Introduction:
Herpes simplex is a viral disease caused by the herpes simplex virus. According to the World Health Organization, viruses of the Herpesviridae family infect 90% of the Earth’s population. Humans are the hosts of at least nine unique herpes viruses. The most prevalent is herpes simplex virus type 1 (HSV-1), which establishes latent infection but reactivates causing cutaneous or genital herpes, conjunctivitis, keratitis, encephalitis, or eczema herpeticum. HSV often coinfects HIV-infected patients, complicating treatment of AIDS. HSV-1 might be also involved in the pathogenesis of multiple sclerosis.
Herpesviruses are large enveloped viruses. The viral genome is by and regulated by viral encoded and cellular nuclear factors. Replication of the viral genome is performed by viral encoded . There are 3 subgroups of herpesviruses; (1) alpha which have latency in the CNS, (2) beta which have latency in monocytes and (3) gamma which have latency in and have oncogenic potential.
Herpesviruses encode their own DNA-dependent DNA polymerase, which is a core enzyme required for replicating the viral genome. All members of the herpesvirus family possess this viral polymerase, making it a conserved and essential component of the viral replication machinery and a key target for antiviral therapies.
Infections are classified accordingly to the part of the body affected: Cold sores can cause small blisters placed in groups and sore throats, whereas genital herpes presents with minimal symptoms such as small blisters that break and cause mild ulcers. The presentation of herpes symptoms occurs cyclically, with periods of active illness followed by asymptomatic periods. The first episode is often more severe and may be associated with fever, muscle pain, swollen lymph nodes and headaches. Over time the episodes of illness decrease both in frequency and in severity.
There are two types of herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2). HSV-1 most commonly causes oral infections while HSV-2 most commonly affects the genitals. They are transmitted by direct contact with body fluids or through injuries to an infected individual. Transmission may also occur when symptoms are not present. Genital herpes is classified as a sexually transmitted disease. During delivery, herpes simplex can be transmitted to the baby.
People with immature or suppressed immune systems, such as newborns, transplant recipients or people with AIDS, are prone to get serious complications from HSV infections. These infections are also associated with cognitive deficits in bipolar disorder and Alzheimer’s disease, although this often depends on the genetics of the infected person. The spread of pathogens from the oral environment to the brain has recently been reported. In all cases, HSV is never removed from the body by the immune system. See Crimi
Structure:
HSV-1 and HSV-2 contain a large, linear double stranded DNA genome protected by an icosahedral capsid surrounded by a proteinaceous layer termed the tegument and wrapped in an envelope containing viral glycoproteins.
Cell Entry and Pathogenesis:
Primary Infection: During primary infection, HSV infects epithelial cells in the mucosa or skin and then establishes latency in neurons, mainly of the peripheral nervous system.
HSV1 and 2 typically initiate primary infection by gaining access to the deep layers of the epidermis of oropharyngeal and genital mucosal tissue. From these infection sites HSV spreads into the axons of sensory neurons in the epidermis and then travels towards the trigeminal/dorsal root ganglia where it establishes a lifelong latent infection, protected from immune eradication. After recurrence HSV1 & 2 usually cause self-limiting lesions which are primarily found around the mouth, face and eye (HSV1) or genital area (HSV1 and 2), or asymptomatic infection. Occasional severe complications include encephalitis, blindness, predisposition to HIV acquisition, and in severe cases in neonates and immunosuppressed individuals, death. See Cunningha
Latent Infection: After infection, the viruses are transported along the sensory nerves to the bodies of nerve cells. The causes of recurrence can include decreased immune function, stress and exposure to the sun. Globally, rates among HSV-1 or HSV-2 adults are between 60% and 95%. HSV-1 is usually acquired during childhood. The incidence of HSV-1 is between 70% and 80% in populations of low socio-economic status and between 40% and 60% in those with a higher status. HSV infections cause several distinct medical disorders. Common infections of the skin or mucous membranes can affect the face and mouth (orofacial herpes), genital organs (genital herpes) or on the hands (herpetic fever). More serious disorders occur when the virus infects the eye (herpes keratitis) or invades the central nervous system, damaging the brain (herpetic encephalitis). See Crimi
HSV1 infection of the eey is a serious disease, with herpes keratitis as one of the leading cuses of infectious blindess in the world HSV1 infeciton of the murine corneal epithelium leads to products of many cytokines and chemokines hich a key for recruitment of leukocytes intot he cornea. RNA expression of CCL3, CCL4, CCL5 and CCL2 have been shown to persist into the latent stage of ocular HSV1 infection which can cause extensive damage ot the eye.
