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Home , Herpes gladiatorum, Herpetic whitlow, Smallpox

Introduction to

u “” originates from Latin word “poison”.

u Term was originally used by Pasteur to describe infectious agent for rabies. Chapter 13: u First virus discovered was tobacco mosaic disease virus (TMV) in 1890s. Viruses u Distinguished from bacteria by being “filterable agents” in early 1900s.

u In 1930s: TMV was isolated and purified. Electron was used to observe viruses.

u By 1950s of was well established.

Patient infected with virus Characteristics of all viruses

u Acellular infectious agents u Obligate intracellular parasites u Possess either DNA or RNA, never both u Replication is directed by viral nucleic acid within a cell u Do not divide by binary fission or mitosis u Lack genes and enzymes necessary for energy production u Depend on host cell ribosomes, enzymes, and nutrients for protein production u Smaller than most cells Source: Center for Disease Control (CDC)

Viruses are Smaller Than Most Cells Components of mature viruses (virions ): Capsid: Protein coat made up of many protein subunits (capsomeres). Capsomere proteins may be identical or different. Genetic Material: Either RNA or DNA, not both

Nucleocapsid = Capsid + Genetic Material

Additionally some viruses have an: Envelope : Consists of proteins, glycoproteins, and host lipids. Derived from host membranes. Naked viruses lack envelopes.

1 Viruses Have Either DNA or RNA Inside Viruses are classified by the following a Protein Capsid (Nucleocapsid) characteristics:

u Type of genetic material u Capsid shape u Number of capsomeres u Size of capsid u Presence or absence of envelope u Host infected u Type of disease produced u Target cell u Immunological properties

Types of viral genetic material: Genetic material may be single stranded or double stranded: Capsid morphology: u Single stranded DNA (ssDNA):

F Parvoviruses F Helical: Ribbon-like protein forms a spiral around the nucleic acid. May be rigid or flexible. u Double stranded DNA (dsDNA): • Tobacco mosaic virus F Herpesviruses • virus F Adenoviruses F Poxviruses F Polyhedral: Many-sides. Most common shape is F Hepadnaviruses* (Partially double stranded) icosahedron, with 20 triangular faces and 12 u Single stranded RNA (ssRNA): May be plus (+) or corners. minus (-) sense: • Poliovirus F (+) • Herpesvirus

F Retroviruses (+) F Complex viruses: Unusual shapes F Rhabdoviruses(-) • Bacteriophages have tail fibers, sheath, and a plate u Double stranded RNA (dsRNA): attached to capsid. • Poxviruses have several coats around the nucleic acid. F Reoviruses

Host Range: Spectrum of hosts a virus can infect. Life Cycle of Animal Viruses u Bacteria (Bacteriophages) 1. Attachment or adsorption: Virus binds to u Animals specific receptors (proteins or glycoproteins) u Plants on the cell surface. u Fungi 2. Penetration: Virus enters cell through one of u Protists the following processes: Viral Specificity: Types of cells that virus can infect. • Direct fusionwith cell membrane u Dermotropic • Endocytosis through a clathrin coated pit u Neurotropic 3. Uncoating: Separation of viral nucleic acid u Pneumotropic from protein capsid. Lysosomal, cytoplasmic, u Lymphotropic or viral enzymes may be involved. u Viscerotropic: Liver, heart, , etc.

2 Life Cycle of a DNA Virus Life Cycle -Animal Viruses (Continued) 4. Synthetic Phase: Involves several processes:

F Synthesis of viral proteins in F Replication of viral : • DNA viruses typically replicate in nucleus • RNA viruses replicate in cytoplasm F Assembly of progeny virus particles

The synthetic stage can be divided in two periods:

F Early period: Synthesis of proteins required for replication of viral genetic material. F Late period: Nucleic acid replication and synthesis of capsid and envelope proteins

Life Cycle of Bacteriophages Life Cycle -Animal Viruses (Continued) T-Even Bacteriophages : Lytic Cycle 5. Release of progeny virions: There are two main mechanisms of release: Lytic: Cell bursts at end of cycle A.Lysis of cells: Naked viruses and viruses leave 1. Attachment or adsorption: Virus tail binds to cell by rupturing the cell membrane. specific receptors on the cell surface. Usually results in death of the host cell. 2. Penetration: Virus injects genetic material Example: Poliovirus (DNA) into cell. Tail releases lysozyme, capsid B. Budding: Enveloped viruses incorporate viral remains outside. proteins in specific areas of a membrane and bud 3. Biosynthesis: Viral proteins and nucleic acids through the membrane. are made. Envelope contains host lipids and carbohydrates. Host cell does not necessarily die. Eclipse phase: No virions can be recovered Example: Human Immunodeficiency Virus from infected cells.

