H.K. (4.2) - Enveloped DNA Viruses (Herpesviridae, Poxviridae) PDF

Enveloped DNA Viruses (Herpesviridae, Poxviridae) Part 2 Helen Kalandarishvili UG 2023  Hepresviridae  Largest family of DNA viruses that affects humans  HERPES  Icosahedral core surrounded by a lipo...

Enveloped DNA Viruses (Herpesviridae, Poxviridae) Part 2 Helen Kalandarishvili UG 2023  Hepresviridae  Largest family of DNA viruses that affects humans  HERPES  Icosahedral core surrounded by a lipoprotein envelope VIRUSES  The genome is linear double-stranded DNA.  They are large 150–200 nm in diameter All herpes viruses  The virions possess a tegument located between the are structurally similar nucleocapsid and the envelope.  This structure contains regulatory proteins, such as transcription and translation factors, which play a role in viral Replication replication. in the nucleus, form intranuclear inclusions Herpesviruses cause latent infections  They are only viruses that the acute disease is followed by an obtain their envelope by asymptomatic period during which the virus budding from the nuclear remains in a quiescent (latent) state. membrane.  HERPES VIRUSES Three subfamilies based on the type of cell most often infected and the site of latency: Alpha herpesviruses  Beta Herpes Viruses  Gamma herpesviruses  infect epithelial cells infect and become latent in primarily and cause latent infect and become latent a variety of tissues. primarily in lymphoid cells. infection in neurons.  Herpes simplex viruses  Cytomegalovirus CMV HSV-1  Human herpesvirus 4  Human herpesvirus 6  Herpes simplex viruses (Epstein-Barr virus EBV) HHV-6 HSV-2  Human herpesvirus 8  Human herpesvirus 7  Varicella – Zoster virus HHV-8 HHV-7 VZV  HERPES SIMPLEX VIRUS  They exhibit a broad host range Herpes simplex viruses are widespread in the humans  Replicate in many types of cells  They grow rapidly and are highly cytolytic The herpes simplex viruses are responsible for  Gingivostomatitis  Keratoconjunctivitis Recurrences are common  Encephalitis  Genital disease  Infections of newborns  Latent infections in nerve cells  HERPES SIMPLEX VIRUS REPLICATION HSV binds to cell Transported surface receptors  Enters the cell through the heparan sulfate and by fusion cytoplasm to a The linear genome nectin. nuclear pore DNA now becomes  Circular. Virus particles are then transported by vesicular movement to the surface of After uncoating are the cell. Viral DNA replication expressed immediate early begins with viral DNA and early genes (enzymes Maturation polymerase, and late or DNA binding proteins): - occurs by transcripts are produced “alpha” proteins - budding that give rise to “gamma” “beta” proteins. proteins - structural Newly synthesized viral components. DNA is packaged into preformed empty Viral DNA is transcribed by nucleocapsids in the cell cellular RNA polymerase nucleus. II HERPES SIMPLEX VIRUS  HERPES SIMPLEX VIRUS PRIMARY INFECTION  Primary HSV infections are usually mild; most are asymptomatic  HSV is transmitted by contact of a susceptible person with an individual excreting virus.  The virus must encounter mucosal surfaces or broken skin in order for an infection to be initiated (unbroken skin is resistant).  Viral replication occurs first at the site of infection.  Virus then invades local nerve endings and is transported by retrograde axonal flow to dorsal root ganglia, where, after further replication, latency is established.  Viral persistence in latently infected ganglia lasts for the lifetime of the host. HERPES SIMPLEX VIRUS LATENT INFECTION  During latency, viral DNA is not integrated into cellular DNA  The virus can be reactivated from the latent state by - sunlight, hormonal changes, trauma, stress, and fever  Virus migrates down the neuron and replicates in the skin, causing lesions.  Multinucleated giant cells are typically found at the base of herpesvirus lesions  Immunity is type-specific, but some cross-protection exists.  However, immunity is incomplete, and both reinfection and reactivation occur in the presence of circulating IgG.  