Herpesviruses and herpes viral infections: An overview
The History of Discovery of Herpes Viruses
Herpetic infections (Gr. herpes means “to creep or crawl”) are the commonest among humans. They follow humankind throughout all its history. It is generally ascertained that more than 90% of human population are infected with herpesviruses.
The main representatives of herpesiviruses were identified in XX century. At first, A. Lowenstein discovered herpes simplex virus in 1919. Then in 1925 K. Kundratitz confirmed the link between varicella and zoster infections; H. Ruska in the early 1940s found this virus by electron microscopy, and finally the varicella-zoster agent was isolated in 1952 by T. Weller.
In 1955-1956 M. Smith obtained the culture of human cytomegalovirus (CMV).
In 1964 M. Epstein, B. Achong, and Y. Barr established a new herpes virus isolated from Burkitt’s lymphoma cells that was later termed as Epstein-Barr virus (EBV). Further in 1968 W. Henle and G. Henle identified Epstein-Barr virus as the causative agent of infectious mononucleosis.
The first lymphotropic human herpesvirus type 6 was primarily isolated in 1986 by S.Z. Salahuddin and coworkers in laboratory of R. Gallo; another herpesviral species of type 6 was revealed by the group of K. Yamanishi in 1988.
The next lymphotropic human herpesvirus of type 7 was described by N. Frenkel and coworkers in 1990.
The most recently found Kaposi’s sarcoma-associated herpesvirus or human herpesvirus 8 was first detected in 1994 by Y. Chang, P. Moore, and colleagues.
Classification of Herpesviruses
Herpesviruses are placed into order Herpesvirales and Herpesviridae family; the latter comprises multiple viral genera and species of human and animal herpesviruses. To date, 8 types of human herpesviruses are known.
Family Herpesviridae is divided into 3 subfamilies. Subfamily Alphaherpesvirinae includes genus Simplexvirus with species human alphaherpesvirus 1 (herpes symplex virus type 1) and human alphaherpesvirus 2 (herpes symplex virus type 2) as well as genus Varicellovirus with species human alphaherpesvirus 3 or varicella-zoster virus of type 3.
Subfamily Betaherpesvirinae comprises genera Cytomegalovirus (species human betaherpesvirus 5, or type 5, or CMV) and Roseolovirus. The latter include species human betaherpesvirus 6A and 6B (herpesvirus type 6) and species human betaherpesvirus 7 (type 7).
Finally, one more subfamily Gammaherpesvirinae contains genus Lymphocryptovirus with species human gammaherpesvirus 4 known as type 4 or Epstein-Barr virus (EBV) and genus Rhadinovirus with species human gammaherpesvirus 8 also known as herpesvirus type 8 or Kaposi’s sarcoma-associated herpesvirus (KSHV).
Structure of Herpesviruses
Herpesviruses are double-stranded linear DNA-containing enveloped viruses. Herpesvirus size is large (about 150-200 nm). The mature virion is of spherical shape.
Viral nucleocapsid exhibits icosahedral symmetry. It is composed of 162 capsomers. Viral envelope is derived from nuclear membrane of the infected cell and carries viral glycoprotein spikes. The protein coat between the capsid and envelope is termed as tegument.
There is generally low DNA relatedness between various species of herpesviruses except for herpes simplex types 1 and 2 with 50% sequence homology, and herpesviruses of 6 and 7 types, which show limited (30-50%) genomic DNA similarity. DNA homology predisposes to antigenic cross-reactivity between related herpesviruses.
Genomic DNA of herpesviruses is large. Typical herpesviral genome encodes above 100 viral proteins. More than 35 polypeptides are included into the structure of mature virion. Mutiple glycoproteins of spikes, protruding outside the envelope (e.g., gB and gD proteins of herpes simplex virus) promote virion binding to cell receptors. Some glycoproteins (e.g., gG protein) confer virus antigenic specificity. A number of virus-specific enzymes (e.g., DNA polymerase and thymidine kinase) are synthesized in infected cells, but they are not incorporated into the virus particles.
Viral Replication Cycle
Primary virus binding to target cells largely occurs via interaction of envelope glycoproteins with membrane glycosaminoglycans, e.g., heparan sulfate. Viral entry is promoted by next binding of spike glycoproteins (like gD) to a number of special high-affinity membrane receptors (herpesvirus entry mediators).
The virus enters the cell by fusion with the cell membrane. The capsid is transported to a nuclear pore. Then uncoating occurs, and DNA becomes associated with the nucleus. Viral DNA is transcribed by cellular RNA polymerase II. At first immediate-early and early viral proteins are translated that serve for viral replication and genome expression.
A large number of enzymes involved in DNA synthesis are produced. They are subjected to inhibition by specific antiviral drugs. Viral host shutoff protein arrests cellular protein synthesis degrading host mRNAs.
Next late proteins are translated. Most of them are structural proteins of herpesviruses. Encasing of newly synthesized viral DNAs into empty nucleocapsids occurs in the cell nucleus.
Maturation accomplishes by budding of nucleocapsid complexes through nuclear membrane. Enveloped progeny virions are then released by exocytosis from the infected cells. The duration of replication cycle of herpesviruses varies greatly – from 8-16 h for herpes simplex viruses to over 70 h for cytomegalovirus.
Productive infection is followed by cell death with lysis. On the other hand, herpesviruses stay dormant inside infected cells resulting in long-lasting latent infection. In herpes symplex viruses this state is maintained by synthesis of viral latency associated transcript RNA (LAT). It influences normal cell life cycle and slows down viral replication.