Lytic Cycle of Bacteriophage 4. Maturation: Bacteriophage capsids and DNA are assembled into complete virions. 5. Release: Bacteriophage virions are released from the cell. Plasma membrane breaks open and cell lyses.

Burst time: Time from attachment to release of new virions (20-40 minutes). Burst size: Number of new phage particles that emerge from a single cell (50-200).

3 Lytic Cycle of Bacteriophage Life Cycle of Bacteriophages Bacteriophage Lambda: Lysogenic Cycle 1. Attachment and Penetration: Virus tail binds to specific receptors on the cell surface and injects genetic material (DNA) into cell. 2. Circularization: Phage DNA circularizes and enters either lyticor lysogenic cycle. Lysogenic Cycle 3. Integration: Phage DNA integrates with bacterial chromosome and becomes a prophage . Prophage remains latent. 4. Excision: Prophage DNA is removed due to a stimulus (e.g.: chemicals, UV radiation) and initiates a lytic cycle.

Lysogenic versus Lytic Cycles of Bacteriophage Important Human Viruses DNA Virus Families 1. Adenoviruses : Cause respiratory , such as the . First isolated from adenoids. 2. Poxviruses : Produce skin . Pox is a pus filled vesicle. Cause the following diseases: u Smallpox u u Molluscum contagiasum.

Smallpox: Poxviruses Cause Pus Filled Vesicles Important Human Viruses DNA Virus Families 3. Herpesviruses : Herpetic means to cause spreading cold sores. Over 100 species. Eight infect humans: u 1 (oral herpes) u Herpes simplex 2 () u Varicella-zoster virus ( and ) u Epstein -Barr virus u Kaposi’s sarcoma virus

Disease was eradicated worldwide by in 1977. Source: Perspectives, 1999.

4 Important Human Viruses (Continued) Biological Properties of Hepadnaviruses DNA Virus Families u Enveloped virus. Envelope contains middle, 4. Papovaviruses : Cause (papillomas ), large, and major surface proteins. tumors (polyomas ), and cytoplasmic vacuoles u Many incomplete viral particles found in Human papilloma virus is sexually infected individuals. transmitted and causes most cases of cervical u Small circular DNA molecules that are partially cancer in women. Cervical cancers typically double stranded. u Long Strand: Constant length. 3200 nucleotides take over 20 to 30 years to develop, most u Short strand: 1700 to 2800 nucleotides. women develop them in their 40s and 50s or u Genome encodes for a handful of proteins: older. Pap smears are used to detect them. u Surface antigens 5. Hepadnaviruses : Cause hepatitis and liver u Capsid proteins u Polymerase cancer. Hepatitis . u Protein X: Stimulates gene expression

RNA Virus Families Rabies is Caused by a Rhabdovirus 1. Picornaviruses : Naked viruses with a single strand of RNA. Include the following: u Poliovirus u Hepatitis A virus u : Over 100 viruses that cause the common cold. 2. Togaviruses : Enveloped ssRNA viruses. Cause and horse . 3. Rhabdoviruses : Bullet-shaped, enveloped viruses. Cause rabies and many animal Hydrophobia in rabies patient. diseases. Source: Diagnostic Pictures in Infectious Diseases, 1995

Retroviruses Convert RNA into DNA Important Human Viruses (Continued) via Reverse Transcriptase RNA Virus Families 4. Retroviruses : Unique family of enveloped viruses. Have the ability to convert their RNA genetic material into DNA through an enzyme called reverse transcriptase. Viral DNA is integrated into host chromosome (provirus) where it can remain dormant for a long time. Include HIV-1 and HIV-2 which cause AIDS and Human T Lymphocyte viruses which cause cancer.

