Herpes Viruses: Types, Classification, and Replication

Herpes Viruses Overview

• Herpes viruses form a large group containing double-stranded DNA enveloped viruses
• Of the over 100 in existence, only nine infect humans
• Herpesviruses share a similar morphology, replication cycle, and latency
• Cell-mediated immunity provides important viral control
• Advanced age, HIV infection, young age, and pregnancy increase the risk of infection and reactivation

Herpes Viruses: Types and Classifications

• Herpes viruses are divided into alpha, beta and gamma subfamilies
• Subfamilies are differentiated by tissue tropism, cytopathological effects, latency site, pathogenesis and disease manifestations
• Glycoproteins are encoded for attachment, fusion and immune control by mimicking MHC-1 molecules
• The replication cycle involves attachment protein binding to the target cell, with genome delivered to the nucleus
• Viral DNA polymerase is the target of antivirals, which shut down replication

Alpha Herpes Virus Subfamily

• HHV-1 and HHV-2 infect mucoepithelial cells and establish latency in neurons, transmitted through close contact, like kissing or sexual activity
• HHV-3 infects mucoepithelial cells and T cells, establishes latency in neurons, and is transmitted through respiratory and other contact

Beta Herpes Virus Subfamily

• HHV-5 infects monocytes, granulocytes, lymphocytes, and epithelial cells
• HHV-5 establishes latency in B cells and T cells, monocytes, lymphocytes, and epithelial cells and is transmitted through close contact, tissue transplants, or congenitally
• HHV-6 and HHV-7 infect lymphocytes, establish latency in the T cells and other cells, and are transmitted through saliva

Gamma Herpes Virus Subfamily

• HHV-4 infects B cells and epithelial cells, establishes latency in B cells, and is transmitted through saliva
• HHV-8 infects lymphocytes and other cells, establishes latency in B cells, and is transmitted through close contact, potentially saliva, but with a low incidence of transmission

Herpes Simplex Viruses (HSV-1 and HSV-2)

• HSV-1 aka herpes simplex 1, and HHV-1
• HSV-2 aka herpes simplex 2, and HHV-2
• HSV-1 is the cause of herpes labialis
• HSV-2 is the cause of genital herpes
• Transmission occurs through skin-to-skin, oral, and sexual contact with:
• 66% of people aged 0-49 have HSV-1
• 13% of those aged 5-49 have HSV-2
• The types of infection are primary, non-primary, recurrent, and extragenital
• Viral shedding occurs one day before lesions appear and lasts until lesions resolve, about 7 days.
• Diagnosis is through viral culture or PCR of the lesions
• Treatment: acyclovir, valacyclovir, or famciclovir

Herpes Simplex Encephalitis

• A rare, severe brain infection, commonly associated with HSV-1
• The virus infects the temporal lobe
• Encephalitis can arise from primary oropharynx infection via trigeminal nerve or olfactory tract, HSV reactivation, or latent HSV reactivation in the brain
• Without prompt treatment, severe encephalitis is life-threatening
• Treatment results in 70-80% survival rates
• Many survivors have long-term neurologic sequelae
• Diagnosis: PCR of CSF, formerly brain biopsy
• Treatment: acyclovir IV

Varicella Zoster Virus (HHV-3)

• VZV causes chickenpox (varicella) and shingles (zoster)
• Transmission route of primary infection: respiratory system
• Viremia and skin lesions follow
• VZV establishes latency in spinal dorsal root and cranial ganglia neurons

Varicella (Chickenpox)

• Pre-vaccine, a common childhood infection, infecting over 90% of the population
• Very infectious, with over 90% of susceptible individuals infected after exposure
• Infection is more severe for adults, pregnant women, and the immunosuppressed, possibly involving varicella pneumonia
• Antibody production is important, preventing attachment and so passive immunization with varicella-zoster immune globulin (VZIG) within 4 days of exposure prevents infection
• Cell-mediated immunity controls infection, keeps it latent
• Interferon-alpha, NK cells, and T-cells limit the virus's spread
• Incubation period is 14 days
• Clinical illness includes a short (24 h) prodrome of fever, malaise, pharyngitis, then pruritic rash appears in crops over several days, then followed by temporary hypopigmentation
• Lesions are seen in different stages of development at the same time
• New vesicles stop appearing after 4 days
• Vesicles take 6 days to crust over
• Crusts fall off after 1-2 weeks
• 20% of children who receive only one Varicella vaccine dose will still get varicella, usually mild

