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Herpes Simplex

Disease Details

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Description: Herpes simplex is a viral infection caused by the herpes simplex virus (HSV), characterized by periodic outbreaks of painful blisters and sores, typically around the mouth or genitals.
Type: Herpes simplex virus (HSV) infections can be caused by two types of the virus, known as HSV-1 and HSV-2.

The genetic transmission for herpes simplex viruses is not inherited in the traditional sense. Instead, HSV is transmitted via direct contact with an infected person. HSV-1 is typically spread through oral contact, often leading to orolabial herpes (cold sores), while HSV-2 is primarily transmitted through sexual contact, leading to genital herpes. Vertical transmission from mother to child can also occur during childbirth if the mother has an active infection.
Signs And Symptoms: HSV infection causes several distinct medical disorders. Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands (herpetic whitlow). More serious disorders occur when the virus infects and damages the eye (herpes keratitis), or invades the central nervous system, damaging the brain (herpes encephalitis). People with immature or suppressed immune systems, such as newborns, transplant recipients, or people with AIDS, are prone to severe complications from HSV infections. HSV infection has also been associated with cognitive deficits of bipolar disorder, and Alzheimer's disease, although this is often dependent on the genetics of the infected person.
In all cases, HSV is never removed from the body by the immune system. Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell body of the neuron, and becomes latent in the ganglion. As a result of primary infection, the body produces antibodies to the particular type of HSV involved, which can help reduce the odds of subsequent infection of that type at a different site. In HSV-1-infected individuals, seroconversion after an oral infection helps prevent additional HSV-1 infections such as whitlow, genital herpes, and herpes of the eye. Prior HSV-1 seroconversion seems to reduce the symptoms of a later HSV-2 infection, although HSV-2 can still be contracted.
Many people infected with HSV-2 display no physical symptoms—individuals with no symptoms are described as asymptomatic or as having subclinical herpes. However, infection with herpes can be fatal.
Prognosis: Following active infection, herpes viruses establish a latent infection in sensory and autonomic ganglia of the nervous system. The double-stranded DNA of the virus is incorporated into the cell physiology by infection of the nucleus of a nerve's cell body. HSV latency is static; no virus is produced; and is controlled by a number of viral genes, including latency-associated transcript.Many HSV-infected people experience recurrence within the first year of infection.Prodrome precedes development of lesions. Prodromal symptoms include tingling (paresthesia), itching, and pain where lumbosacral nerves innervate the skin. Prodrome may occur as long as several days or as short as a few hours before lesions develop. Beginning antiviral treatment when prodrome is experienced can reduce the appearance and duration of lesions in some individuals. During recurrence, fewer lesions are likely to develop and are less painful and heal faster (within 5–10 days without antiviral treatment) than those occurring during the primary infection. Subsequent outbreaks tend to be periodic or episodic, occurring on average four or five times a year when not using antiviral therapy.
The causes of reactivation are uncertain, but several potential triggers have been documented. A 2009 study showed the protein VP16 plays a key role in reactivation of the dormant virus. Changes in the immune system during menstruation may play a role in HSV-1 reactivation. Concurrent infections, such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks. Reactivation due to other infections is the likely source of the historic terms 'cold sore' and 'fever blister'.
Other identified triggers include local injury to the face, lips, eyes, or mouth; trauma; surgery; radiotherapy; and exposure to wind, ultraviolet light, or sunlight.The frequency and severity of recurrent outbreaks vary greatly between people. Some individuals' outbreaks can be quite debilitating, with large, painful lesions persisting for several weeks, while others experience only minor itching or burning for a few days. Some evidence indicates genetics play a role in the frequency of cold sore outbreaks. An area of human chromosome 21 that includes six genes has been linked to frequent oral herpes outbreaks. An immunity to the virus is built over time. Most infected individuals experience fewer outbreaks and outbreak symptoms often become less severe. After several years, some people become perpetually asymptomatic and no longer experience outbreaks, though they may still be contagious to others. Immunocompromised individuals may experience longer, more frequent, and more severe episodes. Antiviral medication has been proven to shorten the frequency and duration of outbreaks. Outbreaks may occur at the original site of the infection or in proximity to nerve endings that reach out from the infected ganglia. In the case of a genital infection, sores can appear at the original site of infection or near the base of the spine, the buttocks, or the back of the thighs. HSV-2-infected individuals are at higher risk for acquiring HIV when practicing unprotected sex with HIV-positive persons, in particular during an outbreak with active lesions.
Onset: The onset of herpes simplex virus (HSV) infection typically occurs within 2 to 12 days after exposure. Symptoms may include painful sores or blisters at the site of infection, itching, and other flu-like symptoms such as fever and swollen lymph nodes.
Prevalence: Herpes simplex virus (HSV) prevalence varies widely across different populations and regions. Globally, it is estimated that around 67% of the population under age 50 has HSV-1, which commonly causes oral herpes but can also cause genital herpes. Approximately 11% of the population aged 15-49 worldwide is infected with HSV-2, the primary cause of genital herpes. These figures represent millions of cases, highlighting the widespread nature of herpes simplex infections.
Epidemiology: Worldwide rates of either HSV-1 and/or HSV-2 are between 60 and 95% in adults. HSV-1 is more common than HSV-2, with rates of both increasing as people age. HSV-1 rates are between 70% and 80% in populations of low socioeconomic status and 40% to 60% in populations of improved socioeconomic status. An estimated 536 million people or 16% of the population worldwide were infected with HSV-2 as of 2003 with greater rates among women and in those in the developing world. Rates of infection are determined by the presence of antibodies against either viral species.In the US, 58% of the population is infected with HSV-1 and 16% are infected with HSV-2. Among those HSV-2-seropositive, only 19% were aware they were infected. During 2005–2008, the prevalence of HSV-2 was 39% in black people and 21% in women.The annual incidence in Canada of genital herpes due to HSV-1 and HSV-2 infection is not known (for a review of HSV-1/HSV-2 prevalence and incidence studies worldwide, see Smith and Robinson 2002). As many as one in seven Canadians aged 14 to 59 may be infected with herpes simplex type 2 virus and more than 90 per cent of them may be unaware of their status, a new study suggests. In the United States, it is estimated that about 1,640,000 HSV-2 seroconversions occur yearly (730,000 men and 910,000 women, or 8.4 per 1,000 persons).In British Columbia in 1999, the seroprevalence of HSV-2 antibody in leftover serum submitted for antenatal testing revealed a prevalence of 17%, ranging from 7% in women 15–19 years old to 28% in those 40–44 years.In Norway, a study published in 2000 found that up to 70–90% of genital initial infections were due to HSV-1.In Nova Scotia, 58% of 1,790 HSV isolates from genital lesion cultures in women were HSV-1; in men, 37% of 468 isolates were HSV-1.
Intractability: Herpes simplex is not considered intractable. While it is a chronic condition with no cure, antiviral medications can manage and reduce the frequency and severity of outbreaks. Effective treatments can control symptoms and lower the risk of transmission.
Disease Severity: Herpes simplex severity can vary widely among individuals.