5 Viruses and Cancer u DNA Oncogenic Viruses: u Oncogenic viruses: Approximately 10% of all u Adenoviridae (Rodents) cancers are virus induced. u (Epstein-Barr Virus and Kaposi’sSarcoma Herpes Virus) u Oncogenes: Viral genes that cause cancer in u Papovaviridae (Papillomaviruses) infected cells. u Hepadnaviridae () u Provirus: Viral genetic material integrates into host cell DNA and replicates with cell u RNA Oncogenic Viruses: chromosome. Some viruses may incorporate host u Retroviridae (Human T-cell leukemia 1 & 2) genes which can cause cancer under certain conditions. Example: Retroviruses

Detection of Viruses Antiviral Therapeutic Agents u Electron microscopy Agent Virus Mechanism u Immunologic Assays: Detect specific viral Amantadine Inhibits uncoating proteins or to them. u Western Blotting Acyclovir Herpes simplex Inhibits DNA polymerase u ELISA Herpes zoster u Biological Assays: Detect cytopathic effects Gancyclovir Inhibits DNA polymerase

(CPE) caused by viral of cells. Ribivarin Respiratory syncitial Inhibits viral enzymes for u Plaque assays for lytic viruses virus/Lassa virus guanine biosynthesis u Focus formation for transforming oncogenic viruses Azidothymidime HIV Inhibits reverse transcriptase u Hemagglutination Assay: Many viruses clump red blood cells. Cytomegalovirus Inhibits protein synthesis Hepatitis B Degrades ssRNA u Molecular Assays: Assay for viral nucleic acids. u PCR (Polymerase chain reaction) u Southerns (DNA) or Northerns (RNA)

II. Killed or inactivated : Virus is typically VIRAL VACCINES grown in or cell culture and inactivated with formalin. First was used by Jenner(1798) against Examples: (shots, Salk vaccine), rabies, and smallpox and contained live (cowpox) virus. influenza A & B. I. Live attenuated vaccines: Mutant viral strains Advantages: Immunization with little or no risk of infection. produce an infection in host. Disadvantages: Less effective , Examples: Polio (oral, Sabin vaccine), , yellow inactivation may alter viral antigens. , mumps, rubella, and chickenpox. III. Recombinant vaccines: Viral subunits are •Advantages: Better immune response produced by genetically engineered cells. •Disadvantages: May cause disease due to Example: Hepatitis B contamination, genetic instability, Advantages: Little or no risk of infection. or residual virulence. Oral polio vaccine recently discontinued in U.S. Disadvantages: Less effective immune response.

6 Hepatitis B is a Major Threat Infectious Diseases Causing Most u Fifth leading cause of deaths due to infectious disease in the world. Deaths Worldwide in 1998 u 2 million deaths per year. Disease Cause Deaths/year u Over 300 million infected individuals worldwide. Acute Respiratory* Bacterial or viral 4,400,000 u In Southeast Asia and Africa 10% population is infected. Diarrheal diseases Bacterial or viral 3,200,000 u In North America and Europe 1% population is infected. Tuberculosis Bacterial 3,100,000 u Highly contagious. Virus particles found in Protozoan 3,100,000 saliva, blood, and semen. Hepatitis B Viral 2,000,000 u Mechanisms of : Measles Viral 1,500,000 u Mother to infant: Primarily at birth. AIDS Viral 1,000,000 u Intimate or sexual contact. Neonatal Tetanus Bacterial 600,000 u Blood transfusions or blood products. u Direct contact with infected individuals: workers. *: , , influenza, etc.

Characteristics of Hepatitis B Infection Characteristics of Hepatitis B Infection : 2 to 6 months. Several possible outcomes: Several possible outcomes: u Cirrhosis of the Liver: Severe damage, leading to liver failure. u Asymptomatic infection: Most individuals. u Hepatocellular Carcinoma: Usually takes 30 to 50 u Acute Hepatitis: Liver damage, abdominal pain, jaundice, etc. Strong immune response usually years to develop. May develop in children. leads to a complete recovery. u Fulminant Hepatitis: Usually fatal. Rare. u Chronic Hepatitis: Poor immune response to virus, which remains active for years. May be healthy, experience fatigue, or have persistent hepatitis. Associated with development of liver cancer and cirrhosis.

Herpesviruses Morphology of Herpesviruses Family of over 100 viruses which infect a broad range of B animals. u Polyhedral capsid: Icosahedral capsid, 100-110 nm in diameter. u Envelope: Contains viral glycoproteins on its surface. Virion is about 200 nm in diameter. u Tegument: Unique to herpesviruses. Amorphous material surrounding capsid. Contains several viral proteins. A. Schematic Representation B. Electron micrograph u Large genome: 140-225 kb of linear dsDNA which circularizes after infection. Source: Virology 3rd edition, 1996

