Microbiology: Virology

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VIROLOGY STUDY SHEET

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Basic Virology
DNA Viruses
RNA Viruses

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BASIC VIROLOGY

VIRUS MORPHOLOGY:

Capsid: Composed of numerous repeating subunits. Viral genome is thus conserved in that a single protein can be transcribed many times to make the capsid.
Capsomere: Clusters of polypeptides which, when completely assembled, form the capsid.
Nucleocapsid: Genome together with capsid.
Virion: Free viral particle, consisting of nucleocapsid, or nucleocapsid plus envelope.
Envelope: Lipid bilayer, usually obtained from host cell.
Symmetry: Three types

Cubic Symmetry: Icosahedral symmetry. 20 equilateral triangles.
Helical symmetry
Complex: No regular symmetry, as in poxvirus.

Viral Conditions:

Alkaline kills all viruses.
Ether: Enveloped viruses are susceptible to ether. Poxviruses vary in susceptibility.
Enveloped viruses are generally less stabile than naked viruses.

Host-cell Virus Interactions:

Productive Infection: Virus successfully completes replication cycle and produces progeny virions.
Abortive Infection: Virus enters the host-cell but cannot successfully complete replication.

Can result from a non-permissive host-cell, or because the virus is defective.
Abortive infections can become persistent infections.

Restrictive Infection: Cells are only transiently permissive, after which they become non-permissive. This results in transformation of the cell.
Latent Infection: Virus remains in a cell and does not replicate, as in HSV, VZV, CMV, EBV, and HIV.

Replication Cycle:

Divided according to presence of infectious virions:

Eclipse Phase: Virus has entered cell, but no progeny virions are created yet.
Maturation Phase: Viral progeny are produced and infectious virions are again present.

According to biosynthesis sequence

Early Phase: Biosynthesis of prerequisite proteins, required before replication can take place, such as replicase enzymes or enzymes that inhibit host-cell synthesis.
Late Phase: Synthesis of structural capsid proteins, and actual replication of the genome.

BASICS of REPLICATION:

(+)-STRAND RNA: The RNA genome can directly serve as an mRNA, because it contains its own 5' cap and 3' Poly-A tail.

Isolated mRNA strands are infectious.

(-)-STRAND RNA: They contain no cap and tail.

Isolated mRNA strands are not infectious.
They utilize a viral RNA-Dependent RNA-Polymerase to make (1) Subgenomic mRNA's (non-structural and structural proteins), and (2) a complementary (+) RNA genome.
The positive-strand RNA genome then serves as a template to make more minus-strand RNA's, to be packaged with the structural proteins.

Polyproteins are often made by viruses, which are then cleaved, as eukaryotic machinery can't recognize a polycistronic mRNA.
Double-Stranded DNA: Herpes, Papova, Adeno

Early Genes are transcribed by host cell RNA-Polymerase, to form early proteins.
These early proteins include a viral DNA-Dependent DNA Polymerase, which then forms progeny DNA.
After replication, late genes are transcribed and translated, forming structural proteins.

Diagnostic Techniques:

Direct Examination

Light Microscopy
Fluorescent Microscopy

Direct FA: Antigen plus patient's serum will produce antibody if patient's serum contains the appropriate specific antibody.
Indirect FA: Antigen + antibody + anti-antibodies. It is cheaper and more commonly used.

Electron Microscopy

Immune Electron Microscopy

Solid Phase Immunoassay: Most common method today

RIA
ELISA

Nucleic Acid Hybridization

Isolation and Identification
Serodiagnosis

RIA: Detection of antigen.
ELISA: Detection of antigen. Commonly done on HIV.
Neutralization Test: Mix known virus with patient's serum, and if the patient's serum contains antibodies then viral growth will be inhibited.
Hemagglutinin Test:

INTERFERONS (IFN):

GENERAL PROPERTIES:

Is secreted out of host cell, usually found in a dimer or multimeric form.
IFN goes out, binds to specific receptors on neighboring cells, and changes their transcription in such a way as to give them anti-viral properties.
ds-RNA and LPS are both good inducers of IFN.

FUNCTION: Suggested mechanism of action involves RNA endonuclease activity, and induction of transcription of new genes.

IFN also prevents DNA synthesis and thus inhibits cell growth.
ANTI-TUMOR: IFN's generally have some anti-tumor activity, particularly on leukemias and lymphomas. They induce the production of HLA antigens on tumor cells, thereby allowing the immune system to recognize the tumor cell.

RESISTANT: CMV and VZV are resistant to IFN. Other viruses are mostly susceptible.
INTERFERON-alpha: Produced by leukocytes.