Varicella Complications

• Bacterial skin infections (especially group A beta strep) may occur
• More common in adults and immunocompromised ppl, pneumonia may occur
• Risk factors for pneumonia include male sex, pregnancy, smoking
• Acute cerebellar ataxia (1/4000 cases) usually resolves completely
• Diffuse encephalitis is more common in adults
• Diffuse encephalitis can involve delirium, seizures, focal signs with 10% mortality with 15% long-term sequelae
• Aspirin has been linked to Reye's syndrome, an inflammation of the liver and encephalitis
• Hepatitis is rare, and mostly seen in immunosuppressed, with often fatal outcomes

Varicella Vaccine

• Live, attenuated vaccine is given to immunocompetent children, adolescents, and adults without varicella immunity
• Two doses are given to immunocompetent children with:
• First dose: 12-15 months
• Second dose: 4-6 years
• The vaccine virus can remain dormant in the nervous system and cause zoster later in life.

Varicella Treatment

• Oral and IV acyclovir, oral valacyclovir, and famciclovir are agents deemed effective
• Immunocompetent children under 12 are usually not treated
• Oral treatment is recommended for unvaccinated children 13 and older, children, adolescents with chronic skin/pulmonary disorders, immunocompetent adults, and pregnant patients
• IV acyclovir is recommended for immunosuppressed and patients with varicella complications like pneumonia, hepatitis, encephalitis

Zoster (Shingles)

• During varicella infection, the virus infects sensory nerves and moves retrograde along the axons from the skin to the neurons of regional ganglia; latent infection establishes
• The cell-mediated immunity controls latency, with one or a small number of VZV genes transcribed and with no virus found in the ganglia
• In reactivation, VZV spreads in the ganglia, involving multiple sensory neurons, and anterograde spreads down the sensory nerve to cause infection in the dermatome, with the rash of shingles.
• Neuron infection involves inflammation and neuronal necrosis, as well as pain
• Increased prevalence of VZV reactivation depends on age, immunosuppression, and stress
• 30% of people in the U.S. will develop zoster

Zoster Continued

• VZV can be transmitted by patients with zoster
• Resulting in chickenpox, to people with no immunity from natural varicella infection or from varicella vaccination
• occurs through direct contact and/or inhalation of aerosolized virus
• Neuritis: pain in area of rash
• Post-herpetic neuralgia: pain lasting over 90 days after rash onset
• Occurs in 10-15% of patients
  • 5% in those <60
  • 20% in those >80
• Less likely if zoster develops post-zoster vaccination

Complications of Zoster

• Disseminated zoster: cutaneous and visceral
• Ocular zoster can cause:
• Tearing, pain, conjunctival injection, lid involvement
• Uveitis, episcleritis, keratitis
• Acute retinal necrosis
• Ramsay Hunt Syndrome: Ipsilateral facial paralysis, vesicles in auditory canal/auricle, ear pain, involvement of V, IX, X dermatomes
• Neurologic complications include:
• Meningitis and/or encephalitis
• Myelitis
• Guillain-Barré
• Stroke syndrome

Treatment and Vaccine For Zoster

• If given within 72 hours, treatment prevents postherpetic neuralgia and reduces pain, hastening infection resolution
• Acyclovir, famciclovir, or valacyclovir can be used
• Adults ages 50+ and those 19+ with weakened immune systems should get the zoster vaccine
• Even if the varicella vaccine was given earlier in life, the zoster vaccine is still recommended since it's possible the patient had undiagnosed natural varicella infection

Epstein-Barr Virus (HHV-4)

• 90-95% of adults are EBV seropositive though, with most infections inapparent
• EBV causes infectious mononucleosis virus persists for life
• Infections originate in the oropharynx, with oropharyngeal epithelial cells permissive for viral replication
• EBV establishes latency in B cells with 10% of genes expressed latently infected cells
• Sporadic EBV replication in oropharyngeal epithelial cells and infected memory B cells occurs with intermittent shedding in saliva during convalescence.
• EBV is associated with B-cell lymphomas, T-cell lymphomas, Hodgkin's lymphoma, and nasopharyngeal carcinoma.
• Latently infected B cells are oncogenically transformed
• Congenital/acquired immunodeficiencies can cause lymphoproliferative disorders
• Reactivation is not prominent, other than with transplant patients presenting aggressive lymphoproliferative disorders

