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Chapter Outlines

Chapter 15      Herpesviruses

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15.1 History Greek scholars coined the term herpes which means to "creep or crawl" in reference to the spreading of herpetic lesions. Herpesvirus infections have existed for centuries. They are among the most common viruses found in humans. Once an individual has become infected by a herpesvirus, the infection remains in their body for life. Herpesviruses establish a latent state at a specific site in an immunocompetent host. An individual can be infected with more than 1 herpesvirus during their lifetime. Herpesviruses remain silent for many years only to be reactivated later. Infection against one member of the Herpesviridae family does not confer protection against infection or disease with the other members. See Table 15-1 Herpesvirus Nomenclature and Characteristics 15.2 Clinical Signs and Symptoms of Human Herpesviruses Herpesvirus Simplex Virus Type 1 (HSV-1) and Herpesvirus Simplex Virus Type 2 (HSV-2) Preference for the mouth, pharynx and genitals Both cause latent infections HSV-1 reactivation occurs most frequently above the waist. HSV-2 reactivation occurs most frequently below the waist. Lesions of HSV-1 and HSV-2 look similar. HSV-1 Causes a number of herpetic diseases: Cold sores of the mouth Lesions on the lip (Chaper Opener Figure) Herpes keratitis of the eye (the leading cause of corneal blindness in the U.S. Herpes gladitorium (transmitted during frequent contact in wrestling) Herpes rugbeiorum (seen in other contact sports like rugby) Causes genital herpes in about 10% of cases HSV-1 Reactivation is Associated with the Following Factors Immune suppression by cytotoxic drugs Sexual transmission Physical and emotional stress Temperature changes (e.g. hot or cold) Too much ultraviolet light (e.g. sunburn) Menstruation Lactation Malnutrition Excessive fatigue HSV-2 Causes 90% of all genital herpes cases in the U.S. New infections occur at about a rate of 1 million new cases/year. Majority of infections are unrecognized, undiagnosed and untreated. HSV-2 Infections Individuals with HSV-2 can shed virus even during asymptomatic periods. Safe-sex practices (condoms) in combo with valacyclovir therapy reduce the spread of HSV-2 during sexual intercourse by 75%. Pregnant women with active HSV-2 should deliver the infant by caesarean section Varicella Zoster Virus (VZV) Causes chickenpox and shingles. Chickenpox is a mild disease of children but can but can be severe in infants, adults and persons with impaired immune systems. Only herpesvirus that spreads person to person by coughing or sneezing. Chickenpox Symptoms develop 10-21 days after contact with an infected person. VZV infects the skin or mucosa of the respiratory tract and progresses through the blood and lymphatic system to the cells of the reticulo-endothelial system. First sign of disease is the itchy exanthematous rash. Other symptoms Fever Malaise Average of 300-400 lesions on the body during an attack. Blisters dry and form scabs in 4-5 days. Adult complications Pneumonia Bacterial infection of the skin Swelling of the brain CDC recommends that children be vaccinated at 12-18 months or before their 13th birthday. Shingles or Herpes Zoster After a primary VZV infection (chickenpox), the virus remains latent (dormant) in the dorsal root ganglia (neurons of the nerve roots). The virus is reactivated later in life after the age of 60 and the risk of reactivation increases with age. The onset of shingles is more common and severe in immunocompromised patients. Symptoms of Shingles Severe pain Numbness Itching Followed by a vesicular rash forms in a 3-5 day period. The rash follows a nerve on one side of the body. In an otherwise healthy individual, the disease lasts 10-15 days. The disease lasts 3 to 4 weeks in an immunocompromised patient. Chronic shingles may also occur in AIDs patients. An individual suffering from shingles is contagious only to individuals who have not had chickenpox. One cannot get shingles from someone afflicted with shingles. Shingles is caused only be VZV that has been dormant since an individual acquired chickenpox. Cytomegalovirus (CMV) Common in all human populations 50-85% adults in the U.S. Nearly 100% in parts of Africa For the majority of people, CMV is not a serious disease. Once infected, CMV remains dormant within the person's body for life. CMV is an Opportunistic Infection in the Immune Compromised Patient Congenital syndrome in neonates. Infectious mononucleosis with prolonged fever and hepatitis Pneumonia in bone marrow recipients Disease syndromes in lung, liver, kidney and heart transplant recipients Retinitis in AIDS patients CMV Transmission Via close, intimate contact with a person who is excreting virus in Saliva Urine Other bodily fluids. It can be transmitted Sexually Through breast milk Transplanted organs Blood transfusions CMV is the Most Important Cause of Congenital Infections (During Childbirth). 