable clinical illness in individuals with healthy immune systems (Cytomegalovirus section, ¶ 1). HHV-6 causes roseola infantum (Human Herpesvirus 6 section, ¶ 1). HHV-7, closely related to HHV-6, causes no detectable illness (Human Herpesvirus 7 section, ¶ 1). Finally, HHV-8 is associated with Kaposi's sarcoma, especially in HIV-positive patients (Human Herpesvirus 8 section, ¶ 1).

All of these viruses share in common several distinguishing traits ("Herpes," 2002). For example, they all have the ability to remain dormant within the human body over a long period, a common strategy for viral assembly, and a distinctive physical structure (p. 483).

[edit] Viral Structure

Like other members of the herpesviridae virus family, the HSV virion package has four basic structural elements. Starting at the center of the virus and moving outwards, they are the core, the capsid, the tegument, and the envelope.

The core is essentially the DNA of the virus ("Herpes," 2002, p. 483). In HSV, it is a relatively large, double stranded circular DNA genome encoding 100 to 200 genes ("Herpesvirus overview," 2005, ¶ 1).

The capsid is a protein shell containing and protecting the core, taking the form of an icosahedron ("Herpes," 2002, p. 483). Stannard (1995) notes that this structure has 20 facets, with each facet an equilateral triangle, having 12 vertices, and, as with any icosahedral virus, exhibiting cubic symmetry (Design of the Protein Shell section, ¶ 4).

The tegument may be the least straightforward component of the herpes virion package. The Bioscience Division of the Los Alamos National Laboratory ("Herpesvirus overview," 2005) describes it in this way: "Between the capsid and envelope is an amorphous, sometimes asymmetrical, feature named the tegument. It consists of viral enzymes, some of which are needed to take control of the [host] cell's chemical processes and subvert them to virion production, some of which defend against the host cell's immediate responses, and others for which the function is not yet understood" (Virion Structure section, ¶ 2).

Lastly, the envelope is a membrane wrapped around the capsid, and thus forms the outermost component of HSV. It is 150-200 nanometers across, and is derived from the cell membrane of the host cell that was used to manufacture the virus ("Herpes," 2002, p. 483).

This four-part virion structure equips the HSV virus with what is needed for it to infect human host cells successfully, by means of the processes described below.

[edit] Means of Infection

Herpes may infect its host through a variety of mechanisms. The Department of Microbiology at the University of Mississippi Medical Center ("Herpesviridae," 2005) enumerates four manners of herpes infection. First, there is primary infection, occurring when an individual is infected with HSV for the first time. Second, recurrent infection occurs when the latent virus reactivates itself after the primary infection. Third, initial infection refers to infection with one strain (e.g. HSV-2) after having been infected with the other (e.g. HSV-1) previously. Fourth and last, exogenous reinfection happens when the host is infected with a second variant of the same strain of HSV (Herpes Simplex Virus Diseases section, ¶ 1).

Audeskirk (2005, p. 363) identifies a particular sequence of events that characterize a given herpes infection at the cellular level. First, the HSV virion encounters a suitable host cell, such as a skin cell. It then passes through the outer membrane of the cell and enters it via a process known as endocytosis, in which the virus attaches itself to a part of the cell membrane, eventually causing itself to be surrounded and finally engulfed by the cell. These initial activities, called penetration, are the first step of infection. The next step, in which the virus joins with the nucleus of the cell, adds its DNA the nuclear DNA already present, and forces the cell to copy the viral DNA, is known as replication. The third step, transcription, transcribes the viral DNA to messenger RNA which then exits the nucleus and enters the surrounding cytoplasm of the cell. This allows the fourth step, protein synthesis, to occur, as the RNA code is translated into functional proteins needed for step five, viral assembly. In this step, the proteins manufacture parts needed for many new viruses. Eventually, as the viruses are produced in the cell, the sixth and final step occurs: release. The cell buds the new viruses through the cell membrane, or simply bursts, releasing the newly created viruses. The freed viruses roam through the host, perhaps going on to encounter and infect a new cell. The new cell may be in a new individual. Roe (2004) explains how HSV infects a new individual by being "transmitted through direct contact with skin or mucous membranes during a symptomatic outbreak or, more commonly, during episodes of asymptomatic viral shedding" (Natural History of Genital Herpes section, ¶ 1). It does not, however, appear to be transmitted through blood. The Red Cross ("Blood Donation Eligibility Guidelines," 2005) allows healthy individuals diagnosed with herpes to donate blood (Sexually Transmitted Disease section, ¶ 3), suggesting that intravenous infection of HSV, at least through blood transfusion, is not a risk.

