Herpes simplex virus (HSV)

What is herpes simplex virus (HSV)? Symptoms, treatment, prevention and its cause

Herpes Simplex Virus (HSV) is a prevalent human pathogen that induces infection of the mucosal surfaces of the oral and facial regions (HSV-1) as well as the mucosal surfaces of the genital area (HSV-2). Alpha herpesviruses, which are DNA viruses, are constituent members of the Herpesviridae family. Herpes simplex virus infection stimulates the development of vesicular lesions in the epithelium of the mucosa, subsequently allowing for the intrusion of the virus into the sensory neurons. In this instance, a dormant infection is established within the individual and may persist within the patient’s body until the culmination of life. Reactivation of latent HSV will engender the recurrence of the disease either at or in close proximity to the original site of infection

Types of herpes simplex virus

Herpes simplex virus can be categorized into two serotypes, namely HSV-1 and HSV-2, which shall be delineated subsequently. In general, HSV-1 is linked to oral herpes which frequently manifests during childhood, while HSV-2 is associated with genital infections following the onset of sexual activity.

HSV-1

Herpes simplex virus type 1 (HSV-1) is a linear double-stranded DNA virus that is a member of the Alpha Herpesviridae subfamily. Its capsid structure is icosahedral with a diameter ranging from 100 to 110 nm. HSV-1 is accountable for the emergence of primary and recurrent vesicles, primarily within the oral and genital mucosa. The most prevalent mode of viral transmission is via direct contact with the saliva or other bodily secretions of an infected individual.

HSV-1 infection symptoms

The manifestation of the herpes simplex virus encompasses a wide range of symptoms, including but not limited to:

Orolabial herpes
Herpetic sycosis
Herpes gladiatorum
Herpetic whitlow
Ocular HSV infection
Herpes encephalitis
Eczema herpeticum
Severe or chronic HSV infection

Risk factors

Various risk factors are associated with HSV-1 infection, depending on the specific type of infection. These risk factors include:

Regarding oral herpes, the risk factor pertains to any activity that exposes an individual to the saliva of an infected patient, such as the utilization of shared drinking utensils, shared cosmetics and mouth-to-mouth contact.
The primary risk factor for herpetic sycosis involves the act of shaving the face with a razor belonging to an individual infected with HSV-1.
The risk factor for herpes gladiatorum lies in the engagement of certain sports activities such as wrestling, rugby and boxing.
In the case of herpes vitello, the risk factor encompasses the habit of finger sucking, nail biting and dental procedures, all of which can potentially result in the transmission of HSV-1 to an individual.
The risk factor for herpes encephalitis is linked to mutations in TLR-3 (toll-like receptor) or UNC-93B genes, which are likely to impede the natural interferon-based responses.
The principal risk factor for eczema herpeticum is associated with dysfunction of the skin barrier. This condition is commonly observed in atopic dermatitis, Darier disease, Hailey-Hailey disease and various forms of ichthyosis.
In cases of chronic or severe infections, the risk factor lies in immune system failure among individuals with HIV or those who have undergone organ transplantation.

Prevalence

It is estimated that approximately one-third of the global population has encountered symptoms related to herpes simplex virus type 1 (HSV-1) at least once in their lifetime. Roughly 1 in 1,000 infants in the United States acquires neonatal herpes simplex virus infection during vaginal delivery. From an epidemiological standpoint, it is noteworthy that herpes encephalitis stands as the primary cause of fatal encephalitis in the United States, while HSV eye infection remains one of the leading causes of blindness in the country.

HSV-1 genome structure

The genome of herpes simplex virus 1 (HSV-1) assumes the form of linear double-stranded DNA (dsDNA) measuring approximately 152 kb in length. The HSV genome comprises around 75 GC-rich genes that are densely arranged and encode a minimum of 100 distinct proteins. The structure of the HSV genome exhibits two distinctive regions (UL and US), each flanked by inverted repeats (TRL/IRL and TRS/IRS). This structural pattern is characteristic of Alphaherpesvirinae. Viral genes are responsible for encoding over 35 polypeptides that contribute to virus structure, along with at least 10 polypeptides that constitute the viral envelope. Conversely, herpes viruses encode a collection of virus-specific enzymes that participate in nucleic acid metabolism, DNA synthesis, gene expression regulation and protein production. Examples of these enzymes include DNA polymerase, helicase-primase, thymidine kinase, transcription factors and protein kinase. Moreover, the HSV genome structure exhibits numerous repeated sequences, including:

Two copies of long inverted repeats or RL (measuring approximately 8.75 kb in length)
Two copies of the short inverted repeat or RS sequence (measuring approximately 6.25 kb in length)
Three copies of the “a” sequence, which are repeated at both ends of the genome and within the middle region of the long-short (L-S) junction.

