Ch. 19 Human Herpes Viruses

HERPESVIRUSES Herpes Simples Virus type 1 (HSV-1) Herpes Simples Virus type 1 (HSV-1) Herpes Simples Virus type 2 (HSV-2) Herpes Simples Virus type 2 (HSV-2) Varicella-Zoster Virus (VZV) Varicella-Zoster Virus (VZV) Cytomegalovirus (CMV) Cytomegalovirus (CMV) Epstein-Barr Virus (EBV) Epstein-Barr Virus (EBV) Human Herpesvirus 8 (HHV-8) Human Herpesvirus 8 (HHV-8) or Kaposi‘s Sarcoma-Associated herpesvirus) or Kaposi‘s Sarcoma-Associated herpesvirus) (KSHV) (KSHV)

HERPESVIRUSES All are icosahedral enveloped viruses All are icosahedral enveloped viruses ds linear DNA genome ds linear DNA genome Large viruses ( nm) Large viruses ( nm) Replicate in the nucleus (budding) Replicate in the nucleus (budding) Cause latent infections Cause latent infections HSV-1&2 and VZV cause vesicular rash HSV-1&2 and VZV cause vesicular rash

HERPESVIRUSES According to type of infected tissues and latency, it can be subdivided to: According to type of infected tissues and latency, it can be subdivided to: * α-herpesviruses (HSV-1 & 2, VZV) * α-herpesviruses (HSV-1 & 2, VZV),infect epithelial cells (latency in neurons),infect epithelial cells (latency in neurons) * β- herpesviruses (CMV, HHV-6), * β- herpesviruses (CMV, HHV-6), infect variety of tissues infect variety of tissues * γ- herpesviruses (EBV, HHV-8), infect * γ- herpesviruses (EBV, HHV-8), infect lymphoid cells lymphoid cells

1- Herpes Simplex Viruses (HSV) HSV-1 causes acute gingivostomatitis, cold sores, keratoconjunctivitis & encephalitis HSV-1 causes acute gingivostomatitis, cold sores, keratoconjunctivitis & encephalitis HSV-2 causes genital herpes, neonatal herpes & aseptic meningitis HSV-2 causes genital herpes, neonatal herpes & aseptic meningitis Both types can be distinguished by RE & monoclonal Abs Both types can be distinguished by RE & monoclonal Abs Human is the natural host Human is the natural host

Replication The virus attaches to its receptor The virus attaches to its receptor After entry, uncoated occur and the genome DNA enters the nucleus After entry, uncoated occur and the genome DNA enters the nucleus DNA changes from linear to circular DNA changes from linear to circular Early mRNA transcribed by host RNA polymerase Early mRNA transcribed by host RNA polymerase Early nonstructural proteins translated Early nonstructural proteins translated Viral DNA polymerase replicates the genome DNA Viral DNA polymerase replicates the genome DNA

Replication Cont. Late protein synthesis bgins Late protein synthesis bgins Transported to the nucleus Transported to the nucleus Assembly occurs Assembly occurs Envelope obtained from the nuclear membrane Envelope obtained from the nuclear membrane Leave cells by lysis or via tubules (cell-cell ) Leave cells by lysis or via tubules (cell-cell ) Latent infection (only few genes transcribed) Latent infection (only few genes transcribed)

Transmission & Epidemiology HSV-1: saliva HSV-1: saliva HSV-2: sexual contact HSV-2: sexual contact Asymptomatic infections plays important role in transmission Asymptomatic infections plays important role in transmission Primary infections mostly by HSV-1 in childhood Primary infections mostly by HSV-1 in childhood

Pathogenesis & Immunity Initiates infection in skin Initiates infection in skin Migrates and latent in the sensory ganglion cells Migrates and latent in the sensory ganglion cells Reactivation occurs by many reasons Reactivation occurs by many reasons Multinucleated giant cells (vesicle) Multinucleated giant cells (vesicle) Immunity is incomplete Immunity is incomplete Cell-mediated immunity is important Cell-mediated immunity is important

Clinical Findings Gingivostomatitis: primary infection is more severe but may be asymptimatic Gingivostomatitis: primary infection is more severe but may be asymptimatic Herpes labialis: Herpes labialis: crops of vesicles crops of vesicles

Clinical Findings cont. Keratoconjunctivitis: corneal ulcers & lesions Keratoconjunctivitis: corneal ulcers & lesions Encephalitis: has a high mortality rate Encephalitis: has a high mortality rate Herpetic whitlow: pustule lesion on the skin Herpetic whitlow: pustule lesion on the skin

Keratoconjunctivitis

Clinical Findings cont. Genital herpes: painful vesicular lesions Genital herpes: painful vesicular lesions Neonatal herpes: may be mild or severe, mothers with primary infection are more infective than with recurrent infections Neonatal herpes: may be mild or severe, mothers with primary infection are more infective than with recurrent infections

DISEASE

Lab. Diagnosis Tissue culture (CPE in 1-3 days) Tissue culture (CPE in 1-3 days) DFA or ELISA DFA or ELISA Rapid diagnosis by Tzanck smear (giemsa) Rapid diagnosis by Tzanck smear (giemsa) PCR assay (specially in encephalitis) PCR assay (specially in encephalitis) Serologic assay: TORCH Serologic assay: TORCH