7 Biological Properties of Herpesviruses Human Herpesviruses Virus Common Name/Disease Class Size Latency u Encode large array of enzymes involved in HHV-1 Herpes simplex 1 (HSV -1) a 150 kb Sensory nucleic acid metabolism. Oral, ocular lesions, encephalitis nerve ganglia u Synthesis of viral DNA and assembly of capsid HHV-2 Herpes simplex 2 (HSV -2) a 150 kb Sensory occurs in the nucleus. Genital lesions, neonatal infections nerve ganglia HHV-3 a 130 kb Sensory u Production of infectious progeny causes Chickenpox, shingles nerve ganglia destruction of infected cell. HHV-4 Epstein-Barr virus g 170 kb B cells u Latency: Can remain latent in their natural Mononucleosis, tumors` Salivary gland hosts. Viral DNA remains as closed circular HHV-5 Human Cytomegalovirus b 230 kb Lymphocytes Microcephaly , infections in molecule and only a few viral genes are immunocompromised hosts expressed. HHV-6/7 /7 b 160 kb CD4 T cells Infantum HHV-8 HumanHerpesvirus 8 g 140 kb Kaposi’s Kaposi’s sarcoma, lymphoma? Sarcoma tissue

Clinical Manifestations of HSV-1 Recurrent : 70-90% of adults are infected. Most are asymptomatic. u Gingivostomatitis: Most common manifestation of primary HSV-1 infection. Initial infection typically occurs in early childhood. u Recurrent herpes labialis: Cold sores, fever . After primary disease, virus remains latent in trigeminal ganglion. During reactivation, virus travels down nerve to peripheral location to cause recurrence. Less than 1 day with Same patient 24 h later with multiple erythema and burning fluid filled vesicles and erythema u : Infection of finger.

Recurrent Herpes Labialis: Bilateral vesicles on upper and lower lips. : Multiple crusting ulcerations that begin as vesicles. Source: Atlas of Clinical Oral Pathology, 1999. Source: Atlas of Clinical Oral Pathology, 1999.

8 u Keratoconjunctivitis: Most common cause of corneal blindness in US. u Eczema hepeticum: Severe herpetic outbreaks in areas with eczema. u : of abraded skin by contact with infected secretions. u HSV encephalitis: Most common cause of acute sporadic encephalitis in US. u Chronic herpes simplex infection: Lesions in atypical oral locations. Immunocompromised patients.

Chronic Herpes Simplex infection with lesions on tongue and lips. Source: Atlas of Clinical Oral Pathology, 1999.

Clinical Manifestations of HSV-2 Genital Herpes Epidemiology: Acquisition follows typical pattern of STD. Seroprevalence ranges from 10% to 80% Most individuals are asymptomatic. u Genital Herpes: Most common manifestation HSV-2 infection. Most common cause of genital ulcers in U.S. Lesions on cervix, perineum, or penis shaft. Recurrence rates vary widely. u Perirectal Herpes: Can be severe in AIDS patients.

u Orofacial herpes: Less than 5% of cases. u Neonatal Herpes: Due to contact with infected genital secretions during delivery. Severe disease with encephalitis, pneumonitis, hepatitis, and retinitis. Herpes simplex 2 infection with fluid filled vesicles on penis. Source: Mike Remington, University of Clinic

Clinical Manifestations of Varicella Zoster (HHV-3) u Chickenpox (Varicella): Most common manifestation of primary herpes zoster infection. Epidemiology: 3 million cases/year in US, highest incidence in the spring. Highly communicable. Airborne or skin transmission. Incubation period 14 days. Symptoms: , sore throat, rhinitis, and generalized that progresses from macules to vesicles. Intraoral lesions may precede rash. Complications: Reye’s syndrome, bacterial superinfection of lesions, varicella pneumonia and Acyclovir resistant peri-rectal HSV2 infection in HIV infected male. neonatal varicella (30% mortality). Source: AIDS, 1997 Vaccine: Prevents chickenpox in 70-90% of recipients.

9 Clinical Manifestations of Varicella Zoster (HHV-3) u Shingles (Herpes Zoster): Recurrence of latent herpes zoster infection. Epidemiology: Occurs in 10-20% of individuals at some stage of life. Incidence increases with old age, impaired , alcohol abuse, and presence of malignancy. Symptoms: Vesicular eruption on skin or mucosa, that follows pathway of nerves. Typically unilateral, stopping at midline. Complications: Post-herpetic neuralgia can last months to years. Herpes Zoster (Shingles) with vesicles on skin of left hip. Source: Atlas of Clinical Oral Pathology, 1999.