The results of specific investigations indicate that there might be differences in how the HSV-1 genome is expressed in neural and non-neural cells. The transcription of these genes in non-neuronal cells is facilitated by RNA polymerase II. The expression of viral genes occurs through diverse mechanisms, whereby the synthesis of primary proteins precedes the activation of transcription from middle and late genes. Intermediate genes are responsible for DNA replication, while late genes predominantly consist of structural proteins.

HSV-2

Similar to HSV-1, herpes simplex virus type 2 (HSV-2) is a prevalent infection which affecting approximately 22 percent of individuals aged 12 and above. HSV-2 is primarily responsible for oral herpes, while HSV-1 predominantly affects the perioral regions. Genital herpes is a widely prevalent sexually transmitted infection (STI), with HSV-2 being the main causative agent. However, in a few exceptional cases, herpes simplex virus type 1 (HSV-1) has been implicated as the etiological factor in genital herpes. Infection with this particular virus strain often presents with non-specific symptoms, such as pruritus in the genital area, which can lead to delays in diagnosis and treatment. Sexual contact is the most frequent mode of transmission for this disease. The virus selectively targets the skin and mucous membranes, invading epithelial cells upon initial exposure and subsequently undergoing intracellular replication.

HSV-2 infection symptoms

Clinical manifestations of HSV-2 infection are typically evident and can be identified during outpatient examinations. The most common presentation includes the presence of painful lesions in the genital region, accompanied by dysuria and a burning sensation. It is important to note that HSV-2 sores are often associated with pain. Other systemic symptoms may include fever, headache and general weakness in the affected individual.

Risk factors

In the field of herpes simplex virus 2 (HSV-2), infection encompasses various risk factors. These include direct contact with the bodily fluids of an infected individual such as saliva, as well as engaging in sexual intercourse with an infected person. It is important to note that HSV-2 exhibits limited stability outside of the human body and as a result, the risk of transmission through non-sexual means is exceptionally low.

Prevalence

statistics data reveals that the prevalence of genital herpes is higher among women compared to men. Furthermore, the prevalence of this condition tends to increase in relation to the number of sexual partners an individual has had. Notably, prevalence rates of herpes simplex virus 2 (HSV-2) are higher among non-Hispanic African Americans in comparison to non-Hispanic whites. It is estimated that approximately 45 million adults in the United States are affected by this disease.

HSV-2 genome structure

The genome of HSV-2 is approximately 155 kb in size and consists of two distinct regions of unique sequence, namely UL and US. These regions are flanked by a pair of inverted repeat elements known as TRL-IRL and IRS-TRS. Within the structure of the HSV-2 genome, one can observe a directly repeated sequence of 254 bp located at the end of the genome (sequence a). Additionally, there are one or more copies of this sequence (sequence a’) in the internal joint between IRL and IRS. The combination of UL and its flanking repeats is referred to as the long region (L), while US and its flanking repeats are known as the short region (S). Regarding the HG52 strain of HSV-2, its genome consists of approximately 154,746 bp with a GC percentage of 70.4%. It is worth noting that both HSV-1 and HSV-2 possess an equal number of genes, totaling around 75 genes.

HSV infection in newborns

The frequency of herpes simplex virus infection in infants is remarkably low, making it one of the most devastating diseases in this population. In America, the disease has a prevalence of approximately 5 cases per 10,000 newborns. Notably, around 35% of infants are afflicted with central nervous system (CNS) disease, while the remaining infants suffer from diseases affecting multiple organs. Among those infants with multi-organ involvement, mortality rates are alarmingly high reaching approximately 40%. Conversely, mortality rates for infants with CNS diseases are comparatively lower, at around 5%. The utilization of diverse diagnostic techniques has significantly contributed to our enhanced comprehension of HSV disease in infants. For instance, the implementation of the polymerase chain reaction (PCR) method has facilitated the diagnosis of CNS disease without the need for brain biopsy or cerebrospinal fluid culture. In cases where HSV DNA is detected in the patient’s sample, a prolonged treatment period is warranted for the affected infant.

HSV diagnosis

The field of diagnostic techniques for HSV infection has recently witnessed numerous advancements, encompassing novel viral detection methods and serological tests. The diagnosis of HSV typically involves the identification of the complete virus, viral proteins, genetic material or specific antibodies in the bloodstream. Traditional diagnostic strategies encompass viral culture, serological tests, and molecular techniques, which shall be expounded upon subsequently. Generally, tests for detecting herpes simplex virus can be categorized into two groups.