1. **Herpes Simplex Virus Type 1 (HSV-1)**:
- Typically causes oral herpes, leading to cold sores or fever blisters around the mouth.
- Severity ranges from mild, with minimal symptoms and infrequent outbreaks, to more severe, with frequent and painful sores.

2. **Herpes Simplex Virus Type 2 (HSV-2)**:
- Primarily causes genital herpes, leading to sores around the genital or rectal area.
- Severity also ranges from mild to severe, with some individuals experiencing frequent and painful outbreaks.
- Initial outbreaks tend to be more severe, with subsequent outbreaks often less intense.

Most cases are manageable with antiviral medications, which can reduce the frequency and severity of outbreaks. In immunocompromised individuals, herpes infections can be more severe and lead to complications.
Healthcare Professionals: Disease Ontology ID - DOID:8566
Pathophysiology: Herpes is contracted through direct contact with an active lesion or body fluid of an infected person. Herpes transmission occurs between discordant partners; a person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person. Herpes simplex virus 2 is typically contracted through direct skin-to-skin contact with an infected individual, but can also be contracted by exposure to infected saliva, semen, vaginal fluid, or the fluid from herpetic blisters. To infect a new individual, HSV travels through tiny breaks in the skin or mucous membranes in the mouth or genital areas. Even microscopic abrasions on mucous membranes are sufficient to allow viral entry.
HSV asymptomatic shedding occurs at some time in most individuals infected with herpes. It can occur more than a week before or after a symptomatic recurrence in 50% of cases. Virus enters into susceptible cells by entry receptors
such as nectin-1, HVEM and 3-O sulfated heparan sulfate. Infected people who show no visible symptoms may still shed and transmit viruses through their skin; asymptomatic shedding may represent the most common form of HSV-2 transmission. Asymptomatic shedding is more frequent within the first 12 months of acquiring HSV. Concurrent infection with HIV increases the frequency and duration of asymptomatic shedding. Some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified; no significant differences are seen in the frequency of asymptomatic shedding when comparing persons with one to 12 annual recurrences to those with no recurrences.Antibodies that develop following an initial infection with a type of HSV can reduce the odds of reinfection with the same virus type. In a monogamous couple, a seronegative female runs a greater than 30% per year risk of contracting an HSV infection from a seropositive male partner. If an oral HSV-1 infection is contracted first, seroconversion will have occurred after 6 weeks to provide protective antibodies against a future genital HSV-1 infection. Herpes simplex is a double-stranded DNA virus.
Carrier Status: Carrier status for herpes simplex virus (HSV) indicates that an individual is infected with the virus but may not show symptoms. HSV can be categorized into two types: HSV-1, which typically causes oral herpes, and HSV-2, which typically causes genital herpes. Both types can remain dormant in the body after the initial infection and reactivate later. Carriers can transmit the virus to others even if they do not have active symptoms.
Mechanism: Herpes simplex virus (HSV) primarily infects epithelial cells and neurons. The infection mechanism involves several steps:

