Human herpesviruses (HHV) are a group of eight distinct viruses known to cause a wide range of diseases in humans. These viruses are part of the Herpesviridae family, which also includes other viruses that affect animals. The human herpesviruses are classified into three subfamilies based on their genetic and biological properties: alpha, beta, and gamma herpesviruses. Each type of herpesvirus is responsible for specific infections, ranging from mild conditions like cold sores to more severe diseases, such as shingles, mononucleosis, and even certain types of cancer. This comprehensive overview will delve into the characteristics, classification, clinical manifestations, diagnostic methods, and treatments associated with the eight human herpesviruses (HHV 1-8). Understanding these viruses is essential for recognizing their symptoms, managing their reactivation, and preventing complications, especially in immunocompromised individuals who are at higher risk of severe outcomes from these infections.
What Are Herpes Viruses?
Herpes viruses are spherical, large (150–200nm in diameter), double-stranded DNA viruses that are enveloped. They replicate in the nucleus of host cells, establish latent infections, and persist indefinitely in infected hosts. Reactivation is frequent, especially in immunocompromised individuals.
Human Herpesviruses (HHV)
While there are over 100 known herpesviruses, the majority infect animals, including cattle, goats, dogs, cats, horses, pigs, rodents, birds, reptiles, and fish. There are 8 herpesviruses that cause disease in humans, known as human herpesviruses (HHV). Additionally, two other herpesviruses that infect humans include:
- Monkey B virus (Herpesvirus simiae)
- Murid herpesvirus 68 (MHV-68)
Herpesvirus Classification: Understanding the Subfamilies and Genera
Herpesviruses are classified under the Herpesvirales order, Herpesviridae family, and Alphaherpesvirinae subfamily. These are further divided into genera, based on specific characteristics and biological properties.
Subfamilies of Herpesviruses:
- Alpha Herpesviruses
- Genera: Simplexvirus (HHV-1, HHV-2), Varicellovirus (HHV-3)
- Beta Herpesviruses
- Genera: Cytomegalovirus (HHV-5), Roseolovirus (HHV-6, HHV-7)
- Gamma Herpesviruses
- Genera: Lymphocryptovirus (HHV-4), Rhadinovirus (HHV-8)
Biologic Properties of Herpesviruses:
- Alpha herpesviruses (e.g., HSV-1, HSV-2, VZV) tend to have a short growth cycle (~18 hours) and are cytolytic. Their latent infections are primarily located in neurons.
- Beta herpesviruses (e.g., CMV, HHV-6) have a longer growth cycle (~70 hours) and infect glands and kidneys.
- Gamma herpesviruses (e.g., EBV, HHV-8) cause lymphoproliferative diseases and primarily infect lymphoid tissue.
Herpes Simplex Viruses (HSV)
HSV consists of two types: HSV-1 and HSV-2, differentiated based on their DNA structure, antigenic properties, tissue tropism, and growth patterns in cell cultures. HSV-1 is commonly transmitted through oral contact, while HSV-2 is more commonly transmitted sexually.
Clinical Presentation and Infections:
Both HSV-1 and HSV-2 can cause similar clinical symptoms. However, HSV-1 usually affects the upper body, especially the oropharyngeal region, while HSV-2 primarily affects the genital area. There is no significant cross-protection between the two types.
- Oropharyngeal Infections: Often asymptomatic or cause acute gingivostomatitis. Recurrent outbreaks typically occur at the lip margins.
- Dermal Infections: Healthcare workers (HCWs) who come into contact with oral secretions may develop herpetic whitlow (a finger infection). Athletes (e.g., wrestlers) are also at risk of herpes gladiatorum.
- Eczema Herpeticum: A severe skin infection in individuals with eczema, which can be fatal if untreated.
- Ophthalmic Infections: Herpetic keratoconjunctivitis, usually caused by HSV-1, can lead to corneal scarring and vision loss if left untreated.
- CNS Infections: HSV can cause herpes meningitis or HSV encephalitis, the latter being a life-threatening condition.
Neonatal HSV Infections
Neonatal herpes can be congenital (transplacental) or acquired during childbirth. The risk of infection is higher if the mother is in the process of seroconversion near delivery.