Receptor gene for IFN-alpha is on Chrom #21
FNXN: Has been approved as a treatment for rare B-Cell Hairy Leukemia.

INTERFERON-beta: Produced by fibroblasts.

Receptor gene for IFN-beta is on Chrom #21

INTERFERON-gamma: Produced by (1) unsensitized lymphoid cells, or (2) sensitized T_H1 cells.

It is stronger than other two in its antiviral properties.
Receptor gene for IFN-gamma is on Chrom #6

ANTIVIRAL CHEMOTHERAPY:

AMANTADINE and RIMANTADINE:

ACTION: Inhibits the uncoating stage (part of binding) of Influenza A virus.

Binds to M-Protein and blocks the pre-lysosomal uncoating, after attachment has already taken place.
Viruses can acquire resistance with extended use.

VIRUSES: Inhibits primarily the Influenza A virus, but also has activity against Influenza C, Sendai, Dengue, and Rubella viruses.

Parainfluenza 1,2,3, Influenza B, and RSV are resistant

SIDE-EFFECTS: In 10% of patients, CNS toxicity, nervousness, difficulty concentrating.
CLINICAL: Use is restricted to certain subgroups: in epidemics, at-risk patients, hospitalized patients.

RIBAVIRIN:

ACTION: Inhibits viral transcription, by binding to and inhibiting enzymes involved in nucleic acid metabolism. Specifically inhibits inosine monodehydrogenase, involved in the synthesis of GTP.
SIDE-EFFECTS: It is toxic in that it does not discriminate well between host cell and virus. Toxic to liver cells and can cause anemia.
VIRUSES: RSV in infants, and Lassa Fever intravenously.

ACYCLOVIR:

ACTION: It is converted by HSV viral Thymidine Kinase into a monophosphate activated form. Host cell then converts monophosphate form into triphosphate form. This form then does two things:

Binds and inhibits viral DNA polymerase
It is incorporated into viral DNA, where it acts as a chain-terminator.

RESISTANCE in HSV is due to mutations in two different viral proteins:

Viral Thymidine Kinase, preventing conversion of acyclovir to the triphosphate form.
Viral DNA polymerase, such that it doesn't bind the drug.

VIRUSES: Specific for HSV infections: HSV-1, HSV-2, VZV, but not CMV or EBV.

Resistance can occur, due to mutations in either Thymidine Kinase or viral DNA polymerase.

ADENINE ARABINOSIDE (Ara A):

ACTION: Binds to DNA-Polymerase -- cellular or viral, thus bad side effects.
VIRUSES: Used to be used for HSV-Encephalitis cases. Now surpassed by Acyclovir.

GANCICLOVIR:

VIRUS: CMV, promising new treatment. Also works on HSV.

Up to 80% of HIV patients will relapse if therapy is discontinued. CMV pneumonia does not respond as well as other CMV infections.

ACTION: Nucleoside analog of guanosine, similar to Acyclovir.
SIDE-EFFECTS: Reversible neutropenia, liver and CNS toxicity.

AZIDOTHYMIDINE (AZT, ZIDOVUDINE):

ACTION: Inhibits Reverse Transcriptase.

AZT is phosphorylated first by host enzymes.

VIRUS: HIV-1

PRIONS: They are associated with slow infections.

Kuru
Creutzfeldt-Jacob Disease
Scrapie
Mad-Cow Disease

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DNA VIRUSES

PARVOVIRIDAE:

STRUCTURE: Single-stranded DNA. The smallest of the DNA viruses.
REPLICATION: Occurs in nucleus. First, a complementary DNA (cDNA) is formed, which is then used as a template to form progeny virions.
Three Subtypes:

Densovirus: Infects insects.
Parvo Virus: Infects humans and animals, but there is no cross-infection.
Dependovirus: Depends on other viruses to replicate.

HUMAN PARVOVIRUS B19 (HPV B19): A parvovirus.

STRUCTURE: There is only one antigenic type, and immunity is lifelong and protective.
PATHOGENESIS:

It requires dividing cells to divide. It likes erythroid precursor cells.

TRANSMISSION: Respiratory, or by blood transfusion.
DIAGNOSIS: Immune electron microscopy. ELISA or RIA. PCR.

Can assay serum IgM to detect acute infection.

MANIFESTATIONS:

Erythema Infectiosum: "Fifth Disease" in children.

Rash produces a "slapped-cheek" appearance on face, then proceeds to trunk and limb. This progression is like measles -- rash goes from the head down.
In adults, it produces mild fever, arthralgia, and limited rash.