HSV infections feature a common cyclical pattern. Roe (2004) notes that herpes is a chronic, recurrent infection (Introduction section, ¶ 1). First, a display of clinical symptoms known as an outbreak may occur (Natural History of Genital Herpes section, ¶ 1). Following the initial outbreak, after the symptoms disappear, is a period of latency, in which the virus remains dormant within nerve cells ("Herpes," 2002, p.483). After this period of latency, HSV reactivates, and another outbreak may occur. This is known as a recurrence (Roe, 2004, Natural History of Genital Herpes section, ¶ 2). The reactivation process is not well understood ("Herpes," 2002, p.483). This chronic cycle of outbreak, latency, reactivation and recurrence typically produces milder and less frequent symptoms over time (Roe, 2004, Natural History of Genital Herpes section, ¶ 4). Outbreaks may occur less frequently in individuals maintaining good health and avoiding stress ("Herpes, an overview," 2005, Remember section, ¶ 3). This infection process is the basis for the HSV diseases described below.

[edit] HSV Diseases

Herpes is often classified, as by Herpes.com ("Herpes, an overview", 2005), into two broad categories: oral and genital herpes (What is Herpes section, ¶ 1). In this model, HSV-1 is understood to cause oral herpes, while genital herpes is caused by HSV-2 (What is Herpes section, ¶ 3). This approach has the virtue of making herpes easy to describe and to understand. Unfortunately, it is also quite misleading and simplistic. There is much more to the complex relationship between HSV and the human body.

It is more useful to approach the disease in terms of its etiology, or causal factors, and its pathogenesis, or the mechanisms by which the body responds to the presence of the etiological agent. At least seven herpes diseases are known to exist. The Department of Microbiology at the University of Mississippi Medical Center ("Herpesviridae," 2005) identifies six pathogenetically distinct diseases having either or both HSV types as the etiological agent: herpes labialis, herpes genitalis, neonatal herpes, ocular herpes (called keratoconjunctivitis in this list), herpetic whitlow, and herpes encephalitis (Herpes Simplex Virus Diseases section, ¶ 1). Additionally, herpes proctitis, mentioned in passing by Workowski and Levine, is described in some detail by the Community Health Care Medical Library ("Proctitis," 2005).

For the sake of brevity, these diseases are described below as they may manifest in an immunocompetent individual, one with healthy immune system, unless otherwise noted. As the McGraw-Hill Encyclopedia of Science and Technology claims in its article on herpes (2002), "the vast majority of all herpes infections are subclinical; that is, they do not cause specific symptoms or signs attributable to herpes infections, but present symptoms of nonspecific viral illnesses which resolve spontaneously" (p. 483). Conversely, immunocompromised individuals, lacking a healthy immune system, may exhibit far more severe symptoms (p. 483). In particular, it should be noted that HSV-2 has been implicated in the deaths of advanced cancer patients, though a causal relationship has not been established ("Herpes," 2002, p. 483).

Herpes labialis, also known as orolabial herpes or oral herpes, may also be referred to euphemistically as fever blisters or cold sores. The primary symptom at initial outbreak is the presence of blister-like lesions on the mouth or lips ("Mouth infections," 2005, Infections section, ¶ 2). This disease may be caused by either HSV-1 or HSV-2, but the orolabial region is the preferred infection site for HSV-1, which causes most instances of oral herpes and produces more severe symptoms ("Mouth infections," 2005, Infections section, ¶ 2). Roe (2004) notes that "an individual who has been exposed to oral herpes . . . will produce antibodies that reduce the severity and duration of symptoms in the event that the individual is exposed to genital herpes" (Natural History of Genital Herpes section, ¶ 4).

Herpes genitalis, also known as genital herpes, is an infection of the genitals by either HSV-1 or HSV-2 ("Herpes, an overview," 2005, What is Herpes section, ¶ 3). The genital region is the preferred site for HSV-2 infection, and according to Roe (2004), HSV-2 causes 70% of herpes genitalis cases (Natural History of Genital Herpes section, ¶ 1). Symptoms noted by the CDC ("Genital herpes fact sheet", 2005) include blister-like lesions on the genitals and flu-like symptoms such as swollen glands or fever ("What Are the Signs and Symptoms of Genital Herpes," ¶ 1). Condoms can significantly help to prevent genital herpes, but they are not entirely effective. As Roe (2004) states, "use of condoms decreases but does not eliminate the risk of contracting the virus" (Clinical Presentation section, ¶ 2). Additionally, as the CDC notes ("Genital herpes fact sheet", 2005), oral-genital contact permits an individual to with herpes labialis to infect another with herpes genitalis, or the reverse ("How Do People Get Genital Herpes," ¶ 2). Genital-genital contact is therefore not required to transmit the disease.