Diagnosis:
Genital herpes can be more difficult to diagnose than oral herpes, since most people infected with HSV-2 do not have the classic symptoms. Furthermore, the diagnosis can be confused with many other conditions similar to genital herpes, including fungal infection, lichen planus, atopic dermatitis, and urethritis. Laboratory tests are often used to confirm a diagnosis of genital herpes. See Crimi
Cold and genital herpes are usually diagnosed based on the presentation of symptoms. Diagnosis can be confirmed by viral culture or detection of herpes DNA in urine. Blood tests in search of antibodies against the virus may confirm a previous infection.
Prevention:
The most effective way to avoid genital infections is to avoid vaginal, oral and anal sex. The use of condoms slightly decreases the risk. The daily intake of an antiviral drug by the infected person may reduce the spread.
Treatment:
There is no method to eliminate the herpes virus from the body, but taking antiviral drugs can reduce the frequency, duration, and severity of outbreaks. Analgesics, such as ibuprofen and paracetamol (acetaminophen), can reduce pain and fever. Topical anesthetic treatments, such as prilocaine, lidocaine, benzocaine, or tetracaine, are also able to relieve itching and pain. Several antiviral drugs are effective for the treatment of herpes, including aciclovir, valaciclovir, famciclovir, and penciclovir. Aciclovir was the first to be discovered and is now available as an equivalent drug, as is valaciclovir. The evidence supports the use of aciclovir and valaciclovir for the treatment of cold sores, as well as for herpes infections in people with cancer. There is no vaccine available and, once infected, there is no cure. Paracetamol and topical lidocaine can be used to relieve symptoms. See Crimi
Alphaherpesvirinae subfamily:
The Alphaherpesvirinae subfamily includes lytic viruses with relatively short life cycle that infect different cell types, replicate rapidly, and establish latency mainly in sensory ganglia. Simplex virus (HSV-1 and -2), varicella zoster virus (VZV), and some avian viruses are referred to Alphaherpesvirinae. VZV provokes chickenpox in children and herpes zoster in adults.
Herpes Simplex Virus 1 & 2 (HSV-1): See outline
Monkey B virus is closely related to HSV-1/2. Human infection is by saliva or bites and the virus is 70% lethal. It can also spread from person to person. Monkey B virus is naturally occurring herpesvirus in macaques. The virus is not as sensitive to acyclovir as with HSV.
Varicella zoster virus (VZV) (Chicken Pox and Shingles):
Varicella-zoster virus (VZV) is a member of the human alphaherpesvirus family. Primary VZV infection causes chickenpox (varicella) in susceptible individuals, which typically manifests in immunocompetent individuals as a skin blistering rash preceded by flu-like symptoms and is usually self-limiting. In immunocompromised individuals, pregnant women as well as healthy adults, VZV infection may cause serious illness and even be lethal, often as a consequence of bacterial superinfections. See Breuer
VZV is transmitted between hosts by contact with the cutaneous blistering lesions containing the highly infectious cell-free virus or through inhalation of the aerosolized virions released from the skin lesions and to some extent the respiratory tract. During primary infection, VZV initially infects cells of the mucosa lining the upper respiratory tract where it is initially detected by dendritic cells (DCs) and transported to lymphoid tissues, primarily the tonsils, where it infects skin homing markers expressing T-lymphocytes that then deliver it to the skin. During primary infection, VZV infects epithelial cells of the upper respiratory tract mucosa. It is believed that at this location the virus encounters and infects DCs, which then travel to the tonsils and other regional lymphoid tissues, where they transfer the virus to T lymphocytes. It is not clear how T cells get infected by DCs, however it is well recognised that T lymphocytes play a crucial role in the dissemination of the virus from the initial sites of infection to the rest of the body, particularly the skin, during the viraemic stage of infection. VZV-infected T cells are mainly memory CD4+ T cells expressing activation and skin-homing markers, such as CC-chemokine receptor 4 (CCR4) and cutaneous leukocyte antigen (CLA), but VZV also infects and activates naïve T cells. While VZV replicates both the in the dermis and the epidermis, the latter represents the major site of viral replication, as well as the location where blistering lesions laden with infectious VZV virions form, guaranteeing virus transmission to new susceptible hosts. See Breuer
VZV It initially infects the respiratory tract and spreads to the skin after about 13 days. Various stages of lesions are seen simultaneously like macules, papules, vesicles, pustules, ulcers and crusts. VCV is highly contagious and there is over 90% infection with VZV before age 10. All kids are now immunized for VZV. Adults who have never contracted the disease or have been immmunized can get a severe adult chickenpox. Neonatal chickenpox is also very severe. Reactivation of VZV can occur in and cause herpes zoster or shingles. This is a frequent occurrence in aging individuals and cancer patients. Treatment of uncomplicated VZV is not necessary. Otherwise, treatment can include high does of ACV, amciclovir or valacyclovir. Immunsuppressed children may receive preventive high titer IgG within 72 h of exposure.