Symptoms in Newborns:
- Disseminated disease (involving the liver and other organs, often with skin lesions).
- Encephalitis: Can occur with or without skin lesions.
- Skin, Eye, Mouth involvement: More common after 10 days of age.
Diagnosis of neonatal HSV includes:
- Isolation of HSV from skin, CSF, or other bodily fluids
- NAAT for detection in CSF
- Ruling out other infections like CMV, VZV, rubella, and enteroviruses
Diagnosis of HSV Infections
Various diagnostic methods are employed to detect HSV:
- Serology: IgG and IgM antibody tests, though not reliable for determining the timing of infection or viral activity.
- Microscopy: Tzanck smear, though largely replaced by PCR, DFA, and culture methods.
- Culture: HSV grows rapidly in cell cultures, and typing can differentiate between HSV-1 and HSV-2.
- Molecular Methods: NAAT is more sensitive than culture and is the preferred diagnostic method for distinguishing between HSV types.
Varicella-Zoster Virus (VZV)
VZV causes varicella (chickenpox) in children and herpes zoster (shingles) in adults.
Varicella (Chickenpox)
- Transmission: Highly contagious, primarily through respiratory droplets or direct contact with fluid from vesicles.
- Symptoms: Characterized by a centripetal rash, usually starting on the trunk and progressing to the limbs. Lesions appear in successive crops.
Herpes Zoster (Shingles)
- Reactivation of latent VZV in the dorsal root ganglia leads to localized vesicular lesions, typically along a dermatome.
- Pain is often severe in affected areas.
Diagnosis and Vaccination
- Diagnosis: Based on clinical presentation, serology, Tzanck smear, DFA, and PCR.
- Vaccination: Available for both chickenpox and shingles. Passive immunization with varicella-zoster immune globulin is also available for immunocompromised individuals.
Human Herpesvirus 6 (HHV-6) and 7 (HHV-7)
HHV-6 is classified into two variants: HHV-6A and HHV-6B, with HHV-6B being the main cause of exanthem subitum (6th disease), also known as roseola infantum.
Symptoms of 6th Disease:
- Sudden high fever, followed by a rash that typically starts on the trunk and spreads to the limbs.
HHV-7, discovered in 1990, is another cause of roseola and shares similarities with HHV-6. Both viruses belong to the Roseolovirus genus.
Epstein-Barr Virus (EBV) – HHV-4
EBV is one of the most common human viruses, with over 90% of people worldwide being infected at some point. It is primarily transmitted through oropharyngeal secretions and is known for causing infectious mononucleosis (IM).
Clinical Manifestations:
- Infectious mononucleosis: Often called the “kissing disease,” it is characterized by fever, sore throat, and swollen lymph nodes.
- EBV is also associated with various cancers, including Burkitt’s lymphoma, Hodgkin’s lymphoma, and nasopharyngeal carcinoma.
Diagnosis:
- Serology: Detection of antibodies against EBV antigens (VCA, EA, EBNA).
- Molecular Methods: NAAT to detect EBV DNA.
- Histology: In situ hybridization can be used to visualize EBV infection in tissues.
Cytomegalovirus (CMV) – HHV-5
CMV is a common virus that can cause severe complications in immunocompromised individuals and newborns. It is primarily transmitted via bodily fluids like saliva, blood, and breast milk.
Symptoms in Healthy Individuals:
- Mild flu-like symptoms, often asymptomatic.
Congenital CMV:
- Can cause hearing loss, vision impairment, and developmental delays in newborns.
- CMV is the most common infectious cause of birth defects in the U.S.
Diagnosis of CMV:
- Viral Culture: Preferred for detecting CMV in newborns.
- NAAT: PCR for detecting CMV DNA.
- Antigen Detection: ELISA and IFA for detecting CMV antigens in bodily fluids.
- Serology: IgG and IgM testing for past and active infections.
Kaposi’s Sarcoma-Associated Herpesvirus (HHV-8)
HHV-8 is associated with Kaposi’s Sarcoma, a type of cancer that commonly occurs in immunocompromised individuals, especially those with HIV/AIDS.
Real-time PCR (RT-PCR): Principle, Procedure, and Applications