Aplastic Crisis in people with Sickle Cell Anemia. Virus replicates in erythroid precursor cells and thus can result in fall in hemoglobin and aplastic crisis.
Hydrops Fetalis, Spontaneous Abortion: Hydrops fetalis occurs as a result of infection of fetal heart, liver, kidney, and RBC's, with consequent fall in hemoglobin.
Mild systemic and respiratory illnesses

ADENO-ASSOCIATED VIRUS (AAV): A Dependovirus. Defective virus requires Adeno or Herpes virus coinfection.

PATHOGENESIS:

It produces a latent infection.
It integrates into host on specific site of chrom #9 as a provirus, so it is a good candidate for gene therapy.

MANIFESTATIONS: We don't know what disease, if any, this virus is associated with.

RA-1: Virus associated with Rheumatoid Arthritis.

PAPOVAVIRIDAE: Pappiloma-Polyoma-Vacuolating Agents virus.

STRUCTURE: ds-DNA, circular. No envelope. Supercoiled double-stranded circles of DNA, wrapped around host histones to form a chromosome-like structure.
HUMAN PAPILLOMAVIRUSES:

PATHOGENESIS: Papillomavirus replicates in host nucleus but it does not integrate as a provirus.

Virus is species-specific, and it is tissue-specific to epithelial cells only.

REPLICATION: Genome divided into Early region (early proteins) and late region (late proteins)

Early Proteins (E1-E8): Synthesized before DNA replication. The proteins are important in replication, transcription, and oncogenic transformation.
Late Proteins (L1-L2): Synthesized after DNA replication. Structural proteins.

DIAGNOSIS: Cytology, EM, or PCR. Does not grow well in culture.
MANIFESTATIONS:

Common Warts (verruca): HPV-2,4 Thickening of the epidermis, and hyperkeratosis.

Terminally differentiated surface epithelial cells are permissive, so the virus multiplies in those cells. These cells eventually die from lytic infection.
Basal Cells are non-permissive. Only the early genes are produced in these cells -- until they differentiate to epithelial ccells.

Gene products of the early genes stimulate differentiation of the basal cells and growth of the wart.

Common in children. Lower incidence in adults may be because of acquired immunity.

Deep Plantar Warts: HPV-1,2
Genital Warts (Condylomata Acumulata): HPV-1,2,6,11,16,18
Cervical Carcinoma: HPV-16,18. It starts as cervical dysplasia, and not all forms progress to cancer.

TREATMENT:

Podophyllin, or salicylic acid with glutaraldehyde may be used. Or use alpha-IFN IM for severe genital warts or laryngeal papillomas.

POLYOMAVIRUSES: They are asymptomatic in immunocompetent hosts. They are ubiquitous viruses. Both viruses are tumorigenic.

PATHOGENESIS: Polyoma can integrate into host DNA as a provirus.
DIAGNOSIS: It does grow well in culture.
JC VIRUS (JCV): Progressive Multifocal Leukoencephalopathy (PML), in immunocompromised host. It infects microglial cells in brain.

5-10% of AIDS patients.
It is a slow virus disease.

BK VIRUS (BKV): Infects kidney and causes Ureteral Stenosis and Hemorrhagic Cystitis in immunocompromised host.
Simian Virus 40 (SV40): Formerly called vacuolating agent. Not associated with any disease in humans.

Resides in latent state in monkey kidney cells.
REPLICATION: Early and late proteins are formed. Large T-Antigen and small T-Antigen are formed respectively. dsDNA is duplicated in a semiconservative anti-parallel fashion, utilizing leading and lagging strand, and okazaki fragments.

HEPADNAVIRIDAE:

STRUCTURE: Circular DNA, partially double-stranded, partially single-stranded.
REPLICATION: DNA replication with an RNA intermediate, utilizing Reverse Transcriptase.

Upon entry of virus into cell, the viral DNA-Polymerase repairs the single-stranded end of the molecule, forming a supercoiled dsDNA genome.
Host-cell RNA Polymerase then forms mRNA's from the DNA genome:

Full-length (+) mRNA
Subgenomic mRNA's, from which structural and non-structural proteins are made.

The full-length mRNA gets enclosed around a core-capsid.
Inside the core, viral DNA Polymerase then serves as a Reverse Transcriptase, to make DNA out of the full-length mRNA.

cDNA is formed, forming a DNA:RNA hybrid. The RNA is then degraded, and then a complementary DNA strand is formed, making dsDNA.

dsDNA progeny genome is then put out of cell, taking outer envelope with it as it leaves host cell.

HEPATITIS-B VIRUS (HBV):

STRUCTURE:

Dane Particle: The entire infectious virion, including nucleocapsid, core antigens, and surface antigens.
HBV Surface Antigen (HBsAg): 4 phenotypes, useful for epidemiology: adw, ayw, adr, ayr.