HHV-6 is of the beta-herpesviruses which is common in very young children (6 months to 4 years of age). AFter primary infection CD4 T cells are the site of life-long latency.
HHV-7 is sometimes called an “orphan” virus in that it has no disease association. It has been shown present in AIDS patients.
Betaherpesvirinae subfamily:
The Betaherpesvirinae subfamily includes viruses with long life cycle and slow progression of infection of a limited number of hosts. Infected cells thrive and increase in size (cytomegaly). Latent infection localizes in secretory glands, lymphoreticular cells, kidneys, and other tissues. Human cytomegalovirus (CMV) and roseoloviruses (HHV-6) are Betaherpesvirinae.
Cytomegalovirus (CMV): CMV is a member of the beta-herpesviruses. CMV often causes retinitis in patients with immunodeficiency (e.g., AIDS). The histological hallmark of CMV infection and a way of diagnosis is the cytomegalic (enlarged) cells which contain a dense central “owl’s eye” intranuclear inclusion.
50% of the US population is + for CMV. Semen is a major vector for sexual spread of CMV and thus the use of condoms limits its spread. It is also a congential infection (infection through the placenta) .
The virus establishes latent infection in CD33pos BM precursors of DCs and can be reactivated from blood cells bearing DC markers by stimulation with allogeniec cells. HCMV enters immature myloid DCs via DC-SIGN, leading to trans infection of human lung fibroblasts. Infection of imamture MDDCs or Langerhans-like DCs by HCMV inhibits their maturation and caapcity to activate T cells. Infection of mature myloid DCs upregulateds CD95L (FasL) and TNF-related apoptosis inducing ligand (TRAIL_, leading to apoptosis in T cells. Furthermore, HCMV infection of mature myloid DCs downregulates HLA class I expression, possibly mediated through US11 and US2 coded proteins of the virus.
CMV causes persistent infection, which can lead to diseases affecting various organs in immunosuppressed persons. CMV can be reactivated from latency in immunocompromised states such as those persons with HIV. The upregulation of CMV infection by TNF is mediated via the with a downstream signaling process that involves activation of protein kinase C and NFkB. The activated p65/050 NFkB translocates into the nucleus and binds to the 18-base pair repetitive sequence motifs with the human CMV immediate early 1 enhancer region.
Ganciclovir and cidofovir are used for treatment.
Murine gamma herpesvirus 68 (MHV-68) is a member of the gamma-2 subgroup.
Gammaherpesvirinae subfamily:
The Gammaherpesvirinae subfamily includes Kaposi sarcoma-associated herpes virus (HHV-8), Epstein–Barr virus (EBV) (see outline) that causes Burkitt’s lymphoma mainly in Central Africa residents, and infectious mononucleosis in USA and other countries.
Herpesvirus saimiri (HVS) is a member of the gamma-2 subgroup. The squirrel monkey is the natural host of HVS. STP (Saimiri Transforming Protein), TIP (Tyrosine Kinase interacting protein) LANA (latency-Associated Nuclear Antigen) and HSURs (herpesvirus Saimiri U-type RNA) are all associated with ongogenesis in HVS. STP-A activates c-ras and along with STP-c activates c-Src which turns on STATS as well as NF-KB. TIP binds the Lck protein and is essential for immortalization of T cells. HSURs are RNA polymerase II transcripts which contain AUUUA repeats and compete for AU-Binding Factors (AUBF). They exclude RNAse and prevent RNA degradation. LANA upregulates B-catenin which is also an oncogene and displaces repressive transcription factors and histone deacetylase.
Immune Response:
Keratinocytes: While not usually considered an immune cell, keratinocytes can detet pathogens, including HSV through pattern recognition receptors (PRRs) such as TLRs. Keratinocytes are the first cells to be infected by HSV, which is initially detected by TLR2 binding of viral glycoproteins. TLR2 signalling induction results in the produciton of pro-inflammatory cytokines such as TNF, IL-1, IL-6 and antiviral cytokines such as Type I interferons. These cytokines can act on the surrounding keratinocytes and immune cells to reduce viral spread. See Cuninghham
DCs: are a crucial part of the immune response to HSV. LCs are one of the first immune cells to encounter HSV. They are infected by HSV and migrate down into the dermis wehre they cluster with dermal DCs, the cells that then present HSV antigens to T cells. See Cuninghham
B cells: immigrate to sites of infeciton by HSV stimulated by CCL19, CCL21 and CXCL12 and CXCL13 through CCR7 and CXCR4 receptors respectively.