Herpes Flashcards
Herpes Latency Key Points
- Latency produces a chronic infection
*latently infected cells are not recognized as being infected by CD8+ T cells, thus they are not cleared
*virus is not actively replicating, thus there is no available target for antivirals to act upon
*herpes genome maintained as circular, extra-chromosomal DNA
- Limited transcription generates LATs (latency-assoc. transcripts)
*LATs do not encode a viral protein
*encode a regulatory microRNA (miRNA)
*miRNAs inhibit expression of viral genes
- Some heresviruses express a few viral proteins to help maintain latency
Herpes Reactivation Key Points
- Reactivation
*may or may not result in clincal disease, however, infected individual is infectious and can transmit virus
*infection is endogenous and does not require re-exposure to the virus
*may be frequent in immunocompromised hosts
*recurrent infections are less severe, more localized and cleared more quickly b/c of immunological memory
Herpes Productive Infection Key points
- Viral gene expression and replication of the genome occurs in stages:
*immediate-early (alpha) genes
*early (beta) genes (genome replication)
*late (gamma) genes
Cell types infected by herpesviruses in vivo graph
Herpes clinical manifestation of infection chart
Herpes virus attachment
- Alpha: HSV-1, HSV-2, VZV
*Initial attachment via heparin sulfate (glycosaminoglycan found on most cells)
*Tighter attachment via a variety of cell surface receptors, collectively called herpesvirus entry mediators (HVEM)
- EBV (gamma virus)
*receptor for C3d component of complement (called CD211 or CR2); receptor present on B-cells
Herpes virus entry and uncoating
- Viral/cell fusion at the plasma membrane or receptore mediated endocytosis
- Capsid and some tegument proteins migrate to the nucleus, other proteins remain in the cytoplasm
*CMV tegument contains mRNA to help initiate viral replication
- Uncoating occurs at the nuclear membrane
EBV Latency
- Occurs in B-cells
Acyclovir
- Nucleoside (guanosine) analogue that inhibits productive herpesvirus replication
- Antiviral drug that is only active in an infected cell during productive infection
- MOA:
*requires phosphorylation to be acitve
*1st phosphate added by a virus specific enzyme, thymidine kinase (more actively phosphorylated by HSV’s than VZV’s)
*2nd and 3rd phosphates added by cellular enzymes
*competitively inhibits dGTP for insertion into DNA
*lacks a 3’-OH group so it can not accept a base; chain termination
Acyclovir-resistant HSV w/thymidine kinase mutations will still be susceptible to cidofovir
Ganciclovir
- Guanosine analogue
- Active against CMV
- MOA:
*phosphorylated by a protein kinase phosphotransferase (UL97) encoded by CMV
*competitively inhibits incorporation of dGTP into DNA; chain termination
*cellular enzymes can also phosphorylate ganciclovir; some toxicity
*inhibits viral DNA polymerase preferentially over cellular DNA polymerase
*has activity against other herpesviruses; HSV, VZV, EBV, HHV-6 and HHV-8
Cidofovir
- Cytidine analogue
- Already has 1 phosphate group on it so its going to be active in both an infected and non-infected cell
- MOA:
*Has 1 phosphate; 2nd and 3rd are added by cellular enzymes
*Higher affinity for viral DNA polymerases than cellular DNA polymerases
*Competes w/dCTP for incorporation into DNA
Acyclovir-resistant HSV w/thymidine kinase mutations will still be susceptible to cidofovir
Foscarnet
- Pyrophosphate analogue
- Prevents cleavage of pyrophosphate from dNTPs, stopping DNA synthesis
- Binds to herpesvirus DNA polymerases and HIV reverse transcriptase
- Ganciclovir and cidofovir- resistant isolates of CMV are usually still susceptible to foscarnet
- Higher affinity for viral polymerases than cellular polymerases
HSV types of infection
- Encephalitis usally HSV-1
- Meningitis usually HSV-2
- Encephalitis assoc. w/neonatal herpes usally HSV-2
HSV-1 Primary Infection
- Localized throughout the mouth
- Enters neurons at site of infection and travels via retrograde transport to the trigeminal ganglion
HSV-2 Primary Infection
- Remains localized at the genital mucosa
- Enters neurons at site of infection
- Travels via retrograde transport to the sacral ganglion where it establishes latent infection
VZV Primary Infection
HSV vs VZV Reactivation chart
Exanthem subitum
- AKA roseola, sixth disease) in infants
- Assoc. with infection of herpesviruses 6 or 7
- May cause febrile seizure w/o rash in infants (6 or 7)
- May contribute to morbidity in AIDS and following transplants
Epstein-Barr Virus
- Cell tropism determined by presence of EBV receptor (CR2/CD21)
- Expressed on B cells and epithelial cells of the oropharynx and nasopharynx
*B cells- productive, immortalizing or latent infection; transformation
*Epithelial cells- productive infection; transformation
- MHC class II molecules are used as co-receptors
EBV Latent Infection
- Occurs in infected B cells that differentiate into memory cells in the presence of complement T cells
*T cells eliminate EBV-activated (immortalized) B cells
- Genome remains non-integrated and replicates during cell division
*no protein synthesis occurs during latency except for Epstein-Barr nuclear antigen 1 (EBNA-1); expressed during cell division to retain the viral genome in cells
EBV Immortalization of B cells
- B cells are stimulated to divide and secrete antibody
*EBNA 2 essential for immortalization
*Polyclonal activation
*Heterophile antibodies
- EBV-activate B cells are eliminated by T cells
*activation and proliferation of T cells => mononucleosis
Infectious Mononucleosis
- T cell response to EBV-infected/immortalized B cells
- Symptoms:
*lymphadenopathy, splenomegaly and exudative pharyngitis
*fatigue, fever, hepatosplenomegaly
*rash in patients treated w/ amoxicillin for suspected strep throat
- Dx
*Increase WBCs; large, atypical T cells (Downey cells)
*Detect heterophile antibodies
+Monospot test, EIA
+Detected from end of 1wk for several months
*Serology
EBV Serological data chart
EBV Reactivation
- Virus latently infects memory B cells
- Activation of latently infected memory B cells allows for transcription of ZEBRA
*ZEBRA turns on expression of immediate early genes, initiating productive infection
- Common in tonsils and oropharynx
*virus is shed in the saliva
- Reactivation is asymptomatic but individual is infectious
Serology for EBV
- Acute infection is confirmed by detection of:
*IgM to VCA
*VCA antibody, but no EBNA antibody (early acute)
*EA antibody (detected after VCA antibody)
- alpha-EBNA antibody requires lysis of infected cells
*occurs as T cells clear the infection
*assoc. w/convalescence/resolution of infection
- Detection of both VCA IgG and EBNA antibodies indicates previous infection
EBV Serology Chart