Neonatal herpes, also called perinatal herpes, is the transmission of HSV from a pregnant mother to her unborn child ("Herpesviridae," 2005, Herpes Simplex Virus Diseases section, ¶ 1). As an unborn child is not yet immunocompetent, this disease can have very serious consequences, and has a "high rate of morbidity and mortality" (Roe, 2004, ¶ 3). The University of Washington Academic Medical Center ("Neonatal herpes," 2001) claims that "infection at the time of labor and delivery is the situation for the overwhelming majority of cases," as opposed to in utero transmission (Transmission of Neonatal Herpes section, ¶ 1). Symptoms for the child include skin lesions, pneumonia, hydranencephaly, microcephaly, keratoconjunctivitis (ocular herpes), blindness, and learning disabilities (multiple sections, ¶ 5-23). Death occurs in 57% of treated cases (Prognosis section, ¶ 1). Fortunately, Roe goes on to say that "perinatal transmission of HSV has a relatively low incidence in the United States" (¶ 3). HSV is not automatically transmitted from mother to child. "The risk of perinatal transmission from mother to neonate at the time of birth is greatest during a primary infection" (Roe, 2004, Clinical Presentation section, ¶ 3). That means that practicing infection avoidance strategies can help. For example, during the third trimester, HSV positive women can go on antiviral suppressive therapy (Genital Herpes Infection in Pregnancy section, ¶ 5), while HSV negative women can avoid sex with HSV positive partners (Genital Herpes Infection in Pregnancy section, ¶ 2).

Ocular herpes, also known as herpetic eye disease and sometimes identified as keratoconjunctivitis, is defined by the University of Illinois Eye Center (Ocular herpes simplex, 1989) as an HSV-1 infection of the eye. Typically the cornea of only one eye is affected, though it may infect the inside of the eye or the retina. Usually symptoms are mild to nonexistent, but may include scarring of the cornea, loss of vision, and blindness (Eye Involvement and Symptoms section, ¶ 1). Causes of this disease in adults are not fully understood, but it may be caused by HSV exposure to facial nerves. Up to 25% of patients will, in two years following initial infection, experience recurrence. (Causes section, ¶ 1).

Herpetic whitlow, a skin infection, is described by Walker (2004) as "a painful, vesicular inflammation of the tip of the finger or toe . . . caused by herpes simplex virus type 1 or 2." The disease originates from contact between a cutaneous break, such as a skin cut or torn cuticle, and the mucus or oral secretions of an HSV-infected individual. Health care workers can be particularly at risk for this disease (first section, ¶ 1). Some who develop herpetic whitlow may lose sensation or motion near the site of infection (How an Infection Develops section, ¶ 3).

Herpes encephalitis, an infection of the central nervous system, is described as a "rare but devastating infection of the brain with high mortality and morbidity" ("Herpesviridae," 2005, Herpes Simplex Virus Diseases section, ¶ 1). The United States produces roughly 2000 cases each year ("Herpes encephalitis," 2005, Overview section, ¶ 1). WebMD ("Encephalitis, herpes simplex," 2001) identifies "symptoms includ[ing] headaches, fevers, drowsiness, hyperactivity, and/or general weakness" (General Discussion section, ¶ 1). No skin lesions are presented, but other symptoms resembling meningitis may appear (General Discussion section, ¶ 1). Neuroland ("Herpes encephalitis," 2005) offers additional symptoms such as behavioral changes or seizures (Symptoms section, ¶ 1). Untreated, it has a 70% mortality rate, which is lowered to 19% if treated. 62% of those infected are permanently impaired ("Herpes encephalitis," 2005, Prognosis section, ¶ 1).

Herpes proctitis is defined by the Community Health Care Medical Library ("Proctitis," 2005) as an inflammation of the rectum (Definition section, ¶ 1) that may be caused by HSV. Like herpes genitalis, it is spread through sexual contact (Symptoms section, ¶ 1). It may include symptoms resembling herpes genitalis, such as open sores (Symptoms section, ¶ 2).

[edit] Testing and Diagnosis

Though the presence of clinical symptoms may suggest a herpes infection, the presence of HSV is usually demonstrated definitively through laboratory tests ("Herpesvirus Clinician FAQ," 2005, How Do I Diagnose Genital Herpes section, ¶ 1). WebMD lists four types of tests ("Herpes tests," 2003) that may be performed to establish whether or not an individual carries the HSV. First, a viral culture test involves collecting a sample of fluid from an open sore and observing changes to the cells that are caused by the presence of HSV. This test may include optional chemical tagging substances, allowing it to distinguish between HSV-1 and HSV-2. Second, the antigen test detects antigens that appear on the surface of infected cells obtained from an open sore. Third, the polymerase chain reaction test, or PCR test, detects the presence of HSV in spinal fluid. Fourth and last, the antibody test examines a blood sample for the presence of antibodies produced as an immune response to the presence of herpes.

