Shared morphology of Herpesviruses
- Spherical, enveloped virions
- Highly labile and sensitive to environmental condition such as UV light and detergents
- Icosohedral Capsid surrounded by tegument, a containing protein to deliver to the host cell and RNA.
- Enclosed in an envelope from the host cell membrane during egress
Shared genetic characteristics of herpesviruses
- Linear dsDNA
- During lytic replication: sequential transcription with Immediate Early (IE) 1st followed by Early (E) then Late (L).
- DNA replication in the nucleus via virally encoded DNA polymerase.
- Establish latent infections during which only a small number of genes are expressed.
Subdivisions of herpesviruses
- EBV (HHV-4)
- Karposi’s Sarcoma/HHV-8
Characteristics of alpha herpesviruses
- (HSV 1), 2 (HSV 2), and (VZV or HHV 3).
- Replicate quickly and lyse infected cells of mucosal epithelial cells (12-24 hours).
- The α herpesviruses are neurotropic:
- establish latent infections @ peripheral nervous system, primarily in sensory nerve ganglia.
- Variable host range.
Characteristics of beta herpesviruses
- owl eye” inclusions on histology
- CMV) (HHV 6), (HHV-7).
- Replicate VERY slowly (80-120 hours).
- Cell lysis does not occur until several days after infection.
- Latency @ myeloid lineage, also possibly endothelial cells.
- Narrow host range (only humans)
- Evidence of germline transmission of HHV-6 due to viral genome integration events
Characteristics of gamma herpesviruses
- (EBV or HHV 4) and(KSHV or HHV 8).
- Narrow host range, restricted to humans.
- Grows VERY slowly, long replication cycle
- In vitro, all ɣ herpesviruses replicate in lymphoid cells and some are capable of lytic replication in epithelial cells, endothelial cells and fibroblasts.
- EBV and KSHV establish latency in, and can transform, B lymphocytes.
- Have Cyclins
Stages of lytic replication cycle
- virus attachment/entry/uncoating
- viral gene expression and genome replication
- viral assembly and egress
Characteristics of herpesvirus attachment/entry
a. Weak association of Virion with extracellular matrixstrong interaction between viral
glycoprotein and cellular receptoràbinding results in conformation change of viral
glycoprotein and fusion of viral envelope with cell membrane.
b. Nucleocapsid transit to nucleus (nuclear pore)
c. Linear viral genome extruded into nucleoplasmàviral genome circulariz
Characteristics of herpesvirus gene expression and genome replication
a. Viral/cellular transactivators stimulate IE gene expressionàtranslation of IE mRNA
b. IE viral proteins activate viral E gene expression/translation=viral genome replication
c. Circularized Genome is template for genome replication generating long concatomerslinked
end to end (Figure 1).
d. Viral DNA polymerase catalyzes new viral DNA synthesis (Figure 2) by synthesizing
new viral DNA in 5’à3’ direction (Figure 2).
Characteristics of herpesvirus virion assembly and egress
L protein synthesis of structural viral proteins including capsid result in packaging and
b. Expression of capsid proteins in the nucleus cause nuclear viral inclusions seen on
Molecular targets of anti-herpesviral tx
- DNA polymerase inhibitors.
- Prodrugs that are activated by phosphorylation.
- Monophosphorylated by viral kinase (resistant if lack kinase)
- Then converted to triphosphates by cellular kinase.
- Nucleoside analogs = incorporate into the elongating DNA chain and act as terminators.
HSV1/2: target cell, target latent site
- target = epithelial cells
- latent = Trigeminal Ganglion
- target = epithelial
- latent = Sacral Sensor Ganglion
VZV: target, latent site
Epithelial Cells, T-Cells Sensory Neurons
CMV: target, latent site
Epithelial Cells, endothelial cells
Myeloid precursor cells
HHV6/7: target, latent site
T-Cells, B-Cells, myeloid cells?
EBV: target, latent site
B-Cells, Epithelial Cells
Karposi’s: target, latent site
Lymphocytes, endothelial cells
B-Cells, endothelial cells
Innate response to herpesvirus
- TLR recognition of virus and virus components, interferon signaling, NK cell responses and DC activation participate in the control of primary lytic herpesvirus infections.
- Herpesviruses encode proteins and non-coding RNAs that modulate and evade many host innate immune responses, typically expressed as IE and E genes.
Adaptive response to herpesvirus
- Humoral: neutralizing Abs to herpesvirus envelope glycoproteins.
- Herpesvirus encode Fc receptor decoys that stop host antibodies
- Cellular: Herpesvirusesavoid f infected cells by altering MHC I and MHC II
- also express proteins that inactivate or dampen CTL function and helper T cell activities.
HSV1/2 spread and transmission
- HSV 1 and 2 cause localized oral or genital epithelial lesions and spread only into sensory neurons innervating the site of replication.
- Both can be sexually transmitted.
VZV spread and transmission
- VZV initially infects upper respiratory epithelium and spreads rapidly to lymph nodes and the reticuloendothelial system.
- Dendritic cells and T cells are key players in the dissemination
- also spreads to dorsal root ganglia
- Transmission of VZV is by respiratory droplets.
CMV spread and transmission
- HCMV infects various types of mucosal epithelial cells, depending upon the route of exposure.
- Virus is disseminated by peripheral blood monocytes and dendritic cells.
- HCMV can be sexually transmitted, passed to infants in breast milk and saliva or urine or to fetus in pregnant women.
- Blood transfusion and transplants are also sources
EBV spread and transmission
- EBV infects oral mucosal epithelial cells and adjacent intraepithelial B cells and then rapidly establishes a latent infection in resting B memory cells.
- EBV is transmitted to new host via saliva.
Herpesvirus spread in immunocompetent hosts
- Herpesviruses rarely spread beyond those described above in the immunocompetent host
- Herpesviruses can be shed by immunocompetent hosts in the absence of symptoms for long periods of time. This has been well documented for HSV 1, HSV 2, HCMV and EBV.
Herpesviruses associated w/malignancy