Acute Infectious Mononucleosis

• Symptoms include malaise, headache, fever, pharyngitis, tonsillitis, and cervical lymphadenopathy
• Palatal petechiae, rash, nausea, vomiting are commonly seen
• A rash after taking penicillin can emerge but is not a true allergy
• Splenomegaly is seen in up to 50% of patients
• Splenic rupture (spontaneous in ½ cases) is seen in 1-2 cases/1000 from days 4-21 of illness
• Airway obstruction results from lymphoid hyperplasia and mucosal edema
• Atypical lymphocytes on a blood smear and those with elevated liver enzymes are commonly seen

Infectious Mononucleosis: Complications and Diagnosis

• Uncommon complications include pneumonia, myocarditis, pancreatitis, meningitis, myositis, glomerulonephritis, genital ulceration, Guillain-Barré, aseptic meningitis, encephalitis, facial nerve palsy, transverse myelitis, optic neuritis, peripheral neuritis, hemolytic anemia, thrombocytopenia, aplastic anemia, TTP, and DIC.
• Oral hairy leukoplakia: white, painless plaques on the lateral aspects of the tongue in HIV patients
• Heterophile antibodies (monospot test): detects agglutination of horse/sheep RBC by patient’s serum
• 70-90% sensitivity and specificity overall but less sensitive in young children
• EBV serology: best detected with viral capsid antigen IgM (VCA IgM)

Infectious Mononucleosis Treatment

• Treatment is supportive
• Avoid trauma to the spleen for several weeks without contact sports
• Corticosteroids are given for airway obstruction
• Acyclovir does not provide a clinical benefit, but acyclovir inhibits EBV DNA polymerase and replication

Lymphoproliferative Disorders Linked to EBV

• Hemophagocytic lymphohistiocytosis: can be caused by EBV, fever, generalized lymphadenopathy, hepatosplenomegaly, hepatitis, pancytopenia, coagulopathy, and hemophagocytosis
• Seen in immunodeficiency patients, lymphomatoid granulomatosis involves fever and weight loss symptoms and pathology in the lung, kidney, liver, skin, and CNS
• X-linked lymphoproliferative disease: a selective immunodeficiency to EBV, and often fatal
• Post-transplant lymphoproliferative disease: ranges from benign polyclonal B cell proliferation to malignant B cell lymphoma, usually seen in primary EBV infection in EBV-negative transplant recipients from EBV-positive donors

EBV-Associated Malignancies

• All diseases express the EBV protein EBNA-1 binds to DNA of chromosome 11
• Common childhood malignancy in equatorial Africa, where tumors arise from infected B-cells
• EBV genome is found in over 95% endemic cases, 15-20% sporadic cases
• Malaria appears to reactivate EBV in latently infected B-cells
• Non-Hodgkin lymphoma (often CNS lymphoma), leiomyomas, and leiomyosarcomas commonly develop in HIV patients
• EBV genome can be found in all nasopharyngeal carcinomas
• Nasal angiocentric lymphoma
• EBV genome found in 9-10% of cases of gastric carcinoma
• T cell lymphoma

Human Cytomegalovirus (HHV-5)

• CMV is a common herpes virus that infects ½ children by age 5 & ½ adults by age 40 in the U.S., with higher rates in resource-limited countries
• It transmits through saliva, urine, blood, semen, breast milk, close contact, sexual contact, or pregnancy
• Acute infection in immunocompetent hosts is asymptomatic/causes CMV mononucleosis with fever, sore throat, rash, fatigue, lymphadenopathy, hepatitis, monocytes in the blood smear, & atypical lymphocytes
• The human CMV latency is established in CD34+ hematopoietic progenitor cells and the CD14+ monocytes
• When the CD14+ monocytes differentiate into macrophages/dendritic cells viral replication resumes
• Anemia, positive cold agglutinins, rheumatoid factor, ANA, thrombocytopenia, hemolysis, and DIC may be seen

Human Cytomegalovirus Continued

• Immunocompetent hosts develop colitis, severe hepatitis, thrombosis, encephalitis, Guillain-Barré, transverse myelitis, brachial nerve, myocarditis, pericarditis, anterior uveitis
• 1/200 babies are born with congenital CMV and, of this share, 1% have birth defects or long-term health issues
• In the immunocompetent, reactivation is also seen in critically ill patients, but is a marker, not direct cause
• CMV reactivation in transplant is associated with allograft rejection
• Immunosuppressed reactivation can cause nonspecific CMV syndrome with fever, malaise, weakness, leucopenia, thrombocytopenia, viremia, retinitis, encephalitis, pneumonitis, hepatitis, nephritis, esophagitis, & colitis