TRANSMISSION: Sexual, fecal-oral, or intravenous or by exposure to blood products.
DIAGNOSIS:

Term	Abbrev	Description
Hepatitis-B Surface Antigen	HBsAg	Surface antigen present on viral envelope. Its presence indicates acute HBV infection.
Antibodies to Hepatitis-B Surface Antigen	Anti-HBs	Antibodies to the surface antigen are not detectable during acute infection even though they are being made, because there is way more antigen and it sops it all up, making it undetectable in the blood. Presence of Anti-HBs indicates immunity to HBV or previous vaccination for HBV.
Hepatitis-B Core Antigen	HBcAg	Its presence indicates acute HBV infection.
Antibodies to Hepatitis-B Core	Anti-HBc	Its presence indicates acute or chronic HBV infection. Whether it is acute or chronic depends on whether IgM is present or IgG.
Hepatitis B e Antigen	HBeAg	This is the hepatitis viral polymerase and is present during acute infection.
Antibodies to Hepatitis-B e Antigen.	Anti-HBe	These aren't usually tested but are present during acute or chronic infection.
Antibodies to Hepatitis-A	Anti-HAV	Indicates acute infection of Hepatitis-A. There is no chronic Hepatitis-A infection.
Antibodies to Hepatitis-C	Anti-HCV	Indicates acute or chronic infection of Hepatitis-C.

MANIFESTATIONS: Cell-mediated immunity is responsible for the symptoms.

Acute Infection: Acute infection may or may not lead to persistent infection. HBsAg and Anti-HBc will show up in blood.
Chronic (Persistent) Infection: Hepatitis-B virus is still being produced. 5-10% of HBV can be expected to develop an HBV carrier state.

Vasculitis, arthralgia, rash, and kidney problems can all result from immune-complex disease involving immune complexes of the HBsAg.
Primary Hepatocellular Carcinoma: 80% of primary hepatomas are due to HBV infection.

Other Hepatitis Infections:

Hepatitis-A (HAV): Enterovirus-72
Hepatitis-C (HCV): Flavivirus.
HEPATITIS-D (Delta Agent): Hepatitis-B is required in order for this virus to infect.

STRUCTURE: ss circular RNA that resembles an intron. RNA encodes the delta antigen, which is in turn enveloped by the HBsAg.
MANIFESTATIONS: Should be tested for as co-infection with HBV. Course is more severe and prognosis is poorer when Delta agent is present.

Hepatitis-E (HEV): Calicivirus

VACCINE: It consists of the Hepatitis-B Surface Antigen, to which we then make protective antibodies. Thus presence of Anti-HBs is indicative of previous vaccination.

ADENOVIRIDAE:

STRUCTURE: ds-DNA, linear, non-enveloped, enclosed in a cubical capsid. Capsomeres form hexons and pentons.
REPLICATION: In nucleus.

The DNA has an accessory protein covalently linked at the 5' end, which aids in viral replication.
Early genes are transcribed in the cytoplasm. Early proteins inhibit host DNA synthesis and promote viral DNA synthesis and late gene expression.
Late genes transcribe a long mRNA that is differentially spliced to form structural proteins.
Replication differs from SV40 virus in that it proceeds from the ends toward the center, but there are no Okazaki fragments.

ADENOVIRUS: 41 serotypes, grouped A-G.

PATHOGENESIS: Infects epithelial cells lining respiratory tract, GI tract, and conjunctiva.

It persists in lymphoid tissues such as Peyer's Patches may be reactivated in immunosuppression.
Produces a cytopathic effect (CPE) of grape-like clusters in culture.

TRANSMISSION: Fecal-oral, respiratory.
MANIFESTATIONS: Only a small number of infections.

Acute Respiratory Infections: Types 4-7. Military recruits now get a vaccine to prevent this.
Conjunctivitis: Types 3 and 8. Epidemic keratoconjunctivitis or Shipyard-Eye.
Acute Gastroenteritis: Types 40 and 41, especially in infants.
Acute Hemorrhagic Cystitis: Young males; types 11 and 22.
Cervicitis and urethritis: Types 37
Pharyngoconjunctival fever: In children, types 3 and 7
Acute febrile pharyngitis

HERPESVIRIDAE:

STRUCTURE: ds-DNA, linear, enveloped.

Tegument: Amorphous protein structure that surrounds the capsid.

DIAGNOSIS: Cell culture will show intranuclear inclusion bodies.
ALPHA-HERPES VIRUSES: Grow very rapidly, have a broad host-range. Latency is usually in neural tissue.

REPLICATION: Occurs in the nucleus.