1. **Attachment and Entry:** HSV initially binds to cell surface glycosaminoglycans, primarily heparan sulfate. This interaction is mediated by viral envelope glycoproteins such as gB and gC. Subsequent binding to entry receptors like nectin-1 or HVEM (Herpesvirus entry mediator) through glycoproteins gD and gB facilitates fusion of the viral envelope with the host cell membrane.

2. **Nuclear Transport:** After entry, the viral capsid is transported to the nucleus via microtubules, where it releases the viral DNA into the nuclear pore.

3. **Gene Expression:** Inside the nucleus, the viral DNA circularizes and is transcribed using the host's RNA polymerase. HSV gene expression follows a tightly regulated temporal cascade consisting of immediate-early (IE or α), early (E or β), and late (L or γ) genes. Immediate-early proteins, such as ICP0 and ICP4, are transactivators necessary for the regulation of early and late gene expression. Early gene products are primarily involved in DNA replication, while late genes encode structural proteins necessary for virion assembly.

4. **DNA Replication:** HSV DNA replication follows a rolling circle mechanism, generating concatemeric DNA that is later cleaved into unit length genomes.

5. **Assembly and Egress:** Viral capsids are assembled in the nucleus and filled with viral DNA. The virus acquires its final envelope by budding through the nuclear membrane and Golgi, incorporating viral glycoproteins into the envelope. Mature virions are then transported to the cell surface and released.

Molecular Mechanisms:
1. **Latency Establishment and Maintenance:** HSV can establish latency in sensory neurons. During latency, the viral genome persists as an episome with minimal transcription, primarily of latency-associated transcripts (LATs). These LATs help in the maintenance of latency by inhibiting apoptosis and viral gene expression.

2. **Reactivation:** Stress, immunosuppression, or other triggers can lead to reactivation of the latent virus. Reactivation involves the resumption of the lytic cycle, starting with the expression of immediate-early genes.

3. **Immune Evasion:** HSV employs multiple strategies to evade the host immune response:
- **ICP47 Protein:** Inhibits the transporter associated with antigen processing (TAP), reducing the presentation of viral peptides by MHC class I molecules.
- **Glycoprotein C (gC):** Binds complement component C3b, inhibiting complement activation.
- **Latency-Associated Transcript (LAT):** Inhibits apoptosis of infected neurons and reduces the detection of viral antigens.

These molecular mechanisms help HSV persist in the host, establish lifelong infections, and periodically cause recurrent disease.
Treatment: Herpes simplex is treated with antiviral medications to reduce symptoms and the frequency of outbreaks. Common medications include acyclovir, valacyclovir, and famciclovir. These antivirals do not cure herpes but help manage the condition. Treatment can be episodic (taken during outbreaks) or suppressive (taken daily to reduce outbreak frequency). Over-the-counter pain relievers, warm baths, and topical creams may also help alleviate symptoms.
Compassionate Use Treatment: For herpes simplex, compassionate use treatments and off-label or experimental treatments may include:

1. **Maribavir**: Though primarily developed for CMV infections, it has shown some activity against herpes simplex in limited cases.
2. **Foscarnet**: This antiviral drug is typically used for acyclovir-resistant herpes simplex infections. It is administered intravenously.
3. **Cidofovir**: Another antiviral for severe or resistant herpes infections, normally used for cytomegalovirus retinitis in AIDS patients.
4. **Docosanol (Abreva)**: While available over-the-counter for herpes labialis (cold sores), its extended use for genital herpes is considered off-label.
5. **Trifluridine**: Primarily an ophthalmic solution for herpes simplex keratitis but has been used experimentally for other herpes simplex infections.
6. **VZV DNA vaccines**: Currently, several vaccines targeting the herpes virus are under investigation in clinical trials.
7. **Gene Editing (CRISPR/Cas9)**: Experimental studies are exploring use of gene-editing technology to target and disrupt herpes simplex virus DNA.