Cell-mediated immunity is important in limiting herpesviruses, because its suppression often results in reactivation, spread, and severe disease.  HERPES SIMPLEX VIRUS There are two distinct herpes simplex viruses: HSV-1 HSV-2 Is spread by respiratory Transmitted sexually or from droplets or by direct contact a maternal genital infection with infected saliva to a newborn  Acute gingivostomatitis causes several diseases, both primary and recurrent Herpes Labialis (cold sore)  Herpes Genitalis  Ocular Herpes  Neonatal Encephalitis  Encephalitis  Aseptic Meningitis  Other forms of cutaneous herpes  Other forms of neonatal herpes  HERPES SIMPLEX VIRUS - 1 ACUTE GINGIVOSTOMATITIS  Acute gingivostomatitis is the commonest manifestation of primary herpetic infection.  The patient experiences pain and bleeding of the gums.  1 - 8 mm ulcers with necrotic bases are present.  Neck glands are commonly enlarged accompanied by fever.  Usually a self limiting disease which lasts around 13 days. HERPES SIMPLEX VIRUS - 1 HERPES LABIALIS (cold sore)  Herpes labialis (cold sore) is a recurrence of oral HSV  characterized by crops of vesicles, usually at the mucocutaneous junction of the lips or nose  A prodrome of tingling, warmth or itching at the site usually heralds the recurrence.  About 12 hours later, red­ness appears followed by papules and then vesicles.  Following primary infection 45% of orally infected individuals are experience reactivation.  The actual frequency of recurrences varies widely between individuals.  HERPES SIMPLEX VIRUS - 1 KERATOCONJUNCTIVIT IS  HSV-1 infections may occur in the eye  Recurrent lesions of the eye are common and appear as dendritic keratitis or corneal ulcers or as vesicles on the eyelids  Recurrent keratitis can lead to scarring and blindness HERPES SIMPLEX VIRUS - 1 ENCEPHALITIS  The disease carries a high mortality rate, and those who survive often have residual neurologic defects.  About half of patients with HSV encephalitis appear to have primary infections, and the rest appear to have recurrent infection.  Neonatal encephalitis – there is global involvement and the brain is almost liquefied - The mortality rate approaches 100%.  Focal disease – the temporal lobe is most commonly affected - The mortality rate is high (70%) without treatment.  This form of the disease appears in children and adults.  It is possible that many of these cases arise from reactivation of virus.  Fever, headache, vomiting, seizures, altered mental status are typical clinical features.  The onset may be acute or protracted over several days.  MRI often reveals the lesion. Examination of the spinal fluid typically shows a moderate increase of lymphocytes, a moderate elevation in the amount of protein,  HERPES SIMPLEX VIRUS There are two distinct herpes simplex viruses: HSV-1 HSV-2 Is spread by respiratory Transmitted sexually or from droplets or by direct contact a maternal genital infection with infected saliva to a newborn  Acute gingivostomatitis causes several diseases, both primary and recurrent Herpes Labialis (cold sore)  Herpes Genitalis  Ocular Herpes  Neonatal Encephalitis  Encephalitis  Aseptic Meningitis  Other forms of cutaneous herpes  Other forms of neonatal herpes  HERPES SIMPLEX VIRUS - 2 GENITAL HERPES  Infections can be severe, with characterized lesions of the penis of the male or of the cervix, vulva, vagina, and perineum of the female.  The lesions are very painful and may be associated with fever, malaise, dysuria  The lesions are prone to secondary bacterial infection  Viral excretion persists for about 3 weeks  Recurrences of genital herpetic infections are common  Some recurrences are asymptomatic.  Whether a recurrence is symptomatic or asymptomatic, a person shedding virus can transmit the infection to  HERPES SIMPLEX NEONATAL  VIRUS - 2 HERPES HSV infection of the newborn may be acquired in utero, during birth, or after birth.  The mother is the most common source of infection in all cases.  Neonatal herpes infections are almost always symptomatic. ASEPTIC MENINGITIS  The overall mortality rate of untreated disease is 50%.  