HSV-1 and HSV-2 binds to a heparin sulfate receptor, present on every cell in the body.
Immediate Early Genes:

alpha-Trans inducing Protein, associated with the tegument, induces the production of the immediate early genes.
The protein-products from these genes are transported back into the nucleus, where they induce transcription of the delayed early genes.

Delayed Early Genes: Encodes about 15 proteins involved in viral DNA replication, including DNA polymerase and Thymidine kinase. Viral DNA replication then occurs.
Late Genes: They encode structural proteins, formed after DNA replication is complete. More than 50% of formed virions are released from cell.

HERPES SIMPLEX:

STRUCTURE: More than 8 glycoproteins on viral envelope. HSV-1 and HSV- show about 50% antigenic relatedness.
PATHOGENESIS:

Acute infection is usually local, producing vesicles which are infectious and often ulcerate.
Latent Infection: Virus travels up neuron to ganglion where it becomes latent.

During latent infection, the virus does not replicate. Only a set of genes called latency-associated transcripts (LAT) are transcribed.
For oral Herpes (HSV-1), the virus remains latent in the Trigeminal Ganglion.
Reactivation can occur as a result of stress, immunosuppression, illness, etc.

DIAGNOSIS: Look for Cytopathic Effect (CPE) 24-36 hrs after inoculation of vesicular sample in tissue culture.

Can see multinucleated Giant cells.
Can use Neutralization Test or immunofluorescence.

HERPES SIMPLEX 1 (HHV-1, HSV-1): Infection usually occurs early in childhood, and in some communities more than 90% seroconversion is seen by age 10.

MANIFESTATIONS:

Encephalitis: Acute febrile disease.
Keratoconjunctivitis: May result in permanent corneal damage and visual impairment.
Acute Herpetic Gingivostomatitis: Almost always caused by HSV-1. Happens in toddlers.
Herpes Labialis: Primarily HSV-1, but both can infect.

HERPES SIMPLEX 2 (HHV-2, HSV-2):

Due to cross-reactivity, individuals with HSV-1 infection get a milder form of HSV-2 infection.
MANIFESTATIONS:

Genital Herpes: Primarily HSV-2, but both can infect.

May be associated with fever, malaise, and inguinal lymphadenopathy.
Virus goes up and remains latent in lumbo-sacral ganglia.

Neonatal Herpes: Perinatal transmission of HSV-2, during an active infection, through the birth canal. Outcome can range from subclinical to severe.
Proctitis:
Meningitis:
Whitlow: HSV-1 or HSV-2. Infection of fingers in healthcare personnel or kiddies who suck their thumbs.

TREATMENT:

Idoxuridine: Topical ointment
Ara-A: Older drug inhibits DNA replication, but it's toxic. Used for encephalitis, or topically for keratitis.
IUDR: Acts on DNA replication and is too toxic to use systemically.
Acyclovir: Converted into triphosphate form by viral Thymidine Kinase. It blocks viral DNA polymerase and is virtually non-toxic. It does not cure latent infection but it's great for symptomatic infections.

VARICELLA-ZOSTER VIRUS (HHV-3, VZV):

REPLICATION: Daughter virions remain largely cell-associated.
TRANSMISSION is probably respiratory. Nasal mucosa.
PATHOGENESIS:

Latent Infection: VZV virus remains latent in dorsal root ganglion, where it can later reactivate to form Zoster.

MANIFESTATIONS:

Chicken-Pox (Varicella):

Symptoms: Fever and malaise. Rash starts on trunk and spreads outward to extremities.
In early infection, eosinophilic inclusion bodies are found in nuclei of infected cells.
Complications:

Encephalitis is a rare complication, associated with increased mortality (10%) and permanent CNS residual damage (10%).
Varicella Pneumonia: Rare in children; 20-30% of adults.

Shingles (Zoster): Reactivation infection, occurs (usually) unilaterally over a single dermatome, often over the face.

Skin lesions identical to Varicella.

BETA-HERPES VIRUSES: Grow slowly, have a narrow host range, latency in various tissues.

CYTOMEGALOVIRUS (HHV-5, CMV):

REPLICATION: About 25% of infected virions leave the cell.
PATHOGENESIS:

Primary infection is usually asymptomatic.
Found in cervix of up to 10% of healthy women.

EPIDEMIOLOGY:

50-70% of women of child-bearing age are seropositive.
Pregnant women usually have subclinical infection. 10-15%
CMV is the most common agent of congenital infection, about 1% of all live births.

MANIFESTATIONS:

In children, may see hepatitis, interstitial pneumonitis, or acquired hemolytic anemia.
Cytomegalic Inclusion Disease: Congenital CMV infection. Either intrauterine or early post-natal infection with CMV.