These treatments are generally considered when standard therapies are unsuccessful or contraindicated.
Lifestyle Recommendations: For herpes simplex, here are some lifestyle recommendations to help manage the condition:

1. **Stress Management**: Stress can trigger outbreaks, so practicing stress-reducing techniques such as yoga, meditation, and deep-breathing exercises can be beneficial.

2. **Healthy Diet**: Maintain a balanced diet rich in vitamins and minerals to support your immune system. Some people find that avoiding foods high in arginine (like chocolate and nuts) and consuming more lysine-rich foods (such as fish and dairy) can help reduce outbreaks.

3. **Adequate Sleep**: Ensure you get enough rest, as lack of sleep can weaken the immune system and trigger outbreaks.

4. **Hydration**: Drink plenty of fluids to help your body stay healthy and maintain a strong immune system.

5. **Avoid Triggers**: Identify and avoid personal triggers, such as sunlight, extreme weather, or certain foods, that may prompt an outbreak.

6. **Hygiene Practices**: Wash hands frequently and avoid touching sores to prevent spreading the virus to other parts of your body or to other people.

7. **Safe Sexual Practices**: Use condoms and consider antiviral medication to reduce the risk of spreading the virus to sexual partners.

8. **Topical Care**: Keep affected areas clean and dry. Applying a cold compress can help alleviate discomfort during an outbreak.

9. **Regular Exercise**: Engage in regular physical activity to boost overall health and immune function.

Following these lifestyle recommendations can help manage herpes simplex and potentially reduce the frequency and severity of outbreaks.
Medication: Herpes simplex is typically treated with antiviral medications. Commonly prescribed antiviral drugs include:

1. Acyclovir
2. Valacyclovir
3. Famciclovir

These medications can help reduce the severity and frequency of symptoms but do not cure the virus. They work best when taken at the onset of symptoms.
Repurposable Drugs: Certain repurposable drugs have shown potential in the treatment of herpes simplex virus (HSV) infections:

1. **Valacyclovir**: This antiviral medication, originally developed for herpes treatment, has also been explored for other viral infections.
2. **Famciclovir**: Another antiviral primarily used for herpes, considered for its potential effectiveness against different viruses.
3. **Acyclovir**: Similarly, this drug is used for herpes but its efficacy against other viruses is under investigation.

Research into drug repurposing is ongoing, and these medications may offer insights into broader antiviral applications.
Metabolites: In the context of herpes simplex virus (HSV) infections, there aren't specific metabolites of the virus itself that are typically noted. However, the body's metabolic response to an HSV infection can involve various changes. Important metabolites to consider include:

1. **Arginine**: This amino acid can play a role in viral replication.
2. **Lysine**: Increased lysine can inhibit the replication of HSV.
3. **Nitric Oxide**: Produced as part of the immune response, potentially inhibiting viral replication.
4. **Amino acids and nucleotides**: Alterations can occur due to cellular response to HSV infection.

Research may focus on these and other metabolic pathways to understand HSV pathology better and develop potential treatments.
Nutraceuticals: Nutraceuticals, such as lysine supplements, have shown potential in managing herpes simplex by possibly reducing the frequency of outbreaks. Lysine is believed to counteract arginine, an amino acid that promotes the replication of the herpes simplex virus (HSV). However, the effectiveness of lysine and other nutraceuticals in treating HSV varies among individuals, and they should be considered as complementary to conventional treatments.

Nanotechnology approaches (nanomedicine) are being explored to improve the treatment of herpes simplex infections. Nanoparticles can be used to enhance drug delivery, increase bioavailability, and target the virus more effectively while minimizing side effects. Research is ongoing to develop nanoparticle-based formulations that can deliver antiviral agents directly to infected cells, thereby improving therapeutic outcomes.
Peptides: Herpes Simplex virus (HSV) infections can be managed and studied using diverse approaches, including peptide-based therapies and nanotechnology.

**Peptides:**
- **Antiviral Peptides:** Certain peptides exhibit antiviral properties that can inhibit HSV replication. These can work by blocking viral entry into cells, inhibiting viral enzymes, or disrupting viral assembly.
- **Peptide Vaccines:** Research is ongoing to develop peptide-based vaccines targeting specific HSV antigens to elicit an immune response and provide immunity or therapeutic benefits.

**Nanotechnology:**
- **Nanoparticles:** These can be used to deliver antiviral drugs more effectively. Nanoparticles can target infected cells precisely, improve drug stability, and reduce side effects.
- **Nanovaccines:** Nanoparticles can serve as adjuvants in vaccine formulations, enhancing the immune response against HSV.
- **Diagnostic Tools:** Nanotechnology-based diagnostic tools can provide rapid and sensitive detection of HSV, improving the timeliness and accuracy of diagnosis.

Both peptides and nanotechnology represent promising avenues for advancing the prevention, diagnosis, and treatment of Herpes Simplex virus infections.