Introduction to Herpesviruses

Introduction to Herpesviruses

• The Herpesviridae family consists of large, enveloped, icosahedral, double-stranded DNA viruses.
• Eight known human herpesviruses (HHVs) exist, plus a large number of animal herpesviruses.
• Herpes simplex virus-1 (HSV-1) and HSV-2 cause orofacial and genital lesions.
• Varicella-zoster virus (VZV) causes primary chickenpox and reactivated shingles.
• Epstein-Barr virus (EBV) causes mononucleosis, Burkitt lymphoma (BL), and other B-cell lymphomas.
• Cytomegalovirus (CMV) causes mononucleosis symptoms in adults, pneumonia, diarrhea, and retinitis in immunocompromised individuals, and is the most common congenital infection.
• HHV types 6 and 7 (HHV-6 and HHV-7) cause roseola in infants.
• HHV-8, also known as Kaposi Sarcoma (KS)-associated herpesvirus (KSHV), causes KS and some B-cell lymphomas.
• Simian herpesvirus, or herpes B virus, has occasionally caused lethal human disease in primate center workers.
• All herpesviruses establish lifelong latent infections in their hosts, with periodic reactivation events.

Herpesviruses: Group Characteristics

• Herpesviruses are morphologically similar, with an overall size of 180 to 200 nm.
• An icosahedral capsid with a diameter of 75 nm encapsidates the linear, double-stranded DNA genome and core proteins.
• The capsid is surrounded by the tegument, a protein-filled region unique to herpesviruses, which contains viral proteins and enzymes.
• The tegument plays a structural role and is required for viral replication upon initial infection.
• A lipoprotein envelope, derived from the nuclear membrane of the infected host cell surrounds the tegument, forming the complete virus particle of 180 to 200 nm.
• The envelope contains multiple viral glycoproteins, such as gB to gE and gH to gM, that act as viral binding, fusion, and entry proteins.
• Herpesvirus genomes range from 125 kbp (VZV) to 240 kbp (CMV) of DNA, and code from around 75 to over 200 viral proteins.
• Herpesviruses express enzymes necessary for viral DNA synthesis, allowing them to infect both dividing and quiescent cells.
• HHVs have six blocks of orthologous genes with interspersed species-specific viral genes and substantial differences in their genomic sequences.
• Antigenic analysis differentiates among herpesviruses, despite some cross-reactions (e.g., between HSV-1 and HSV-2).
• Based on virologic similarities, herpesviruses are divided into three subfamilies: α, β, and γ herpesviruses.
• HSV-1, HSV-2, and VZV are in the α subfamily, characterized by relatively rapid replication and neuronal latency.
• CMV, HHV-6, and HHV-7 are in the β subfamily, characterized by slow replication rates and extremely limited host range.
• EBV and KSHV (HHV-8) are in the γ subfamily, characterized by relatively rapid replication, replication in lymphocytes, and restricted host range.
• HSV has the widest range of cell tropism, infecting many animal and human host cells, although only found in humans.
• VZV infects only humans and is best grown in cells of human origin.
• Human CMV replicates well only in limited human cell lines, such as human foreskin fibroblasts.
• HHV-6 and HHV-7 preferentially grow in T-lymphocyte cell cultures.
• EBV can be grown in continuous human or primate lymphoblastoid cell cultures where it is present in the latent state.
• KSHV establishes latency in cultured cells, where only a low percentage of the cells support active replication.