May be asymptomatic, or result in mental retardation or death.
Large intranuclear inclusions can be seen on histo, in salivary glands, liver, pancreas, kidneys, endocrine glands, brain.

Infectious Mononucleosis: CMV is responsible for 10% of cases. It differs from EBV Mono in that you won't see heterophil antibodies.
IMMUNOCOMPROMISED:

CMV Pneumonitis or hepatitis is common, or occasionally generalized disease.
CMV infection is frequently seen in transplant patients.

TREATMENT: Ganciclovir

Acyclic analog of guanosine inhibits CMV DNA Polymerase.

In Immunocompromised, the drug is good for CMV retinitis, esophagitis, and colitis, and less effective for CMV pneumonitis.

VACCINE: Live vaccine under clinical trials.

HUMAN HERPES VIRUS 6 (HHV-6): Infects T-Cells and monocytes, producing a latent infection.

MANIFESTATIONS:

Roseola (Exanthem Subitum): HHV-6 has etiological role in this childhood disease. Child presents with drastically high fever for 3-4 days, followed by rash all over body.
Fever, encephalitis, hepatosplenomegaly are all possible.
Persistent lymphadenopathy, fatigue and malaise may happen in adults.
Fatal Fulminant Hepatitis: HHV-6 was isolated from one infant with this disease.

HUMAN HERPES VIRUS 7 (HHV-7): Not much known. T-Cells are primary target, and it may cause some cases of childhood roseola.

GAMMA-HERPES VIRUSES: Intermediate growth speed, lymphotropic viruses that infect B and T cells.

EPSTEIN-BARR VIRUS (HHV-4, EBV):

REPLICATION:

EBV binds complement receptor CR2 on B-Cells to gain access to cell.
About 25% of infected virions leave the cell.

PATHOGENESIS:

EBV infects and immortalizes human B-Cells. This can result in B-Cell transformation, as in Burkitt's Lymphoma.
Infected cells contain multiple virions and express viral antigens. Expressions of these antigens may occur alone, or in conjunction with a productive infection of viral particles.

Lymphocyte-detected Membrane Antigen (LYDMA)
EBV-Specific Nuclear Antigen (ESNA)

DIAGNOSIS: Monospot Test. Look for antibodies against sheep RBC's. If you see hemagglutination, then the antibodies are present and the test is positive.
MANIFESTATIONS: Generally ubiquitous virus usually infects in early childhood.

Infectious Mononucleosis: Results when initial infection occurs at a later time. EBV causes polyclonal activation of B-Cells.

Heterophil Antibodies: Infected B-Cells make these antibodies, which are directed against whatever antigen to which the B-Cell has been sensitized.
Atypical Lymphocytes: Activated T-Cells. In response to the B-Cells, the T-Cells proliferate, leading to fever and lymphadenopathy. The T-Cells get activated and form atypical lymphocytes.
In the end, the B-Cell is put under control and infection stops. Virus becomes latent in B-Cells.

IMMUNOCOMPROMISED: Particularly susceptible to reactivation disease. May see invasive lymphomas, or EBV lesions of mouth called hairy leukoplakia.
Burkitt's Lymphoma: Malignant tumor of jaw and face, usually found in kids in Africa.

Results from translocation of c-Myc oncogene next to an IgG gene in B-Cells, as a result of EBV infection.

Nasopharyngeal Carcinoma: In adults, endemic to China.

VACCINE: Vaccine against C3B complement receptor is under development.

HUMAN HERPES VIRUS 8 (HHV-8):

MANIFESTATIONS: Kaposi Sarcoma.
TRANSMISSION: HHV-8 is probably sexually transmitted.

POXVIRIDAE: Human poxviruses are all in the family Ortho poxviridae

STRUCTURE: ds-DNA, linear, enveloped. Complex symmetry, i.e. no regular symmetry.

Lateral Bodies are on each side of the dumb-bell shaped capsid.

REPLICATION: Poxvirus has its own transcriptase, thus replication occurs exclusively in the cytoplasm.

Replication is carried out in small granules in cytoplasm. This is the same place from which the poxvirus gets its envelope.

VARIOLA MAJOR and MINOR: Causative agent of smallpox.

History: VACCINE

1798, Jenner used cowpox virus to innoculate against smallpox.
Smallpox vaccination was stopped in 1972.

VACCINIA VIRUS: Attenuated vaccine strain, used in research.
COWPOX VIRUS: Produces self-limited localized infection in humans.
MONKEYPOX VIRUS: Not widespread or contagious like human smallpox.
MOLLUSCUM CONTAGIOSUM VIRUS: Wart-like slightly elevated lesions.