Babies with neonatal herpes exhibit three categories of Usually a mild, self-limited disease: disease with few  Lesions localized to the skin, eye, and mouth sequelae.  Encephalitis with or without localized skin involvement  Disseminated disease involving multiple organs, including the central nervous system.  Many survivors of severe infections are left with HERPES SIMPLEX VIRUS – 1-2 SKIN INFECTIONS  Cutaneous HSV infections are uncommon in healthy persons  Localized lesions caused by HSV-1 or HSV-2 may occur in abrasions that become contaminated with the virus (traumatic herpes).  Cutaneous infections are often severe and life threatening when they occur in individuals with disorders of the skin, such as eczema or burns, that permit extensive local viral replication and spread. HERPES SIMPLEX VIRUS – 1-2 ERYTHEMA MULTIFORME  The rash appears as a central red area surrounded by a ring of normal skin outside of which is a red ring (“target” or “bull’s eye” lesion).  The lesions are typically macular or papular and occur symmetrically on the trunk, hands, and feet.  Many drugs, especially sulfonamides among the antimicrobial drugs, commonly cause erythema multiforme.  Other causes are: Fungal and bacterial infections.  Erythema multiforme major, also known as Stevens- Johnson syndrome  characterized by fever, erosive oral lesions, and extensive desquamating skin lesions. HERPES SIMPLEX VIRUS DIAGNOSIS  HSV-1 and HSV-2 are among the easiest viruses to cultivate.  It usually takes only 1 - 5 days for a result to be available.  The typical cytopathic effect occurs in 1 to 3 days:  fluorescent antibody staining of the infected cells  ELISA  A rapid diagnosis from skin lesions  stained with Giemsa stain - presence of multinucleated giant cells  PCR - now used routinely for the diagnosis of herpes simplex encephalitis  Serology is used to document the recent infection. HERPES SIMPLEX VIRUS Drugs of choice for most situations  TREATMENT Acyclovir - Valacyclovir - Vidarabine Avoiding contact with the vesicular or PREVENTION ulcer.  No drug treatment of the primary infection prevents recurrences  Drugs have no effect on the latent state, but prophylactic, long- term administration of acyclovir, valacyclovir, can suppress clinical recurrences.  VARICELLA-ZOSTER VIRUS Varicella (chickenpox) is the primary disease; Zoster (shingles) is the recurrent form.  Varicella (chickenpox) is a mild, highly contagious disease of children  Characterized by a generalized vesicular eruption of the skin and mucous membranes  It is common in winter and spring than in summer  The disease may be severe in adults and in immunocompromised children  The virus is transmitted by respiratory droplets and by direct contact with the lesions.  The route of infection is the mucosa of the upper respiratory tract or the conjunctiva VARICELLA-ZOSTER VIRUS  VZV infects the mucosa of the upper respiratory tract, then spreads via the blood to the skin, where the typical vesicular rash occurs.  Multinucleated giant cells with intranuclear inclusions are seen in the base of the lesions.  The virus infects sensory neurons and is carried by retrograde axonal flow into the cells of the dorsal root ganglia, where the virus becomes latent.  VZV DNA is not integrated into cellular DNA  At times of reduced cell-mediated immunity or local trauma, the virus is activated and causes the vesicular skin lesions and nerve pain of zoster.  Immunity following varicella is lifelong  Zoster can occur despite this immunity to varicella. VARICELLA-ZOSTER VIRUS  Initial replication is in regional lymph nodes  Primary viremia spreads virus and leads to replication in liver and spleen  Secondary viremia involving infected mononuclear cells transports virus to the skin, where the typical rash develops  Subclinical varicella is unusual  The incubation period of typical disease is 10–21 days  Malaise, fever, rash - first on the trunk and then on the face, the limbs, and the buccal and pharyngeal mucosa in the mouth.  The rash lasts about 5 days, and most children develop several hundred skin lesions.  