Herpes Simplex Virus Replication

• HSV generally causes lytic infection in epithelial cells and establishes latency in neuronal cells.
• Glycoproteins in the HSV envelope interact with cellular receptors, leading to fusion with the cell membrane.
• Fusion delivers tegument proteins and the capsid containing viral DNA into the cytoplasm, then the capsid migrates to the nucleus.
• In the nucleus, the viral DNA genome circularizes, and viral gene expression is initiated.
• Host RNA polymerase transcribes the genome in three distinct classes of mRNAs: immediate early (IE), early (E), and late (L).
• IE mRNAs, synthesized 2 to 4 hours after infection, encode proteins involved in regulation of viral gene expression and host defense.
• E mRNAs require prior protein synthesis of IE genes and encode proteins involved in viral replication (DNA binding proteins, DNA polymerase, thymidine kinase, etc).
• L mRNAs require viral genome replication for full expression and encode major structural proteins: capsid subunits, tegument proteins, and envelope glycoproteins.
• The early (E) proteins thymidine kinase and DNA polymerase are important targets of antiviral chemotherapy.
• Synthesis of IE genes is required for E genes, and E genes shut off the IE genes.
• The E genes are required for viral genomic replication, which in turn is required for optimal synthesis of most L genes.
• Viral DNA replication occurs in a rolling circle fashion producing high-molecular-weight DNA concatemers.
• Genomic concatemers are cleaved and packaged into preassembled capsids in the nucleus.
• Herpesviruses assemble in the nuclei, acquiring their envelope from the inner lamella of the nuclear membrane.
• Budding occurs at the nuclear membranes, and virions are then transported through the ER and Golgi. Re-envelopment and de-envelopment through the ER and Golgi ultimately leads to the cytoplasmic membrane.
• Host cell protein synthesis shut-off occurs for both α- and γ-herpesviruses by cleavage of mRNAs by viral protein complexes.
• Viral replication and host cell shut-off lead to cell death.
• Due to their long replication cycle, β-herpesviruses do not exhibit host cell shut-off.

Herpes Simplex Latency and Reactivation

• In vivo, herpesviruses produce an initial lytic infection controlled by the host immune system, and latent infection is also established.
• Latent infection allows herpesvirus infection to be maintained for the life of the host.
• During latency, the viral DNA is maintained as an episome in the nucleus, but infectious virus is not recovered.
• Latent infection differs from chronic infection in that the viral genome is not rapidly replicated, and virions are not produced.
• During latency, there is minimal viral gene expression, with only 1 to 10 latent genes being regularly expressed depending on the virus.
• Latent genes encode functions for maintenance of the viral episome, preventing host cell death, and inhibiting the host’s immune response.
• Many herpesviruses also express microRNAs during latency, controlling gene expression without producing a peptide product.
• HSV-1 expresses only microRNAs during latent infection; the immune system has difficulty recognizing latently infected cells.
• Periodic reactivation provides a constant source of new infections in the population.
• Reactivation rates vary depending on the virus and the host.
• Immunosuppressed patients experience more common and severe reactivation, indicating that the immune system suppresses reactivation.

Herpes Simplex Virus (HSV) Overview

• Herpes simplex virus (HSV), HSV-1 and HSV-2 are double-stranded DNA, icosahedral, enveloped viruses with 50% homology, replicating in the nucleus.
• HSV is transmitted through direct contact with lesions and infected secretions.
• Both HSV-1 and HSV-2 initially infect and replicate in muco-epithelial cells, initiating viral-mediated multinucleated giant cells and cellular death.
• Lytic or productive infection at the site of contact with associated inflammatory response is followed by establishing latent infection in the nerve ganglion.
• HSV-1 usually causes orofacial infections involving skin, mouth, conjunctiva, and the nervous system.
• HSV-2 predominantly causes genital infections, but HSV-1 can also cause genital infection and aseptic meningitis.
• Both HSV-1 and HSV-2 cause latency, with the site determined by the location of the primary infection.
• Orofacial infection (by HSV-1) resides as extrachromosomal episomal DNA in the trigeminal ganglion.
• Genital infection (HSV-270%, HSV-130%) resides in the dorsal ganglion in the sacral region.
• Neonates can acquire HSV during birth, with high mortality and neurologic sequelae in survivors.
• Humoral and cell-mediated immunity play a role in controlling the virus; particularly, CD8 T cells destroy virus-infected cells.
• Latent HSVs are periodically reactivated by sunlight, ultraviolet light, fever, excitement, emotional stress, and trauma.
• Acyclovir, a nucleoside analog monophosphorylated by HSV thymidine kinase, inhibits viral DNA synthesis; it is used for acute treatment and prevents frequent reactivation.
• There is no vaccine approved against HSV infection.