Walker (2004) notes two different kinds of antibody tests. Testing for immunoglobulin M, or IgM, checks for short term antibodies generated by an acute HSV infection or outbreak. The immunoglobulin G, or IgG, test is for longer term antibodies and is used to determine past exposure to HSV (How Infection Develops section, ¶ 6). HerpeSelect ("Laboratory tests," 2005) notes that while IgM tests is not type specific, and cannot distinguish between HSV-1 and HSV-2, certain IgG tests can (Antibody Detection section, ¶ 4). As antibodies may take eight weeks or longer to reach detectable levels, these tests can produce false negatives in the early stages of infection (Antibody Detection section, ¶ 10).

[edit] Therapy and Prevention

Therapeutic focus is on suppression via antiviral drugs such as the ones Roe (2004) lists: acyclovir, valacyclovir, and famciclovir (Pharmacological Management of Genital HSV Infection section, ¶ 2). The operating principle behind each of these drugs is to interfere with HSV replication, specifically by disrupting the function of enzymes needed in the viral assembly stage ("Herpes," 2002, p. 483). Roe (2004) finds no evidence to suggest that the drugs cause HSV to adapt, and thus evolve, into drug-resistant strains, even for individuals with compromised immune systems (Pharmacological Management of Genital HSV Infection section, ¶ 3).

No preventive vaccine is currently available for HSV, though candidate vaccines have entered human trials. The National Institutes of Heath, or NIH, published a press release ("Major Herpes Vaccine Trial Launched in Women," 2002) announcing a herpes vaccine trial for women. Roe (2004) describes a later clinical trial of a vaccine developed by GlaxoSmithKline, one that exhibited some success (Herpes Vaccine section, ¶ 1). One day, perhaps in the near future, a vaccine may become part of the standard clinical arsenal against herpes.

Today, prevention strategies vary based on the particular disease form. For example, prevention of herpes genitalis centers on the use of prophylactics to reduce the likelihood of sexual transmission, as well as sexual abstinence (Roe, 2004, Genital Herpes Infection in Pregnancy section, ¶ 2), whereas prevention of herpetic whitlow is achieved through the use of latex gloves and thorough use of antiseptics (Walker, 2004, Healing and Prevention section, ¶ 3-4). As a general principle, any herpes disease may be treated with antiviral drugs. Roe (2004) provides evidence that antiviral medications may prevent or reduce the number of recurrences in those already infected (Pharmacological Management of Genital HSV Infection section, ¶ 7).

It can be inferred from the nearly universal clinical emphasis on strategies of suppression and prevention of transmission that no cure exists for any form of herpes. This basic fact is taken as a given by all authoritative medical or scientific sources of herpes information, so few if any bother to mention it.

[edit] Conclusion

As a reflection of its characteristics as an infection, the name 'herpes' comes from the Greek word herpein, meaning "to creep," referring to its chronic, latent and recurrent nature (Sander, 1999, ¶ 1). While a herpes infection is normally acquired sexually in only two cases, and may be communicated non-sexually in the other five cases, any form of herpes carries the social stigma of an STD. As a consequence, those who do not have it may not want to face the real possibility of being infected. Similarly, those who do test positive may be viewed negatively by others, and may be considered irresponsible, sexually promiscuous, or even immoral. In either case, accurate communication of knowledge is inhibited, promoting ignorance and fueling speculation. A cloud of misinformation surrounds the subject of herpes, as even the trivial act of searching the Internet for "herpes cure" will reveal.

Fortunately, there is a great deal of knowledge about this virus, and more is discovered every year. HSV is a nuclear replicating, icosahedral, enveloped, double stranded DNA virus taking cells in the human body as its host. There are two known strains. Through four routes of infection it can cause seven different diseases, only two of which involve infection via sexual contact. All of these diseases share a pattern of outbreak, latency, and recurrence. There are four types of tests to detect the presence of the virus. Three antiviral therapies predominate, and in the long run, a herpes vaccine may be on the horizon. By moving past the stigma and looking at the empirical facts, it's possible to get a clear picture of what is true, and what is not, about herpes.

[edit] References

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Jason Wells is a philosophy student at UCSD and the VP of Natural Language Products at Semantic Research, Inc.