Histologically you see large cytoplasmic inclusions called Molluscum Bodies.

Psuedopox: Animal poxvirus transmitted from cows. Lesions are nodular and on fingers, and can ulcerate.

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RNA VIRUSES

PICORNAVIRIDAE:

STRUCTURE: Smallest of RNA viruses, ss (+) RNA, non-enveloped, linear, infectious. No cap but there is a viral protein linked to the 5' end.

Rigid capsule makes fecal-oral transmission possible
A large number of infectious viral particles is produced. Humoral immunity is crucial to fighting these.
Non-enveloped structure makes it a good GI pathogen, able to survive in GI tract.

REPLICATION: Cytoplasmic, RNA-Dependent RNA Polymerase.

Entire genome is immediately translated into a polyprotein.
Polyprotein is cleaved into several small constituents:

Viral RNA-Dependent RNA Polymerase
Structural proteins

RNA Dependent RNA Polymerase then makes a minus-strand RNA out of the plus-strand RNA.
The minus-strand RNA is then used as a template for making additional (plus-strand) viral particles.

ENTEROVIRUSES:

CONDITIONS:

Stable at pH 3, thus it can replicate in stomach.
Optimal temp is 37C, favoring GI tract.

EPIDEMIOLOGY: Highly communicable. Fecal-oral transmission, respiratory, person-to-person.

Peak occurrence in summer and fall.
Incubation period of 3-5 days for localized infections, or longer for generalized illnesses.
Virus is tropic for lymphoid tissue in small intestine and pharynx.

General Manifestations: Usually asymptomatic or associated with mild illness. Even though GI tract is a major site of replication, GI symptoms are rarely seen (except as a consequence of generalized illness).
IMMUNITY: Acquired immunity is lifelong and serotype specific. Humoral and mucosal immunity is important, to counteract free viral particles.

Enteroviruses that infect the gut produce a good IgA response, whereas viruses that infect only the upper respiratory tract do not produce as good a response.

POLIOVIRUS:

STRUCTURE: 3 serotypes.

Ig-Superfamily cell-surface receptor protein has been identified.

DIAGNOSIS:
MANIFESTATIONS: Only 1 in 200 infections come down with Paralytic Poliomyelitis.

Infection of anterior horn cells of spinal cord (spinal poliomyelitis) or pontine nuclei (bulbar poliomyelitis).
Symptoms: Myalgia, generalized weakness, followed by flaccid paralysis.
Post-Polio Syndrome (PPS): Strange symptoms, thought to be due to nerve cell attrition, very late in the course of disease. Fatigue, muscle weakness, and respiratory difficulty.

VACCINE: Sabin (live, oral) and Salk (dead). Most remaining cases of Polio today are residuals of the live attenuated vaccine.

The Sabin Oral Polio vaccine should not be given to people with HIV. Other live vaccines (measles, mumps, HBV, influenza) can be given.
Enhanced Polio Inactivated Vaccine has been developed recently. Will be given as the first shot -- inactivated vaccine, in order to prevent patient from getting polio from vaccine. Subsequent booster shots will then be the oral polio vaccine.

COXSACKIEVIRUSES:

COXSACKIEVIRUS A: 26 serotypes.

MANIFESTATIONS: Usually just mild respiratory disease.

ASEPTIC MENINGITIS:

Viral Meningitis occurs in Summer and Fall -- not Winter and Spring as in Mumps virus.
Coxsackie A&B, and Echovirus account for 80-90% of all cases of viral aseptic meningitis.
Important to distinguish it with partially treated bacterial meningitis: lumbar puncture will show lymphocytes (not PMN's), and a normal glucose (not low glucose).

HERPANGINA: Severe febrile, vesicular pharyngitis -- vesicles or nodules on soft palate.
Acute Hemorrhagic Conjunctivitis. Very contagious pain and swelling of eyelids. Occurs in Coxsackie A24.
HAND-FOOT-AND-MOUTH DISEASE: Vesicular rashes. Coxsackie A9 and A16.
Hemolytic Uremic Syndrome (HUS): Can be seen in strains of Coxsackie A and B, and Echovirus. Also due to E. Coli strains.

COXSACKIEVIRUS B: 6 serotypes.

MANIFESTATIONS: The leading viral cause of myocarditis and pericarditis.

Myocarditis and Pericarditis.
Aseptic meningitis.
Pleurodynia: Sharp muscle pain. Peak age of incidence in adolescent -- older than most enteroviral infections.
Newborn Disease: Myocarditis, encephalitis, hemorrhagic hepatitis. Also found in Echovirus. Non-immune neonate (no maternal antibodies) is susceptible, and can be fatal.