Herpes Simplex Virus (HSV) Virology

• The genomes of herpes simplex 1 and 2 (HSV-1 and HSV-2, respectively) are approximately 150 kbp of DNA.
• Although epidemiologic and antigenic differences exits, their genomes contain approximately 50% homology.
• HSV-1 and HSV-2 share many glycoprotein and structural antigens.
• Differences in glycoprotein B, among other glycoproteins, enable them to be distinguished antigenically.
• The viruses can be distinguished by PCR assays.

Herpes Simplex Disease Epidemiology

• Herpes simplex viruses are distributed worldwide, with an estimated 3.7 billion people under age 50 (67%) having HSV-1 and 491 million people aged 15 to 49 (13%) having HSV-2 infection globally.
• There are no known animal vectors, and humans appear to be the only natural reservoir.
• Infection occurs via direct contact with infected secretions
• Orofacial herpes is most often associated with HSV-1, while genital infections are most often associated with HSV-2
• Both HSV-1 and HSV-2 are prevalent worldwide.
• Prevalence of HSV antibody varies by age and socioeconomic status of the population studied.
• Direct sexual transmission is the major mode of spread.
• Asymptomatic shedding accounts for transmission from a partner with no active genital lesions or history of genital herpes.
• Genital herpes, which includes both HSV-2 and HSV-1, is not a reportable disease in the United States.
• Infection with genital herpes increases the risk of other sexually transmitted infections, including HIV

Herpes Simplex Disease Pathogenesis

• Transmission occurs by direct contact with infected secretions.
• HSV-1 and HSV-2 initially infect and replicate in the mucoepithelial cells, initiating viral-mediated cellular death.
• Pathologic changes include ballooning degeneration of epithelial cells with condensed chromatin, nuclear degeneration, and formation of multinucleated giant cells
• The virus spreads to local sensory neurons and travels in retrograde fashion to the sensory ganglia that innervate the site of infection.
• Latency is established in the ganglionic neurons, site is determined according to where the acute (initial) infection occurs
• Latent infection of neurons by HSV replicates multiple viral genomes, does not result in the death of the cell

Herpes Simplex Disease Reactivation and Immunity

• Reactivation can occur over the entire life of the host
• Precipitating factors include exposure to ultraviolet light, sunlight, fever, excitement, emotional stress, and trauma
• Upon reactivation, the virus initiates lytic replication and virus particles travel down the neuronal axons (anterograde transport), most often to or near the site of initial infection
• The virus replicates in the epithelium, which subsequently infects, produces vesicles, and leads to localized spread and ulceration
• Immunocompetent hosts generally contain the viral infection, the virus may spread to proximate skin surfaces.
• Metabolic changes switch on the virus replication cycle, and the virus travels down the peripheral nerves to the skin, where it replicates in the epidermal cells and produces lesions
• Host factors determine clinical effects
• Both cellular and humoral immune responses are important in immunity is important in immunity and in preventing reinfection

Herpes Simplex Type 1 Manifestations and Diagnosis

• Infection with HSV-1 is more often associated with orofacial disease though it causes an increasing number of genital infections
• Vesicular lesions become pustular and then ulcerate
• Primary infection with HSV-1 is most often asymptomatic, however with symptoms include fever, ulcerative lesions especially among children
• Lesions usually recur on a specific area of the lip and the immediate adjacent skin with premonitory "cold sores" or "fever blisters"
• Virus in saliva with or without symptoms
• Diagnosis: PCR, isolating virus from lesions

Herpes Simplex Type 2

• Genital herpes is a significant sexually transmitted disease from both HSV-1 and HSV-2
• HSV-2 associated with genital infections
• Can culture from lesions; lesions from HSV-2 patients may not exhibit overt disease
• Diagnosis: PCR, isolating virus from lesions

Treating Herpes Simplex

• Several antiviral drugs such as acyclovir that inhibit HSV have been developed
• Acyclovir or its prodrug can decrease duration of acute and recurrent disease

Varicella-Zoster Virus Overview

– Varicella-zoster virus (VZV) is a member of Herpesviridae family with same morphologic and genomic features as other herpes viruses, transmitted through respiratory route and causes primary infection (chickenpox) and recurrent infection (shingles) – Symptoms include fever and lesions generally appear then spread to the the face, neck, trunk, and proximal extremities and Immunocompromised patients develop to pneumonia, etc

• In children that are vaccinated, acyclovir provides some extreme cases

VZV Virology and Epidemiology

– VZV has the same features that has similar family and also highly contagious – Virus is difficult to isolate from patients after the rash passes and Communicability is greatest before or after a rash

Understanding and Applying Think 14-1

– Oroficial and genital herpes is common and result in the spread of shingles.