Complications are rare in normal children, and the mortality rate is very low.  Varicella is mild in children but more severe in adults. VARICELLA-ZOSTER VIRUS stages of the rash macules papules vesicles VARICELLA-ZOSTER following maternal VIRUS cases of chickenpox during pregnancy occur in rare cases and have been can be life-threatening described. Encephalitis Congenital varicella Neonatal varicella Varicella pneumonia the infection is contracted from rare in healthy children but is the mother just before or after the most common birth but without sufficient complication in neonates, immune response to modify the adults, and disease. immunocompromised  Virus is often widely patients. disseminated and may prove fatal. VARICELLA-ZOSTER Zoster VIRUS (shingles) Zoster (shingles) is a sporadic disease of adults or immunocompromised individuals Characterized by a rash limited in distribution to the skin innervated by a single sensory ganglion The lesions are similar to those of varicella. Zoster occurs sporadically without seasonal prevalence. Both diseases are caused by the same virus. Varicella is the acute disease that follows primary contact with the virus, whereas zoster is the response of the partially immune host to reactivation of varicella virus present in latent form in neurons in sensory ganglia. VARICELLA-ZOSTER VIRUS Zoster usually starts with severe pain in the area of skin or mucosa supplied by one or more groups of sensory nerves and ganglia. The most common complication of zoster in the elderly is postherpetic neuralgia—protracted pain that may continue for months Visceral disease, especially pneumonia, is responsible for deaths that occur in immunosuppressed patients with zoster (< 1% of patients). VARICELLA-ZOSTER VIRUS IMMUNITY  Previous infection with varicella is believed to confer lifelong immunity to varicella.  Antibodies induced by varicella vaccine persist for at least 20 years.  Zoster occurs in the presence of neutralizing antibody to varicella.  The development of varicella-zoster virus-specific cell-mediated immunity is important in recovery from both varicella and zoster. VARICELLA-ZOSTER VIRUS DIAGNOSIS  The clinical presentations of varicella or zoster are so characteristic that laboratory confirmation is rarely required.  Laboratory diagnosis is required only for atypical presentations, particularly in the immunocompromised.  Virus Isolation in cell culture - requires 2-3 weeks for a results.  Direct detection - electron microscopy may be used for vesicle fluids but cannot distinguish between HSV and VZV.  Multinucleated giant cells are seen in VZV as well as HSV lesions  Immunofluorescence on skin scrapings can distinguish between the two.  Serology - the presence of VZV IgG is indicative of past infection and immunity. The presence of IgM is indicative of recent primary infection. VARICELLA-ZOSTER VIRUS  Varicella requires no treatment TREATMENT  Neonates and immunocompromised patients with severe infections should be treated.  Acyclovir, Valacyclovir, Famciclovir, and Foscarnet  TWO live attenuated vaccine is available - Varivax and Zostavax PREVENTION  The varicella vaccine - children 1 and 12 years  The zoster vaccine - older than 60 years and who have had varicella.  Varicella infections can occur in vaccinated persons, but they are usually mild illnesses.  A shingles vaccine is a more potent version of the varicella vaccine.  Varicella-zoster immune globulin (VZIG), which contains a high CYTOMEGALOVIRUS  Cytomegalic inclusion disease is a generalized infection of infants  Inapparent infection is common during childhood and adolescence.  Severe cytomegalovirus infections are frequently found in adults who are immunosuppressed.  Cytomegalovirus is endemic in all parts of the world  Epidemics are unknown.  It is present throughout the year, with no seasonal variation seen in infection rates.  Humans are the only known host for cytomegalovirus.  It has a single serotype.  Giant cells are formed, hence the name cytomegalo. CYTOMEGALOVIRUS  The prevalence of infection varies with socioeconomic status, living conditions, and hygienic practices.  