Shingles in an AIDS Patient EBV Associated Diseases (HHV-4) Epidemiology: 90% of adults are infected. Initial infection typically occurs in early childhood or adolescence. Most individuals are asymptomatic, but shed virus in saliva throughout life. u Infectious mononucleosis: A minority of infected individuals. Fever, pharyngitis, and . Splenomegaly is common. u Burkitt’s Lymphoma (Africa) u Nasopharyngeal carcinoma (Asia) u Oral Hairy Leukoplakia: In HIV + individuals.

Oral Hairy Leukoplakia with bilateral thickening of the tongue. Source: AIDS, 1997. Burkitt’s Lymphoma with right facial swelling. Associated with EBV. Source: Handbook of pediatric oral pathology, 1981.

10 u Non-Hodgkin’s Lymphoma: In HIV + Clinical Manifestations of individuals Cytomegalovirus (HHV-5) u Hodgkin’s Lymphoma: 50% of cases. Epidemiology: 50% of US population is seropositive. u Smooth muscle tumor (children) Transmission: Perinatal, early childhood, sexual, u Thymic lymphoepithelioma transfusions, and organ transplants. u Salivary gland carcinoma Symptoms: Most cases are asymptomatic. u Congenital CMV: May cause intellectual or hearing u Urogenital carcinoma deficits. u Pneumonitis in transplants. u Retinitis, esophagitis, and colitis are common in AIDS patients

HHV-8 Associated Diseases First identified in 1995. u Kaposi’sSarcoma: Accounts for 80% of all cancers in AIDS patients. Lesions are flat or raised areas of red to purple to brown discoloration. May be confused with hemangioma or hematoma. u Strong male predominance. u 2/3 of affected patients present oral lesions u Oral lesions are initial presentation in 20% of patients. u Progressive malignancy that may disseminate widely. u Oral lesions are a major source of morbidity and Extensive symmetric tumor lesions of Kaposis’s sarcoma in an frequently require local therapy. AIDS patient. Source: AIDS, 1997

Kaposi’s Sarcoma hemorrhagic mass on anterior maxillary gingiva. Endemic Kaposi’s Sarcoma, nodular form. Source: Atlas of Clinical Oral Pathology, 1999. Source: AIDS, 1997.

11 Introduction to Influenza Viruses Structure of Influenza Virus u Enveloped ssRNA virus (negative strand).

u Genome is divided into 8 segments, each containing 1 or 2 genes. u RNA is replicated in cell’s nucleus. u Helical nucelocapsid contains transcriptase. u Envelope forms as virus buds from cell membrane. u Two surface glycoproteins:

u : Binds to sialic acid on host cell surfaces.

u Neuraminidase: Enzyme that cleaves sialic acid. u Fusion of envelope with cell surface membrane requires cleavage of hemagglutininby host cell enzymes.

u Serine proteases found in respiratory tract of mammals and digestive tract of birds. u Mutant hemagglutinin can be cleaved by other enzymes in body, causing infections throughout body.

Influenza Virus Strains Influenza Virus Strains I. Influenza A: II. Influenza B: u Promiscous: Infects humans, pigs, chickens, seals, horses, u Only infects humans.

whales, and birds. u Little diversity: Only one form of HA and NA. u Diverse group of substrains: u Lacks M2 protein and not inhibited by antiviral drugs u 15 different hemagglutinin molecules amantidine and rimantidine. u 9 different neuraminidase molecules u Can mutate through antigenic drift only. u Also contains M2 protein: Ion channel, blocked by antiviral drugs amantidine and rimantidine u Can mutate through antigenic shift in cells that are III. Influenza C: infected with two or more substrains. u Not important human u Responsible for all .

Influenza Pandemics Influenza Epidemics u All caused by influenza type A. u Smaller than pandemics, occur regularly. u The deadliest major occurred in 1918, during u In 1994 flu epidemic:

World War I (). u Infected 90 million Americans (35% of population)

u Over 30 million deaths worldwide in less than 10 months. u Over 69 million lost days of work. u 600,000 deaths in the U.S. u Typical epidemics in the U.S. u Caused by H1N1 subtype of influenza A u Infects 10-20% of population. u Asian flu in 1957: u Causes 20,000 deaths per year from complications. u Caused by H2N2 subytpe of influenza A u 1968 Hong Kong flu:

u Caused by H3N2 subtype of influenza A u In 1997 a new strain appeared in Hong Kong (H5N1) that appeared to have jumped directly from birds to humans.

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