CMV: Diagnosis & Treatment

• Diagnosis for immunocompetent: Detection of IgM or 4x rise in IgG
• IgG takes weeks to be present, IgM persists for months after primary infection
• Diagnosis for immunosuppressed: Quantitative PCR, pp65 antigenemia, culture, histopathology
• Treatment for immunocompetent hosts is not given unless in pregnancy, or rare tissue invasive diseases (fetal infection, colitis, encephalitis, or uveitis)
• Can be treated with valganciclovir
• For immunosuppressed patients:
• Available drugs are ganciclovir, valganciclovir, foscarnet, cidofovir
• Treat asymptomatic viremia via modification or immunosuppressive regimen/antivirals
• Treat CMV syndrome/tissue invasive disease via antivirals

Congenital CMV Infection

• Congenital infection is asymptomatic, may involve hearing loss at birth/later in life or mild microcephaly at birth that worsens as baby gets older presenting abnormal tone/seizures
• Pregnant women are diagnosed early and given antenatal treatment to prevent passing CMV to the infant
• Postnatal treatment includes treating infants with symptomatic congenital congenital CMV, and infected infants with immunodeficiency

HHV-6A and HHV-6B

• First isolated in patients with lymphoproliferative disorders, HHV-6 was changed from human B-lymphotropic virus once its tropism characterized
• There are two variants: HHV-6A and HHV-6B, HHV-6B infects most ppl by age 3 and becomes latent, with reactivation possible with immunosuppression.
• There is a rare primary infection in adults with mononucleosis syndrome that presents prolonged lymphadenopathy and HHV-6 seroconversion.
• Immunocompetent patients can develop encephalitis, resulting in possible death
• Mesial temporal lobe epilepsy can have HHV-6 DNA
• Reactivation of HHV-6 in immunosuppressed patients (transplant patients) results in viremia and/or clinical illness like pneumonitis, hepatitis, encephalitis, and bone marrow suppression.

HHV-6 Treatment

• Diagnosis requires isolation of the virus by culture or PCR testing for HHV-6 DNA
• Treatment is not given for immunocompetent patients for self-limited infections
• In the rare immunocompetent with encephalitis, ganciclovir has been given but with no apparent benefit
• Immunocompromised patients usually treat with limit efficacy

HHV-7

• Lymphotropic herpes virus replicates only in CD4 T lymphocytes
• 95% of adults test positive with antibodies
• Most infections occur in childhood
• Not much is known about it, but cases have been associated with fever, rash, febrile seizures in children, renal transplant patients, symptomatic CMV disease, encephalitis and Guillain-Barré

Roseola Infantum (Exanthem Subitum)

• Roseola occurs in young children with 90% under 2
• 3-5 days of fever, then a macular/maculopapular rash
• Most cause of HHV-6B cases, with association to HHV-7, parainfluenza virus type 1, adenoviruses, coxsackieviruses A & B, and echoviruses

HHV-8

• (Kaposi sarcoma-associated herpes virus)
• Infects 50% of people in sub-Saharan Africa, 20-30% in Mediterranean countries, <10% in Europe, Asia, U.S.
• Transmitted via saliva, organ donation, blood transfusions
• HHV-8 infects endothelial cells, monocytes, and B-cells
• Primary infection is asymptomatic:
  • Children develop fever and rash
  • Adults develop lymphadenopathy, diarrhea, localized rash
  • Immunosuppressed develop fever, lymphadenopathy, hepatosplenomegaly, and pancytopenia
• In latent infection, very limited gene expression causes viral persistence and immune evasion

HHV-8 Associated Diseases in the Immunosuppressed

• Common cause in patient with acquired immunodeficiency syndrome, HHV-8 presents
• Kaposi sarcoma (KS), an AIDS-defining illness
• Primary effusion lymphoma (PEL)
• Multicentric Castleman's disease (MCD)
• KS associated inflammatory cytokine syndrome (KICS)
• 1/2 of untreated HIV patients develop KS, presenting purple, brown, or red papules or plaques affecting the skin and mucous membranes