Treatment Acyclovir Acyclovir For eye infections: trifluridine (viroptic) are used topicallly. For eye infections: trifluridine (viroptic) are used topicallly. Valacyclovir (valtrex) & famciclovir (famvir) are used for genital herpes Valacyclovir (valtrex) & famciclovir (famvir) are used for genital herpes Penciclovir: recurrent orolabial HSV-1 Penciclovir: recurrent orolabial HSV-1

2- Varicella-Zoster Virus (VZV) Primary disease: varicella, recurrent form is chingles Primary disease: varicella, recurrent form is chingles Only one serotype Only one serotype Humans are the natural hosts Humans are the natural hosts Replication cycle is like HSV Replication cycle is like HSV Transmission electron micrograph of varicella- zoster virions from vesicle fluid of patient with chickenpox

Transmission & Epidemiology Respiratory droplets Respiratory droplets Direct contact to the lesions Direct contact to the lesions > 90% in USA children are seropositive > 90% in USA children are seropositive Highly contagious disease (very important in hospitals in case of immunocompromised patients) Highly contagious disease (very important in hospitals in case of immunocompromised patients)

Pathogenesis & Immunity 1st infect the mucosa of URT, then spread via blood to the skin 1st infect the mucosa of URT, then spread via blood to the skin Causing vesicular rash (M.Ncl. Giant cell) Causing vesicular rash (M.Ncl. Giant cell) Latency occurs in dorsal root ganglia Latency occurs in dorsal root ganglia Reactivation causes vesicular skin lesions & nerve pain of zoster Reactivation causes vesicular skin lesions & nerve pain of zoster Immunity is lifelong (varicella), (Zoster??) Immunity is lifelong (varicella), (Zoster??)

Clinical Findings Varicella: IP (14-21 days), prodromal symptoms are fever & malaise. A papulovesicular rash appears, develop to vesicles, pustules and then crusts Varicella: IP (14-21 days), prodromal symptoms are fever & malaise. A papulovesicular rash appears, develop to vesicles, pustules and then crusts More sever in adults More sever in adults Reye‘s syndrome (encephalopathy & liver degeneration) Reye‘s syndrome (encephalopathy & liver degeneration)

Clinical Findings cont. Zoster (Shingles ): Zoster (Shingles ): a painful vesicles along the course of a sensory nerve of the head or trunk a painful vesicles along the course of a sensory nerve of the head or trunk

Lab. Diagnosis Clinically Clinically Tzanck smear Tzanck smear Cell culture Cell culture

Treatment No antiviral is needed in case of immunocompetent children No antiviral is needed in case of immunocompetent children Acyclovir for adults Acyclovir for adults Also for immunocompromised Also for immunocompromised Foscarnet for acyclovir-VZV resistant strains Foscarnet for acyclovir-VZV resistant strains

Prevention Vaccination by live attenuated VZV (Varivax) Vaccination by live attenuated VZV (Varivax) One dose for children 1-12y. One dose for children 1-12y. Teenagers need 2 doses Teenagers need 2 doses Prophylaxis using acyclovir or VZIG Prophylaxis using acyclovir or VZIG

3- Cytomegalovirus (CMV) The most common cause of congenital abnormalities in USA The most common cause of congenital abnormalities in USA It causes also pneumonia in immunocomp. It causes also pneumonia in immunocomp. Only one serotype Only one serotype Giant cells are formed and human is the natural host Giant cells are formed and human is the natural host

Transmission & Epidemiology Across the placenta Across the placenta During birth During birth Breast milk feeding Breast milk feeding Via saliva (children) Via saliva (children) or sexually or sexually also via blood transfusion or organ transpl. also via blood transfusion or organ transpl. > 80% adults are seropositive > 80% adults are seropositive

Pathogenesis & Immunity Fetus infection cause cytomegalic inclusion disease in many organs Fetus infection cause cytomegalic inclusion disease in many organs Congenital abnormalities occure (1st trimester) Congenital abnormalities occure (1st trimester) Asymptomatic infections (adults & children) Asymptomatic infections (adults & children) Latency occurs in leukocytes & kidneys Latency occurs in leukocytes & kidneys It causes inhibiting for T cells It causes inhibiting for T cells Host defenses include both humoral & cell- mediated immunity Host defenses include both humoral & cell- mediated immunity

Clinical Findings ~ 20% of infants show microcephaly, deafness, jaundice & purpura ~ 20% of infants show microcephaly, deafness, jaundice & purpura Hepatosplenomegaly Hepatosplenomegaly In adults, heterophil-negative In adults, heterophil-negative mononucleosis mononucleosis Systemic infections?? Systemic infections?? H&E stain of lung section showing nuclear inclusions Owl‘s-eye shape

