Lymphotropic Herpesviruses Flashcards
Lytic:
Latent:
Lytic: virus production and cell lysis
Latent: Viral genome silent in cells
Replication and Latency
Cytomegalovirus:
Epstein-Barr virus and Kaposi’s sarcoma virus:
Roseolovirus:
Cytomegalovirus: Macrophage
Epstein-Barr virus and Kaposi’s sarcoma virus: Plasma cell
Roseolovirus: T-lymphocyte
Cytomegalovirus
- Rate of seropositivity associated with _______ _____ and ____
- Infected cells identified by:
- Socio-economic condition; age
- Owl eye; inclusion body
Cytomegalovirus disease
- Asymptomatic in healthy adults
- Leading cause of congenital birth defects
- Symptomatic upon immunosuppression
- Long term persistent infection associations
- atherosclerosis
- Immunosenescence
- Neuroblastoma
TORCH
Congenital birth defects: TOxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex
Basic characteristics of CMV
- 230 kbp double stranded DNA genome
- Expresses >750 different proteins
- Encodes its own DNA replication machinery
- Icosahedral nucleocapsid
- Tegument proteins and RNA
- Envelope with glycoproteins
CMV lytic replication cycle
- Binding/penetration
- Entry
- Transcription
- DNA replication (24-48 hours)
- Encapsidation (48-72 hours)
- Envelopment/Release (72-96 hours)
Stages of gene expression
Immediate, early, late
What is the assembly compartment?
Proteins released from the nucleus into a compartment in the cytoplasm where virion assembly occurs
Cytomegalovirus Transmission
- Direct contact with virus-containing secretions
- bodily liquids
- Inoculation onto a mucosal site
- Other routes
- blood transfusion
- organ transplants
- transplacental transmission
- Shedding with or without symptoms
Transmission most often occurs at _________
daycares
CMV dissemination
- Cell associated
- Slow replication cycle
- Lytic replication
- epithelial, dendritic, fibroblasts, smooth muscle…
- Latent infection
- CD34+ hematopoietic progenitor cells, monocytes
Frequency of CMV reactivation
1 in 10,000 of infected monocytes
Immune responses to CMV
Innate response:
Humoral response:
Cell-mediated immune response:
Innate response: Macrophage, interferon and NK cells control but are insufficient to clear
Humoral response: Does not clear, but may limit reinfection or reactivation
Cell-mediated immune response: Important cytotoxic T cells kill CMV infected cells up to 10% of all CD* T cells in the body may be directed against CMV
Common CMV viral antigens
gB, gH, pp65, pUL128-31
CMV symptoms in healthy adults and children
- Usually mild disease but often unapparent
- Fever, fatigue, sore throat, headache
- Liver function abnormalities
- Lymphocytosis
- Lymphadenopathy
- Mononucleosis
Diagnosis of CMV
- Serology
- Owl’s eye cells in urine or other tissues
- Culture virus from clinical material and detect with immunofluorescence
- Detection of viral DNA using PCR/NAT
Serology of CMV
- IgM testing is highly variable
- IgG indicates recent or distant past infection
- Serial testing of IgG negative to positive can define positive infection
- IgG avidity increases with time and can distinguish between recent and past infection
Treatment of CMV infection
- Ganciclovir - inhibits viral DNA polymerase
- Foscarnet - Inhibits the pyrophosphate binding site on viral DNA polymerase
- Cidofovir - Inhibit viral DNA polymerase
- CMV does NOT encode thymidine kinase so Acyclovir is less effective
Congenital CMV
- Only 14% of women have heard of CMV
- Perinatal infections
- infection at birth from cervical/vaginal secretions
- Transmission via mother’s milk
- Usually no clinical signs
Symptoms of infection
At birth:
Permanent symptoms:
At birth:
- Petechial lesions
- Small size
- Hepatosplenomegaly
- Jaundice
Permanent symptoms:
- Hearing loss
- Vision loss
- Mild to severe mental retardation
Diagnosis of Congenital CMV infection
- Screening pregnant women for CMV remains controversial
- Detection of virus in amniotic fluid is a definitive test
- Newborns who are symptomatic are candidates for ganciclovir treatment
CMV infection in immunosuppressed
- Life threatening
- Transplant patients
- HIV patients (Retinitis)
- Monitored by PCR/NAT or IgG and managed with antivirals
ß-Herpes virus: HHV-6B
Disease in children:
Replication
Detection:
Disease in children:
- 90% of children > 2 years old are seropositive
- High fever
- Rash occurs in 10%
Replication: Replicates in CD4+ T cells
Detection: Using PCR/NAT or serology
Epstein-Barr Virus (HHV4)
Seropositivity:
Disease:
Seropositivity: >95% by early 20s worldwide
- Asymptomatic infection
Disease:
- Infectious mononucleosis
- Post Transplant Lymphoproliferative Disorder (PTLD)
- Lymphomas (B, T and NK-cell)
Basic characteristics of EBV
- 172 kbp dsDNA genome
- Nucleocapsid, tegument, and envelop with glycoproteins
- Encodes about 70 proteins including DNA replication machinery
- Immediate, early , and late gene expression
Possible outcomes of EBV infection
- Replicate in b cells or epithelial cells
- Latent infection in memory B cells
- Stimulate and immortalize B cells
EBV lytic replication cycle
- Transmission by saliva and blood
- Limited to epithelium of pharynx and B cells due to restricted cellular receptor expression
- Reactivation of latently-infected activated B cells
EBV
Latency type I/II:
Latency III:
Latency type I/II:
- Viral antigens in memory B cells
- EBNA1 (Latency I and II)
- LMP1 and LMP2A (Latency II)
- RNA EBER 1&2
- Can lead to Burkitt’s, Hodgin lymphomas, nasopharyngeal carcinoma
Latency III:
- Viral antigens made in proliferating B cells
- EBNA 1, 2, 3A, 3B, 3C, LP
- LMP 1, 2A, 2B
- RNA EBER1&2
- Infectious mononucleosis, PTLD
Immune Response to EBV
Humoral Response:
Cell Mediated:
Disease:
Humoral Response:
- Neutralizing antibody - no effect on virus shed
Cell Mediated:
- CD8+ T lymphocytes and NK clls - lysis of EBV infected cells
- Loss of T cell function results in B cell proliferative disease
- Mononucleosis from rapid proliferation of atypical T cells (Downey cells)
Disease: Overactive immune response
EBV mediated infectious mononucleosis
Epidemiology:
- Usually age puberty - 25 years
- Primarily exposure to EBV
- 30-40% develop disease/symptoms
- Transmission by saliva
- 5-20% of B cells infected with EBV in first week
Post Transplant Lymphoproliferative Disease (PTLD)
- Immunosupressie therapy activated infection
- Incidence 1-33% transplants depending on organ
- Arises in donor B cells or reactivation in recipient
- Prognosis is often poor 40-70% mortality
Diagnosis of EBV
- Serology - assess antibody status against EBV antigens
- EBV mononucleosis - test for heterophile antibodies by agglutination of animal red blood cells
- Paul Bunnell test - sheep rbc
- Monospot test - horse rbc
- PTLD - fluorescent in situe hybridization; PCR
EBV-Associated Lymphoma
- Burkitts lymphoma
- Nasopharyngeal epithelial carcinoma
- B cell lymphomas
- Hodgkin and non-Hodgkin lymphomas
- Immunosuppressed patients and transplant patients
Kaposi’s Sarcoma Herpesvirus (HHV8)
- 165 kbp dsDNA genome
- 0-5% prevalent in North America and >50% in parts of Africa
- Seropositiveity varies with geographic area and correlates with incidence of KS