1-3% of women infected during pregnancy Developing, unborn babies are at highest risk for developing complications of CMV infection Hearing loss Visual impairment Varying degrees of mental retardation Motor problems Epstein-Barr Virus (EBV) Causes 79% of infectious mononucleosis cases (CMV causes the other 21%) Common infection throughout the world. Most frequently strikes students in high school or college in the U.S. Often referred to as the "kissing disease." Most people become infected with EBV during some time in their lives. In developing countries like Africa, EBV infection is associated with Burkitt's Lymphoma (Chapter 10) EBV Transmission Intimate contact with saliva of an infected person. Kissing Sharing beverages Sharing eating utensils. The incubation period ranges from 4-6 weeks. Symptoms of Infectious Mononucleosis Sore throat Fever Swollen Lymph Glands Malaise Enlarged spleen (sometimes) Enlarged liver (sometimes) Heart problems (rare) Central nervous system (CNS) problems (rare) Symptoms usually resolve within 1 or 2 months. EBV remains latent in the throat and blood for the rest of a person's life. HHV-6, HHV-7 and HHV-8 (Kaposi's Sarcoma Virus) HHV-6 isolated from T-cell cultures derived from the blood of AIDS patients. HHV-7 was isolated from CD4+ T cells of a healthy person. HHV-8 DNA has been found in all Kaposi's sarcoma tumors (Chapter 10) HHV-6 and HHV-7 are orphan viruses - they have not been etiologically linked to any human disease. HHV-6 HHV-6 infects nearly all humans by the age of 2. Two distinct types of HHV-6 HHV-6A HHV-6B-causes sixth disease HHV-6 may play a role in multiple sclerosis Herpes B (Herpesvirus Simiae or Monkey B Virus) Commonly infects macaques (a type of monkey used extensively in biomedical research) Most macaques carry Herpes B infection through direct contact with other macaques (bites, scratches, fomites (e.g. cage scratch) 1932 First human case of Herpes B Researcher bitten by an apparently healthy macaque Died 15 days later of encephalomyelitis Herpes B Infection Incubation period - few days to a month. Numbness and sometimes vesicles or ulcers occur at the exposure site. Symptoms Influenza-like: fever, muscle aches, malaise, headache. Variable symptoms: nausea, vomiting, abdominal pain, hiccups. Neurological symptoms when the infection spreads to CNS. Most patients with neurological symptoms die. Herpes B Vital Statistics 40 cases have been reported. The majority of cases occurred in the 1950's and 1960's during the production of poliovirus vaccines. Before antiviral therapy was available, this virus was a serious zoonotic threat to people who came in contact with macacques. Herpes B is still prevalent in free-ranging macaques native to Southeast Asia. Free-ranging macaques are a tourist attraction and humans are at risk of contact with infected animals. 15.3 Laboratory Diagnosis of Herpesvirus Infections Most definitive test is presence of viable virus in a clinical specimen (e.g. oral and genital lesions) HSV-1 and VZV-Infected Cells Contain Multinucleated Giant Cells and Inclusion Bodies 15.4 Herpesvirus Life Cycle Virus Structure and Classes of Herpesviruses Large (150-300 nm in diameter) Enveloped (obtained via a double envelopment process) Pleomorphic particles. Herpesvirus Envelope Fragile and easily disrupted by heat, desiccation, 70% alcohol, soap and detergents The envelope is extremely sensitive to damage - the virus is usually transmitted by direct contact with the mucosal surfaces or secretions of an infected person (e.g. lips, genitals). Herpesviruses dry out and become damaged when exposed to air so cannot be transmitted by toilet seats or other inanimate objects - a common misconception. Herpesvirus Nucleocapsid and Genome Linear dsDNA Large genome 125-230 kb in length Herpesvirus virion consists of more than 30 virally encoded proteins Virion also contains cellular proteins Capsid that surrounds the dsDNA genome icalled an amorphous proteinaceous tegument. 3 Subfamilies of Herpesviridae Based on Viral Latency and Growth in Cell Cultures Herpesvirus Entry and Uncoating Herpesviruses attach to the cells of the epidermis or dermis of the skin. Entry occurs through multiple cell-surface receptors and proteins located on the surface of the virion. The viral envelop contains more than a dozen viral integral membrane glycoproteins but only 5 of HSV participate in entry: gB gC gD gH gL Nucleocapsid is released into cytoplasm Some tegument proteins remain in cytoplasm Virion host shutoff (vhs) tegument protein plays a role in cellular mRNA degradation, consequently, viral mRNAs accumulate in the cytoplasm and are preferentially translated Other tegument proteins are transported to the nucleus VP16 binds to DNA and is an