By David Moon
Disease Etiology: / /
Herpes Simplex [sim-pleks] is caused by a virus called Herpes Simplex Virus (HSV), of which there are eight or more that can infect humans. ,  However, only two are the most common: HSV-1 and HSV-2.  Both of these viruses have a tendency to infect almost all human ectodermic cells in the body. ,  Usually, the infection is benign for most of patients, but these viruses can lead to numerous complications of serious diseases. 
HSV-1 and HSV-2 are able to spread in both humans and other animals, but the symptoms of disease are shown only in humans.  Generally, HSV-1 infection occurs through kissing or sharing saliva, while the HSV-2 infection occurs through sexual intercourse. ,  HSV must have transporting bodily fluids such as saliva, blister, semen, and vaginal fluid in order to infect cells. Also, an open wound can be a pathway for a virus to enter. , ,  It is critical to know where and how the virus enters the body.  These viruses can infect separately, or both can infect the same individual. 
Human beings are the primary reservoirs for HSV.  Since HSV infection stays for lifetime, it is said to be “one of the most difficult virus to control.” ,  Many infected individuals are unaware of their infection because Herpes Simplex also has an asymptomatic infected period called latency. 
Specific Microbial Characteristics:
HSV-1 and HSV-2 are large fragile viruses that are in the subfamily Alphaherpesvirinae (family: Herpesviridae). ,  Both target mucoepithelia cells and take their latency period at the neuron. ,  Their structures are comprised of an envelope (inserted herpes glycoproteins which makes the cell infected), capsid (contains capsomeres), tegument (initiates replication), and genome (double stranded DNA, encode enzymes). ,  During the latency period, HSV does not have an envelope so it remains ineffective or dormant.  This characteristic of HSV “neurotropism” makes latency possible.  After the primary infection, the virus remains in neural tissue but it extends away from the cell’s central nerve, so it finds a secure place to stay without being lost.  Moreover, HSV can invade the brain and also destroy it. 
Specific Tests for Identification:
HSV is easily identifiable by looking at the lesions of infection. , , [3,] When Herpes Simplex is suspected health professionals can take several different tests to determine the identity of the virus. The best way to confirm the HSV is first to isolate it.  More accurate diagnosis can be made when the fluid sample is scraped from early (1-3 days) lesions.  The scrapings need to be stained and examined under the microscope to observe distinctive characteristics (multinucleated giant cells) of HSV. ,  However, these steps cannot distinguish between the two HSV types. ,  If the virus is found to be Herpes-Simplex-related, then immunologic tests (Western Blot Test, HerpeSelect, etc.) can be done for more specific diagnosis by determining the levels of specific antibody of the scraped sample.  It is known that glycoprotein G-based tests are more accurate and dependable, since the glycoprotein “determines the cell to be infected.” ,  Now, the immunologic tests using urine and saliva are being investigated for testing children.  Other tests like Polymerase Chain Reaction (PCR), Electroencephalograms(EEGs), Brain Biopsy, etc., may be required for diagnosing HSV encephalitis. , 
The Structure of the HSV 
Signs and Symptoms
The signs and symptoms vary greatly in time and area.  About 1/3 of HSV-1 patients and 2/3 of HSV-2 patients do not show their symptoms at all. For this reason, it can be mistaken or many patients can be unaware of it. ,  In each case of HSV-1 and HSV-2 have same initial lesion.  During the primary infection (usually 2-12 days after contacting virus), the initial pimple-like clear vesicles form, which contain infectious virus fluid and the bottom part of the vesicles have a reddish color. , ,  Herpes Simplex can be visually described as “dewdrop[s] on a rose petal.”  Then, painful/shocking ulcerating blisters are dried out and healed within 7-10 days without leaving scars. ,  Lesions can itch but subside as they continue to heal.  As the crust falls off, the virus remains and spreads “into the peripheral nerves,” going into a latency period (not contagious during this period). ,  When certain stimulus like physical/emotional stress, fever, and UV light impact a patient, secondary lesion breaks out, which is less severe than the primary. ,  All these signs and symptoms may show along with fever, muscle ache, chills, headache, swollen lymph nodes, and flu-like symptoms.  There are different names for the Herpes Simplex, according to the name of infected area.
Oral Herpes – Cold sores (infected mouth region)
Ocular Herpes (infected eye)
Herpes Whitlow (infected hands/wrists)
Herpes Gladiatorum (infected head and neck region)
Eczema Herpecticum (infected skin)
Genital Herpes (infected genitals)
HSV Proctitis (infected rectum and anus)
HSV Encephalitis (Infected temporal lobes)
HSV Menengitis (Infected meninges) , 
HSV is said to have infected human populations even during the Middle Ages (5th-16th century). Often, people after this era gained antibodies to the herpes viruses.  However, it is still the most common virus that infects humans throughout all ages.  The word herpes is originally from the Greek word “herpein” which means “to creep” ,  The creeping and spreading pattern along the neural tissues explains the distinctive characteristic of the HSV well. , ,  Shakespeare also describes the effects of HSV in people in his famous work “Romeo and Juliet”. 
