Herpesviridae

Herpesviridae
introduction
The herpes virus family contains several of the most important human pathogens. Clinically, the herpes viruses exhibit a spectrum of diseases. Some have a wide host-cell range, whereas others have a narrow host-cell range. The outstanding property of herpes viruses is their ability to establish lifelong persistent infections in their hosts and to undergo periodic reactivation. Their frequent reactivation in immunosuppressed patients causes serious health complications. Curiously, the reactivated infection may be clinically quite different from the disease caused by the primary infection.
Properties of Herpes viruses
Important properties of herpes viruses are summarized in Table 1.


Table 1. Important Properties of Herpes viruses.



Virion: Spherical, 150–200 nm in diameter (icosahedral) 
Genome: Double-stranded DNA, linear, 125–240 kbp, reiterated sequences 
Proteins: More than 35 proteins in virion 
Envelope: Contains viral glycoproteins, Fc receptors 
Replication: Nucleus, bud from nuclear membrane 
Outstanding characteristics: 
  Encode many enzymes
  Establish latent infections Latent infections are those in which the virus persists in an occult (hidden or cryptic) form most of the time. Viral sequences may be detectable by molecular techniques in tissues harboring latent infections. Inapparent or subclinical infections are those that give no overt sign of their presence.while Chronic infections are those in which replicating virus can be continuously detected, often at low levels; mild or no clinical symptoms may be eviden.
  Persist indefinitely in infected hosts
  Frequently reactivated in immunosuppressed hosts
  Some are cancer-causing

Classification
Classification of the numerous members of the herpes virus family is complicated. A useful division into subfamilies is based on biologic properties of the agents (Table 2). Alphaherpes viruses are fast-growing, cytolytic viruses that tend to establish latent infections in neurons; herpes simplex virus (genus Simplexvirus) and varicella-zoster virus (genus Varicellovirus) are members. Betaherpes viruses are slow-growing and may be cytomegalic (massive enlargements of infected cells) and become latent in secretory glands and kidneys; cytomegalovirus is classified in the Cytomegalovirus genus. Also included here, in the genus Roseolovirus, are human herpesviruses 6 and 7; by biologic criteria, they are more like gammaherpes viruses because they infect lymphocytes (T lymphotropic). Gammaherpes viruses, exemplified by Epstein-Barr virus (genus Lymphocryptovirus), infect and become latent in lymphoid cells.


Table 2. Classification of Human Herpes viruses.



Type Synonym Subfamily Primary Target Cell Pathophysiology Site of Latency Means of Spread
HHV-1 Herpes simplex virus-1 (HSV-1) ? (Alpha) Mucoepithelial Oral and/or genital herpes (predominantly orofacial), as well as other herpes simplex infections Neuron Close contact
HHV-2 Herpes simplex virus-2 (HSV-2) ? Mucoepithelial Oral and/or genital herpes (predominantly genital), as well as other herpes simplex infections Neuron Close contact (sexually transmitted disease)
HHV-3 Varicella zoster virus (VZV) ? Mucoepithelial Chickenpox and shingles Neuron Respiratory and close contact
HHV-4/EBV Epstein-Barr virus (EBV), lymphocryptovirus ? (Gamma) B cells and epithelial cells Infectious mononucleosis, Burkitt s lymphoma, CNS lymphoma in AIDS patients,
post-transplant lymphoproliferative syndrome (PTLD), nasopharyngeal carcinoma, HIV-associated hairy leukoplakia B cell Close contact, transfusions, tissue transplant, and congenital
HHV-5 Cytomegalovirus (CMV) ? (Beta) Monocyte, lymphocyte, and epithelial cells Infectious mononucleosis-like syndrome,[9] retinitis, etc. Monocyte, lymphocyte, Saliva
HHV-6 Roseolovirus, Herpes lymphotropic virus ? T cells Sixth disease (roseola infantum or exanthem subitum) T cells Respiratory and close contact
HHV-7 Roseolovirus ? T cells Sixth disease (roseola infantum or exanthem subitum) T cells and   
HHV-8 Kaposi s sarcoma-associated herpesvirus
(KSHV), a type of rhadinovirus ? Lymphocyte and other cells Kaposi s sarcoma, primary effusion lymphoma, some types of multicentric Castleman s disease B cell Close contact (sexual), saliva

Herpesviruses of other animals
In addition to the herpes viruses considered endemic in humans, some viruses associated primarily with animals may infect humans. These are zoonotic infections:

Zoonotic Herpesviruses
Species Type Synonym Subfamily Human Pathophysiology
Macaque monkey CeHV-1 Cercopithecine herpesvirus-1, (Monkey B virus) ? Very unusual, with only approximately 25 human cases reported.
Untreated infection is often deadly; sixteen of the 25 cases resulted in fatal encephalomyelitis. At least four cases resulted in survival with severe neurologic impairment. Symptom awareness and early treatment are important for laboratory workers facing exposure.[

Mouse MuHV-4 Murine gammaherpesvirus-68 (MHV-68) ? Zoonotic infection found in 4.5% of general population and more common in laboratory workers handling infected mice. ELISA tests show factor-of-four (x4) false positive results, due to antibody cross-reaction with other Herpes viruses.
Herpes virus life-cycle
The replication cycle of herpes virus is summarized as following :
The virus enters the cell by fusion with the cell membrane after binding to specific cellular receptors via envelope glycoproteins. Several herpes viruses bind to cell surface glycosaminoglycans, principally heparan sulfate. Virus attachment also involves binding to one of several coreceptors (eg, members of the immunoglobulin superfamily). After fusion, the capsid is transported through the cytoplasm to a nuclear pore; uncoating occurs; and the DNA becomes associated with the nucleus. The viral DNA forms a circle immediately upon release from the capsid. Viral DNA is transcribed throughout the replicative cycle by cellular RNA polymerase II but with the participation of viral factors.
Maturation occurs by budding of nucleocapsids through the altered inner nuclear membrane. Enveloped virus particles are then transported by vesicular movement to the surface of the cell.
The length of the replication cycle varies from about 18 hours for herpes simplex virus to over 70 hours for cytomegalovirus.
Immune system evasions
Herpesviruses are known for their ability to establish lifelong infections. One way this is possible is through immune evasion. Herpesviruses have found many different ways to evade the immune system. One such way is by encoding a protein mimicking human interleukin 10 (hIL-10) and another is by downregulation of the Major Histocompatibility Complex II (MHC II) in infected cells. The virus can be reactive by provocative stimuli can reactivate virus from the latent state, including axonal injury, fever, physical or emotional stress, and exposure to ultraviolet light. The virus follows axons back to the peripheral site, and replication proceeds at the skin or mucous membranes. Spontaneous reactivations occur in spite of HSV-specific humoral and cellular immunity in the host so that recurrent infections are less extensive and less severe. Many recurrences are asymptomatic, reflected only by viral shedding in secretions. When symptomatic, episodes of recurrent HSV-1 infection are usually manifested as cold sores (fever blisters) near the lip