activator of transcription Replication Upon entry, the virus proceeds in 1 of 2 possible pathways: Productive, lytic infection Latent Infection Productive, Lytic Infection After uncoating, the viral genome in the nucleus cirularizes and is transcribed by the cell's DNA dependent RNA polymerase. Also involves viral UL9 (bind to ORI and unwinds DNA) UL5, UL8, UL52 (helicase, primase complex, synthesizes RNA primers) UL30 (viral DNA polymerase) with UL42 binds to the RNA primers and starts DNA synthesis Hallmarks of Herpesvirus Genomes Encode enzymes required to increase the pool of nucleotides in a cell and to replicate the viral genome. Thymidine kinase Ribonucleotide reductase Uracil DNA glycosylase Deoxyuridine triphosphatase These enzymes are good targets for antiviral therapy. About 50% of HSV-1 and HSV-2 genes encode regulatory proteins involved in latency and evading the host immune system (e.g. virokines). Herpesviruses and Poxviruses Share Transcription Properties Transcription is temporally and sequentially regulated in both herpesvirus and poxvirus life cycles. Poxviruses - early, intermediate, late gene expression. Herpesviruses - early (a), intermediate (b), late (g) gene expression. Herpesvirus VP16 (the 16th protein to accumulate in cells after infection) activates transcription of the a genes. The b genes encode DNA replication and additional viral transcription factors. The g genes encode the late structural proteins of the virion that are produced after viral genome replication occurs. Synthesized g proteins are transported to the nucleus, where capsid assembly begins. Viral Membrane Formation Occurs by a double envelopment process. The viral capsid is enveloped by the nuclear membrane as it translocates the nucelocapsid to the cytoplasm of the cell. The nucleocapsid then buds through the Golgi-derived vesicles and the cellular plasma membrane and cell lysis occurs. Viral Replication and Latency HSV-1 and HSV-2 establish life-long latency in sensory neurons. During latency, a limited number of viral genes are expressed. These are called LATS (latency associated transcripts). No viral particles are detected during latency. The virus hides for months or years until it is re-activated. Once HSV-1, HSV-2, VZV is reactivated, it travels the nerve pathway to the surface of the skin. 15.5 Antivirals: Treatment of Herpesvirus Infections Most commonly prescribed drug is acyclovir. Guanosine analog (ACG) Relatively nontoxic Can be used for long-term prophylaxis Can be administered topically to the skin or eye, intravenous or orally Acyclovir Structure Acyclovir is converted 200X more efficiently to ACG-monophosphate by the herpesvirus thymidine kinase Acts as a chain terminator Diet and Herpesvirus Infections? Research and herpesvirus remission HSV virus proteins synthesized in infected cells contain more arginine than lysine Foods high in L-lysine may help control HSV outbreaks Foods high in I-arginine may cause HSV outbreaks 15.6 Chickenpox and the Development of Other Herpesvirus Vaccines Chickenpox vaccine is a live attenuated Oka strain Oka strain isolated from an otherwise healthy 3 year old Japanese boy who had an acute case of chickenpox Now licensed as Varivax Oka/Merck by the FDA for use in the U.S. in 1995 Recommendations 1 dose between 12-18 months of age If the child has not had chickenpox or the vaccine -- and is 13+, two doses, 4-8 weeks apart. Unanticipated Results of the Chickenpox Vaccine Breakthrough varicella Wildtype virus that causes a mild form of chickenpox (on average, a maximum of 50 lesions or less) Occurs in 0.3 to 3.8% of vaccinees More common in the U.S. than in Japan Will the Chickenpox Vaccine Prevent Herpes Zoster (Shingles) Results of Dept. of Veteran Affairs Shingles Prevention Study - Varivax vaccine reduced shingles cases by 51.3%. Zostavax (Merck) was approved by the FDA in 2006 to reduce shingles in people 60+ years old. Each dose contains 14X more live virus than Varivax Other Herpesvirus Vaccines in the Pipeline: Dream or Reality? Developing a CMV vaccine is a top priority for several reasons: CMV infection is a major disease of the immune compromised. CMV infection is the leading cause of inner ear (cochlea) hearing loss and nervous system damage in children 15.7 The Use of Genetically Engineered HSV to Treat Brain Tumors Patients with malignant gliomas are ideal candidates for novel molecular based therapies because: Metastases are rare MRI studies are available to monitor the outcome Viruses provide a delivery technique that can target the tumor HSV as an Attractive Vector HSV can replicate in neurons and glia. HSV DNA is easy to manipulate (can carry extra genes) HSV is neurovirulent and would need to be engineered to replicate in a dividing tumor but not in surrounding healthy tissue cells of the CNS. Recombinant HSV's are being engineered to be safe vectors for glioma treatment.