Prevention and Manifestations of Postexposure or Shingles

– Shingles may depend on the amount of exposure and can result in varicella or chickenpox

• Varicella, a vaccine can help after exposure

VZV Pathology and Immunity

• Secondary viremia results in skin lesions that can be treated if needed and VZV will remain latent
• Both humoral immunity and cell-mediated immunity are important but one of the most important thing of VZV is a cell-mediated
• Can also result in a complication as most people age that can cause a lot of zoster

Understanding VZV and Its Clinical Aspects

• VZV produces a primary infection in normal children characterized by a generalized vesicular rash that may form papules
• Primary varicella shows multiple stages of rashes with a variety of infection markers seen around the region

Complications and Diagnosising VZV and Treating

• Some complications can occur with various diseases and it more commonly develops in immunocompromised patients
• Diagnosing: diagnosing tests not usually necessary but PCR detection is more commonly done
• Treating: Acyclovir to immunocompromised patients is recommended

Vaccine: VZV & MMRV

• Live attenuated varicella vaccine or MMRV is effective and safe with few known side effects
• Vaccination for shingrix has been approved to protect and prevent with less side effects

Preventing and Key Conclusion

– Some precautions can be taken but immune goblin or variZIG helps

• VZV is easy to contract in normal children and easily spread when near

EBV (Epstein Barr Virus) Overview and Virology

• EBV, a member of the Herpesviridae is the etiologic agent of infectious mononucleosis and can be seen over %90 of populations
• The main etiologic agent is y-herpesvirus

EBV Latency, Epidemiology, and Infection

• LCLs support type III latency which is associated with four EBV nuclear antigens
• EBV (Epstein barr) Infections are mostly asymptomatic
• Most primary infections occur among young adults

Pathogenesis of EBV, and How Immune System Reacts

• EBV initially infects epithelial cells hallmark and hallmark follows
• Immune system responds in EBV for lymphocytes

Diseases Association with EBV/Diagnosis

• EBV known to show several associated and is related to epithelial tumors
• Laboratory analysis done of the EBV which is related to monocytosis or specific positive

Diagnosing EBV and treatment

• Nonspecific heterophile antibodies are the main cause as its mostly detected in commercial places EBV (Epstein barr) is highly infectious but treatment is mostly supportive or limiting saliva

CMV (Cytomegalovirus)

• cytomegalovirus produces "owl's eye", cytopathic effect of intranuclear inclusions.
• Congenital CMV infections are usually very severe for new borns, but other infections are subclinical

CMV Virology, and High Infection rates: Diagnosis

• CMV highly regulated but slow and infection rates extremely high
• High and low end can cause complications such as organ rejection from transplant donor

CMV Pathologies and Immunity Markers

• Can also result in CMV
• humoral/cellular responses are important but may be not enough when infection is persistent

Diagnosing and Treating CMV

• PCR to confirm is sufficient to detect
• A number of conditions come from the viral infection so treatment is difficult
• ganciclovir is a nuceleoside, but valganciclovir has a increased bioavailability to take care of

HIV6 and HIV7 Overview Virus

• HIV 6 is mainly for infants that are being treated for transplants/rejection symptoms
• replicants in CD4/T lymphocytes and are rapidly spreading among hosts

HIV8 and What it causes

• Virus found in tumors are mainly found in younger men who have aids, or are aids related cases(Kaposik) and found in people who are infected with HIV mostly
• Seroprevalance correlates with ks rates in specifc population
• -KHSV infects oral and can be shedded which are highly transmissaible
• Diagnoses :PCR tests are usually difficult to detect and only have 70-90 accurate reads
• Can be treated to try and get ksvh to be stable, but not for long