Transmission requires close person-to-person contact in several different ways:  Oral and respiratory spread  Transplacentally  by blood transfusion  by organ transplantation  by sexual contact.  Virus may be shed in urine, saliva, semen, breast milk, and cervical secretions and is carried in circulating white blood cells. CYTOMEGALOVIRUS  Incubation period 4- to 8-weeks  The virus causes a systemic infection  Cytomegalovirus infections are subclinical  It has been isolated from lung, liver, esophagus, colon, kidneys, monocytes, and T and B lymphocytes.  Like all herpesviruses, cytomegalovirus establishes lifelong latent infections.  Once infected, the person carries the virus for life which may be activated from time to time.  Reactivation or reinfection with CMV is usually asymptomatic except in immunocompromised patients  Salivary gland involvement is common and is probably chronic. CYTOMEGALOVIRUS CYTOMEGALOVIRUS PNEUMONIAE, CYTOMEGALOVIRUS RETINITIS, COLITIS, POSTNATAL INFECTION MONONUCLEOSIS ENCEPHALOPATHY usually asymptomatic. frequent complication in a mild disease, Individuals receiving However, in a minority of complications are rare. organ transplants, with cases, the syndrome of Common subclinical malignant tumors who infectious mononucleosis hepatitis, are receiving may develop which hepatosplenomegaly chemotherapy, with consists of  AIDS. fever, lymphadenopathy, and splenomegaly. CYTOMEGALOVIRUS CONGENITAL INFECTIONS  A high percentage of babies with this disease will exhibit developmental defects and mental retardation.  The virus can be transmitted in utero with both primary and reactivated maternal infections.  About one-third of pregnant women with primary infection transmit the virus.  Cytomegalovirus can also be acquired by the infant from exposure to virus in the mother’s genital tract during delivery and from maternal breast milk.  In these cases, the infants usually have received some maternal antibody, and the perinatally acquired cytomegalovirus infections tend to be subclinical. CYTOMEGALOVIRUS CYTOMEGALOVIRUS characterized by involvement of the central nervous system and the INCLUSION DISEASE of reticuloendothelial system. newborns Clinical features include:  intrauterine growth retardation,  jaundice,  hepatosplenomegaly,  thrombocytopenia,  microcephaly, and  retinitis Mortality rates are about 20%. CYTOMEGALOVIRUS DIAGNOSIS Serology Direct detection Virus Isolation Antibodies to cytomegalovirus Biopsy specimens may be occur in most human sera. conventional cell examined histologically culture is regarded as  The presence of CMV IgG for CMV inclusion antibody indicates past gold standard but bodies or for the infection. requires up to 4 weeks  The detection of IgM is presence of CMV for result. indicative of primary infection antigens. However, the  The presence of antibody in sensitivity may be low. breast milk does not prevent transmission of infection to  PCR breast-feeding infants. CYTOMEGALOVIRUS TREATMENT.  Ganciclovir  has been used successfully to treat cytomegalovirus infections in immunosuppressed patients.  Foscarnet  is recommended for treatment of cytomegalovirus retinitis.  Acyclovir and Valacyclovir  have shown some benefits in bone marrow and renal transplant patients.  Specific control measures are not available to prevent cytomegalovirus spread  Both live and recombinant cytomegalovirus vaccines are under development.  HUMAN HERPESVIRUS The T-lymphotropic human herpesvirus 6 recognized in 6 was first 1986. Infections occur in early childhood. This primary infection is associated with Roseola Infantum, characterized by high fever and skin rash. Most cases occur in infants between the ages of 4 months and two years. The mode of transmission is via oral secretions. Reactivation appears to be common in transplant patients and during pregnancy The virus grows well in CD4 T lymphocytes. Other cell types also support viral replication - B cells and cells of glial, fibroblastic, and megakaryocyte origin It is not known which cells in the body become latently infected. Serology is the mainstay of diagnosis  HUMAN HERPESVIRUS 7 A T-lymphotropic human herpesvirus 7 - first isolated in 1990 from activated T cells recovered from peripheral blood lymphocytes of a healthy individual. HHV 7 is immunologically distinct from HHV 6 Persistent infections are established in salivary glands, and the virus can be isolated from saliva of most individuals. By the time of adulthood, 90-99% of the population had been infected by both viruses. Like other herpesviruses, HHV-6 and HHV-7 remains latent in the body after primary infection and reactivates from time to time.  