Resistance of Herpesviruses
The resistance of herpesviruses is low or moderate. When dried upon inanimate surfaces, these agents survive from several hours to 7 days (cytomegaloviruses), or from few hours to weeks (herpes simplex viruses). HSV-2 is more sensitive than HSV-1.
Epstein-Barr virus is the most labile pathogen; it can’t be isolated from environmental objects due to the rapid loss of viability.
Herpesviruses are readily inactivated by pH<4, UV irradiation or sunlight, and by heating (30 min at 60-80°C).
Viruses are sensitive to most disinfectants (e.g., sodium hypochlorite, povidone-iodine and other halides, phenol, aldehydes, ethanol, isopropanol, and others).
HERPES VIRAL INFECTIONS IN HUMANS
Infections, Caused by Herpes Simplex Viruses of Types 1 and 2
Special features of herpes simplex viruses
There are two distinct herpes simplex viruses: type 1 and type 2 (HSV-1, HSV-2). Their genomes exhibit substantial homology. These two viruses demonstrate serological cross-reactivity.
Herpes simplex viruses express at least 11 structural glycoproteins with versatile biological functions (from gB to gM).
Glycoproteins gD and gB are the viral receptors, responsible for adherence and viral entry. Glycoproteins gD and gB also stimulate the production of virus-neutralizing antibodies.
Several proteins impact host immune responses – protein gС is a complement-binding factor, and gE acts as Fc receptor for human IgG.
Glycoprotein gG is serotype-specific antigen allowing discrimination between HSV-1 (gG-1) and HSV-2 (gG-2). The HSV growth cycle proceeds rapidly being completed in 8-16 h.
Pathogenesis, clinical findings and immunity
Infection with herpes simplex viruses is common among human population. The viruses propagate rapidly being highly cytolytic.
HSV-1 is usually associated with oropharyngeal lesions and causes recurrent attacks of herpes labialis or “fever blisters”. HSV-2 primarily infects the genital mucosal tissues resulting in genital herpes.
The total spectrum of herpes simplex-associated diseases ranges from local gingivostomatitis and conjunctivitis to severe genital disease, encephalitis, and generalized infections of newborns and immunocompromised adults.
Herpes simplex viruses produce latent infection in neural tissues with periodical exacerbations. Recurrences of infections are common. HSVs are transmitted through mucosal surfaces or skin lesions (intact skin is not permeable for virus).
HSV-1 is spread by airborne (aerosole) route or by direct contact with infected saliva. In most cases the infection locally affects the oropharynx.
HSV-2 is usually transmitted by sexual intercourse like other kinds of sexually transmitted diseases.
Neonatal herpes occurs after intra- or postnatal infections with either HSV-1 or HSV-2 (vertical transmission).
Viral replication primarily occurs at the site of entry. Within infected cells HSV inhibits the expression of HLA-I class molecules, thereby impairing presentation of viral Ags and making difficult elimination of infected cells by immune system.
Further HSVs invade local nerve endings and undergo retrograde axonal transport to dorsal root ganglia, where after several replications latency is established.
Oropharyngeal HSV-1 infections result in viral persistence in the trigeminal ganglia, whereas genital HSV-2 persists within infected sacral ganglia.
Herpes simplex viruses stay latent within infected ganglia lifelong. Various triggering stimuli like axonal injury, UV irradiation, fever, stresses and many other challenges induce viral replication. The mechanisms of viral activation are not well-elucidated yet.
The viruses move along axons to their peripheral sites within the skin or mucous membranes, where viral replication reoccurs.
Many of HSV-1 infections are asymptomatic. Symptomatic diseases demonstrate short incubation period (about 3-5 days), and clinical manifestations last for 2-3 weeks.
Gingivitis is the most common lesion in infants, primary infections in adults result in pharyngitis or tonsillitis.
Recurrent HSV-1 infections are commonly manifested as cold sores (fever blisters) near the lips. Primary eye HSV-1 infection leads to severe keratoconjunctivitis.
Genital disease is usually caused by HSV-2. This clinical variant is characterized by vesicular and ulcerative lesions of genitalia, which are very painful. Viral discharge lasts near 3 weeks. Relapses of genital herpes are common but milder.
Herpetic encephalitis is a rare but life-threatening form of herpes simplex infections. The most severe generalized forms of herpetic infections develop in immunocompromised patients, resulting from HSV dissemination.
Neonatal herpes demonstrates variable clinical manifestations, but in many cases it progresses into systemic infection with viremia and viral encephalitis. HSV-2 causes the most severe infections.
Cell-mediated immunity (e.g., T cytotoxic and natural killer cells) as well as host interferon responses are pivotal for efficient control of primary and recurrent HSV infections.
During primary herpetic infection short-term IgM antibodies are next followed by IgG and IgA antibodies that stay for a long period. Specific antibodies don’t abolish reactivation of a latent virus but may reduce disease manifestations.
The specimens for examination are taken from viral herpetic lesions; throat washings and cerebrospinal fluid can be used as well. PCR assays are most commonly used for viral identification. Viral cultivation is performed in primary tissue cultures. HSVs are further identified by immunofluorescence or neutralization tests. The diagnostic value of serological testing is limited. Elevation of specific antibodies in 4-7 days after primary infection with a peak in 2-4 weeks is detected by ELISA.
Principles of treatment and prophylaxis of herpesviral infections
A number of efficient antiviral agents are used for treatment of HSV infections. Among them are acyclovir and valacyclovir. Both inhibit viral DNA synthesis. Topical acyclovir applications are effective in herpes labialis. However, antivirals don’t influence on latent HSVs that stay within sensory ganglia. Experimental vaccines of various types are being developed. Nevertheless, there is no efficient HSV vaccine in current clinical practice.