HSV has an ability to cause the permanent infection in a patient’s life by replicating viral DNAs and releasing them. Therefore, the virus can continuously flourish under favorable conditions. ,  Specifically, the virulent protein ICP 34.5 works with other different cellular proteins to replicate HSV.  Also, HSV can turn off the immune system (interferon, natural killer cells, cytotoxic T cells, macrophages, etc.) by coating viruses with immunoglobulin, which evasively pass through the immune system. For example, gC (herpes glycoprotein) can bind the C3 protein, as well as gE and gI (herpes glycoproteins) can bind IgG through the Fc receptor of the immunoglobulin.  The virus can also escape from humoral antibodies in extracellular space by moving directly from cell to cell  During the latency period, nucleic acid of HSV finds a secure place in the nerves around the infected area, so that it reduces the risk of losing or misplacing their daughter cells. 
Current treatment is effective only on replicating virus and does not work against latent virus. This means that treatment will never terminate the virus.  The most common antiviral agent is nucleooside analog Acyclovir(Zovirax), which is the oldest and more widely used for inhibiting the activity of HSV-1 and HSV-2. ,  There are also medicines that are precursor of Acyclovir: Valacyclovir(Valtrex) and Famciclovir(Famvir). ,  Penciclovir(Denavir) is also used for oral herpes, but is not approved for children.  All of these medications can be taken by two different approaches.  First, episodic therapy implies taking the medicine at the onset of the symptoms, until the lesion disappear.  Secondly, suppressive therapy can be done by taking antiviral medicine daily to prevent possible recurrences.  Since HSV is the most difficult virus to control for the past thousands of years worldwide, and myriads of people are unaware of it, there are poorly documented data compared to other known diseases. , 
One of the initial ways to prevent HSV is to avoid contact with the virus. For example, having good hygiene will prevent possible initial contact with the virus. Using water and soap usually kills the virus. ,  Genital herpes is usually infected by HSV-2, but increasingly genital herpes is transmitted also by HSV-1, since HSV-1 can infect any part of the body. ,  Now, experts say that HSV-1 is “largely transmitted through oral sex.”  For this reason, patients with any type of herpes should avoid having either oral sex or sexual intercourse when there are symptoms around the lesions. ,  Also, it is important to reduce the stimuli that reactivate the latent virus. Frequency of outbreaks might be lessened by managing stress, avoiding UV light, and having adequate diet/rest/exercise. ,  Now, most of the vaccines being developed are to lessen the severity of the symptoms, and to minimize the possible secondary effects and further reoccurrence of infection. 
Herpes Simplex was always there throughout human history and was never completely wiped out due to the HSV characteristics. , ,  Therefore, there were no significant outbreaks that have been recorded, although Shakespeare once described the Herpes Simplex symptoms in his literature.  Fortunately, HSV-2 is somewhat well examined in developed countries. The prevalence of HSV-2 infections in U.S. population (older than 12 years old) is 22% and about 500,000 initial viral infections occur each year. ,  Overall, the prevalence of HSV-2 is higher in women than men. , , ,  Larger mucosal surface in women might be a possible reason for their higher prevalence.  Since HSV-2 is sexually transmitted, the highest HSV-2 infections rates are found in prostitutes, which is 80%.  Ocular herpes occurs in about 50,000 cases per year, and HSV encephalitis occurs about 1000-2000 cases per year. ,  There are 1 million women getting HSV-2 infection who become pregnant; however, the ensuing neonate complications are less than 1/1000(0.3-1.9%). ,  Generally, it is said that more African Americans than whites are infected with HSV-2 and more divorced people than single individuals or married. ,  Moreover, more urban people are infected with HSV-2 than suburban, according to the study.  The contributing importance of socioeconomic factors and family life are obvious. From National Disease and Therapeutic Index in 1994-2004, the seroprevalence of HSV-2 actually decreased compared to the study in 1988-1994.  However, the doctor visits increased, which indicates more recognition of the Herpes Simplex by people. 
Herpes Simplex is more prevalent at a global level.  The HSV prevalence rate is higher in numerous developing countries than in the U.S.  According to the World Health Organization report, those higher rates(>50%) occur in the Sub-Saharan African and Caribbean areas, and Uganda has the highest rate(74%).  On the other hand, Europe has less than 15%. 
Herpes Simplex on patient’s cheek 
Herpes Simplex(possibly Herpes Gladiatorum) on patient’s neck 
Herpes Simplex (possibly Herpes Whitlow) on patient’s wrist 
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