HUMAN HERPESVIRUS 4 – EPSTEIN-BARR VIRUS  Epstein-Barr virus (EBV) is common in all parts of the world.  More than 90% of children are infected by age 6.  In early childhood usually occur without any recognizable disease. The major target cell for EBV is the B EBV is causative agent of acute infectious: lymphocyte. Mononucleosis - Burkitt’s lymphoma - Nasopharyngeal carcinoma - Hodgkin’s disease - and other lymphoproliferative disorders in immunodeficient individuals EBV is associated with several very different diseases where it may act directly or one of several cofactors HUMAN HERPESVIRUS 4 – EPSTEIN-BARR VIRUS  Transmitted by infected saliva and initiates infection in the oropharynx.  Viral replication occurs in epithelial cells (or surface B lymphocytes) of the pharynx and salivary glands.  Many people shed low levels of virus for weeks to months after infection.  Infected B cells spread the infection from the oropharynx throughout the body.  In normal individuals, most virus-infected cells are eliminated, but small numbers of latently infected lymphocytes persist for the lifetime of the host. HUMAN HERPESVIRUS 4 – EPSTEIN-BARR VIRUS  Primary infections in children are usually subclinical, but if they occur in young adults acute infectious mononucleosis (IM) often develops.  IM is usually a self-limited and lasts 2–4 weeks.  Incubation period of 30–50 days  Headache, fever, malaise, fatigue, and sore throat.  Enlarged lymph nodes and spleen. In some patients jaundice may be seen which is due to hepatitis. HUMAN HERPESVIRUS 4 – EPSTEIN-BARR VIRUS  Increase in the number of circulating white blood cells, with a predominance of lymphocytes.  Low-grade fever and malaise may persist for weeks to months after acute illness.  Complications are rare in normal hosts. HUMAN HERPESVIRUS 4 – EPSTEIN- BARR VIRUS DIAGNOSIS  IM is usually made by the heterophil antibody test and/or detection of EBV IgM.  There is no specific treatment. HUMAN HERPESVIRUS 4 – EPSTEIN- BARR VIRUS BURKITT’S LYMPHOMA  Occurs endemically in parts of Africa  Most African tumors (> 90%) contain EBV DNA and express EBNA1 antigen.  It usually occurs in children aged 3-14 years.  It is restricted to areas with malaria. Therefore it appears that malaria infection is a cofactor. HUMAN HERPESVIRUS 4 – EPSTEIN- BARR VIRUS  NASOPHARYNGEAL CARCINOMA  this cancer of epithelial cells of the nasopharynx is common in males of Chinese origin  LYMPHOPROLIFERATIVE DISEASES  Immunodeficient patients are susceptible to EBV induced lymphoproliferative diseases that may be fatal.  From 1% to 10% of transplant patients develop an EBV associated lymphoproliferative disorder, often when experiencing a primary infection.  There is no EBV vaccine available. HUMAN HERPESVIRUS 8  Human herpesvirus 8 also called Kaposi’s sarcoma (KSHV), was first detected in 1994.  KSHV is not as ubiquitous as other herpesvirus.  It appears to be sexually transmitted.  Infections are common in Africa (>50%), with infections acquired early in life by nonsexual routes, possibly through contact with oral secretions. HUMAN HERPESVIRUS 8  The virus can be transmitted through organ transplants and places the recipients at risk of KSHV-related diseases.  HHV-8 infects lymphocytes and epithelial/endothelial cells.  EBV and HHV-8 have been found to be associated with oral lesions and neoplasms in HIV- infected patients. PCR and Serologic DIAGNOSIS assays Foscarnet, TREATMENT. Ganciclovir, and Cidofovir FIN Lecture N4.2!