1) HSV diagnosis methods through lesions

In this particular category of examinations, an endeavor is made to identify the presence of the viral agent in a lesion or the secretions of the genital region. In this instance, the viral agent is procured from the lesions on the integument or the genitalia through the act of swabbing or scraping with a surgical instrument. Ideally, the retrieval of the blisters should be executed within a time frame of less than 24 hours subsequent to their formation, as the sensitivity of the examination diminishes after the commencement of the peeling process. In the subsequent section, a variety of direct diagnostic examinations are introduced, which encompass:

Microscopy and Imaging

Among the most advantageous tests for the detection of the Herpes Simplex Virus (HSV) is the utilization of a Brightfield microscope, wherein the sample is visualized through reflected light. This methodology is employed for the visualization of cells and tissues that have been infected by the viral agent. The direct visualization of individual viral particles cannot be achieved through this approach, as the dispersion and absorption of the viral particles, which are smaller than 150 nm in size, is minimal.

Among other types of microscopes that are employed in this field, one can mention the fluorescent variants (Fluorescence Microscopy). In these microscopes, the marked sample is subjected to illumination by fluorescent materials, resulting in the release of light with a longer wavelength which is subsequently recorded by cameras or photomultiplier tubes. The most extensively employed technique is the direct immunofluorescence technique (DFA), wherein antibodies that are labeled with fluorophores are employed to stain the viral agent. These antibodies typically target glycoproteins that are present on the surface of the viral particles.

Molecular diagnostic tests

The most prevalent molecular technique that is employed for the detection of the Herpes Simplex Virus (HSV) is the Polymerase Chain Reaction (PCR), which enables the swift detection of the viral genome. The Real-Time PCR technique is widely adopted in laboratories at present, wherein primers and probes that are labeled with the TaqMan fluorescent dye are utilized. The merits of this technique encompass heightened sensitivity and accuracy, as well as the ability to observe the reaction process during PCR. In this technique, the majority of primers are designed for diverse regions, such as UL44 (HSV-1) and UL3 (HSV-2), for the purpose of amplification. Viral load quantification is accomplished through the employment of a standard curve.

2) Serological tests

An indirect technique for the diagnosis of HSV infection involves the detection of antibodies in the bloodstream that are produced in response to the presence of HSV. This technique involves the separation of serum from whole blood that is obtained from patients, followed by the utilization of one of the ensuing techniques to identify the presence of specific HSV antibodies.

Hemagglutination Assay

In this technique, red blood cells are absorbed through a soluble antigen that is present on their surface and subsequently clump together with antibodies that are specific to the antigen. The glycoprotein C (gC-1) that is present in HSV-1 has been found to be the principal viral hemagglutinin that is capable of binding to red blood cells during infection. Antibodies that are generated against different glycoproteins (gC-1 for HSV-1 and gC2 for HSV-2) during the early stages of infection can be efficacious in the prompt diagnosis of the infection.

Western blot

The Western Blot technique facilitates the separation of all HSV-1 and HSV-2 antigens from the infected cell lines through electrophoresis. These antigens are subsequently absorbed on the nitrocellulose membrane and exposed to the serum of the patient. The identification of HSV relies on the unique banding patterns that emerge for HSV-1 and HSV-2. This assay exhibits exceptional sensitivity and possesses the ability to distinguish between HSV-1 and HSV-2 antibodies.

ELISA

The Enzyme-Linked Immunosorbent Assay (ELISA) serves as a serological diagnostic method wherein specific antigens are employed to detect antibodies within the patient’s blood. ELISA offers enhanced ease of execution in comparison to the western blot technique, and its results are rapidly obtained. The crux of this approach lies in the identification of the presence of specific IgG antibodies that are generated in response to HSV-1 and HSV-2.

Herpes simplex virus treatment

Researchers are still struggling to find a viable treatment option to completely eliminate the herpes simplex virus from the patient’s body. Nevertheless, medical practitioners effectively impede its proliferation and disease progression by means of antiviral medications. Acyclovir and Famciclovir are two of the first pharmaceutical agents prescribed in this area. Acyclovir, a non-cyclic nucleoside analog known as 9-(2-hydroxyethoxymethyl) guanine, has been established as the standard therapy for HSV, conferring therapeutic advantages for both oral and genital herpes.

This particular drug exhibits remarkable selectivity against HSV-1, HSV-2 and varicella-zoster virus (VZV). While human thymidine kinase enzyme phosphorylates thymidine nucleotides, herpes thymidine kinase phosphorylates guanine nucleotides as well as analogous compounds such as acyclovir in human subjects. Consequently, acyclovir is converted into acyclovir monophosphate, which subsequently undergoes tidylation to generate acyclovir diphosphate and triphosphate. Since acyclovir lacks a ribose moiety and possesses a hydroxyl group in a 5-ring sugar, which is vital for the elongation process catalyzed by DNA polymerase enzyme, the nascent viral DNA chain is cleaved. Additionally, acyclovir competitively deactivates HSV DNA polymerase. Physicians prescribe acyclovir via both oral and intravenous routes. However, its efficacy is contingent upon timely administration.