Lab. Diagnosis Cell cultures (shell vials) Cell cultures (shell vials) Immunofluorescent Abs Immunofluorescent Abs PCR PCR 4-fold increase in Abs 4-fold increase in Abs H&E stain of CMV-infected cells in lung of AIDS patient Specimen of human embryonic lung reveals the presence of cytomegalovirus using immunofluorescent technique

Treatment Ganciclovir (Cytovene) Ganciclovir (Cytovene) Valganciclovir (orally) Valganciclovir (orally) Foscarnet (Foscavir) Foscarnet (Foscavir) Largely resistant to acyclovir Largely resistant to acyclovir Fomivirsen (Vitravene), anti-sense DNA approved for treatment of CMV retinitis Fomivirsen (Vitravene), anti-sense DNA approved for treatment of CMV retinitis

4- Epstein- Barr Virus Infectious mononucleosis Infectious mononucleosis Burkitt's lymphoma Burkitt's lymphoma Nasal pharyngeal carcinoma Nasal pharyngeal carcinoma B-cell lymphomas B-cell lymphomas Hairy leukoplakia Hairy leukoplakia

Transmission & Epidemiology Exchange of saliva Exchange of saliva Blood transmission is very rare Blood transmission is very rare One of the most common infection One of the most common infection > 90% of adults in USA are seropositive > 90% of adults in USA are seropositive

Pathogenesis & Immunity Primary infection occurs in oropharynx Primary infection occurs in oropharynx Then, infect the B-lymphocytes Then, infect the B-lymphocytes EBV remains latent within B-lymphocytes EBV remains latent within B-lymphocytes 1st immune response is IgM (VCA) 1st immune response is IgM (VCA) Followed by lifelong IgG (VCA) Followed by lifelong IgG (VCA) Nonspecific heterophil antibodies are found Nonspecific heterophil antibodies are found These Abs are also seen in Hepatitis B and serum sickness These Abs are also seen in Hepatitis B and serum sickness

Clinical Findings The primary infection is often asymptomatic The primary infection is often asymptomatic Symptoms include fever, sore throat, lymphadenopathy & splenomegaly Symptoms include fever, sore throat, lymphadenopathy & splenomegaly 2 other diseases: 2 other diseases: 1- severe form of I.M. In X-linked lymphoproliferative syndrome 1- severe form of I.M. In X-linked lymphoproliferative syndrome (mortality rate is high „75%“ by age 10) (mortality rate is high „75%“ by age 10) 2- hairy leukoplakia in AIDS patients 2- hairy leukoplakia in AIDS patients

Tongue and palate of patient with infectious mononucleosis Oral hairy leukoplakia of tongue in AIDS Burkitt's Lymphoma Conjunctival hemorrhage due to infectious mononucleosis

Laboratory diagnosis Hematologic approach: absolute lymphocytosis (atypical lymphs) Hematologic approach: absolute lymphocytosis (atypical lymphs) Immunologic approach: Immunologic approach: a) Heterophil antibody test (Monospot test) a) Heterophil antibody test (Monospot test) b) EBV-specific Abs tests: b) EBV-specific Abs tests: - IgM VCA - IgM VCA - IgG VCA - IgG VCA

Treatment & Prevention For mild infections, no need for aniviral drugs For mild infections, no need for aniviral drugs Acyclovir has little activity against EBV Acyclovir has little activity against EBV no vaccine no vaccine

5- Human Herpesvirus 8 (HHV-8) HHV-8 was reported in 1994 HHV-8 was reported in 1994 formerly known as Kaposi's sarcoma associated herpes virus formerly known as Kaposi's sarcoma associated herpes virus The most common cancer in AIDS patients The most common cancer in AIDS patients It resembles lymphotropic herpesviruses more than neutropic one It resembles lymphotropic herpesviruses more than neutropic one In general population, the prevalence of HHV-8 in USA is ~ 3% but in east Africa is ~ 50% In general population, the prevalence of HHV-8 in USA is ~ 3% but in east Africa is ~ 50%

It causes malignant transformation (inactivation of RB by nuclear antigen protein) It causes malignant transformation (inactivation of RB by nuclear antigen protein) Transmission occurs sexually & also by organs trasplantation Transmission occurs sexually & also by organs trasplantation Lab Dx of KS is made by biopsy Lab Dx of KS is made by biopsy Virus is not grown in culture Virus is not grown in culture Treated by surgical excision, radiation, α- interferon or vinblastine Treated by surgical excision, radiation, α- interferon or vinblastine But there is no specific antiviral drug or vaccine But there is no specific antiviral drug or vaccine

6- Human herpes virus 6 This virus is found worldwide This virus is found worldwide Is found in the saliva of the majority of adults (>90%) Is found in the saliva of the majority of adults (>90%) it replicates in B and T lymphocytes with inclusions in both cytoplasm and nucleus it replicates in B and T lymphocytes with inclusions in both cytoplasm and nucleus infection is life-long, and the virus can reactivate in immune-suppression. infection is life-long, and the virus can reactivate in immune-suppression. It causes roseola infantum ( a common disease of young children ) It causes roseola infantum ( a common disease of young children ) In adults, primary infection is associated with a mononucleosis In adults, primary infection is associated with a mononucleosis