ECHOVIRUS: Enteric Cytopathic Human Orphan Virus

STRUCTURE: 30 serotypes. Called "orphan" because it wasn't associated with any disease state. Generally non-pathogenic.
MANIFESTATIONS: Asymptomatic or mild respiratory disease, and can cause aseptic meningitis and HUS, severe diseases of newborn.

ENTEROVIRUSES 68-72: Newer numbered enteroviruses.

ENTEROVIRUS-70:

MANIFESTATIONS: Acute Hemorrhagic Conjunctivitis. Very contagious pain and swelling of eyelids. Also seen with Coxsackie A24.

ENTEROVIRUS-71:

MANIFESTATIONS:

Hand-foot-and-mouth Disease: Herpetiform lesions in hand, foot, and mouth.

ENTEROVIRUS-72: HEPATITIS-A

STRUCTURE: Single stranded RNA, non-enveloped, stable to ether, temperature.
TRANSMISSION: Fecal-oral, sexual. Found in shellfish, where viral particles can become concentrated.
MANIFESTATIONS: Unlike the other picornaviruses, it is not cytocidal.

Damage to liver is due to hypersensitivity, cytotoxic T-Cells -- not due to viral cytopathic effect.
As opposed to HBV and HCV, HAV is only acute -- there is no persistent infection.

DIAGNOSIS: Look for Anti-HAV IgM to diagnose acute infection.

AST will be high early on.
Anti-HAV IgM, increases slowly, and drops off after a few weeks.
Anti-HAV IgG starts afer 5-6 weeks and persists for life.

VACCINE: Available, and given to people traveling to endemic areas. Three doses.

RHINOVIRUS:

STRUCTURE: more than 100 serotypes. "Rhino" = nose.

ICAM cell-surface receptor protein has been identified.

CONDITIONS:

Labile at pH 3, thus it is inactivated in the stomach.
Optimal temp = 33C, thus it likes to grow in the nose.

IMMUNITY: Acquired immunity is poor.
DIAGNOSIS: It isn't cultured, but must distinguish it from bacterial otitis media or pharyngitis. Culture for Strep-A.
MANIFESTATIONS:

Common Cold: 30-50% of cases, occurring throughout year and peaking in summer.

CORONAVIRIDAE: HUMAN CORONAVIRUS

STRUCTURE: ss (+) RNA, lipid envelope, "crown-like," more than twice as large as Picornaviridae.
DIAGNOSIS: It isn't cultured, but must distinguish it from bacterial otitis media or pharyngitis. Culture for Strep-A.
IMMUNITY: Acquired immunity is poor; reinfection with same strain occurs.
MANIFESTATIONS:

Common Cold: 10-15% of cases, peaking in winter / spring months.

CALICIVIRIDAE:

STRUCTURE: Small, spherical, non-enveloped, ss (+) RNA, infectious.

Structure similar to Picornaviruses.
"Calix" = "cup" -- cup-shaped depressions on capsid.

REPLICATION: Cytoplasmic, like Picornaviruses. They do produce subgenomic mRNA for capsid proteins.
HEPATITIS-E:

TRANSMISSION: Fecal-oral, often found in contaminated water. Found primarily in other countries -- India and central Asia.
MANIFESTATIONS: Acute infection similar to HAV.

High fatality rate among pregnant women, and high perinatal fatality.

NORWALK AGENT: Little village in Ohio.

MANIFESTATIONS: Major cause of gastroenteritis. Short-incubation period.

Infection more common in adults.

TRANSMISSION: Fecal-oral.
TREATMENT: None.
IMMUNITY: Induced immunity is poor.

RETROVIRIDAE:

STRUCTURE: ss (+) RNA, cap and tail, diploid (two copies), enveloped.

The two copies of RNA are base-paired to each other, and are hooked to an accessory tRNA which is essential for replication.
Reverse Transcriptase: RNA-Dependent DNA Polymerase. It is encoded by Pol gene and has three different functions.

RNA-Dependent DNA Polymerase (make ds-DNA out of RNA)
RNAse-H: This activity degrades the RNA portion of the RNA:DNA hybrid during replication. Located on the same protein as the RT action.
Integrase: This activity cleaves host and viral DNA in preparation for integration of virus into host genome. Separate protein cleaved from the pol transcript.

Long Terminal Repeats (LTR'S): Genome contains LTR's at each end, which have some sequences in them unique to each virus.

R: Redundant sequences at both ends of genome.
U5: Unique sequence at 5' end.
U3: Unique sequence at 3' end.

THREE RETROVIRAL GENES: These genes are required by all retroviruses for successful replication.

Gag: Group-Antigen. Encodes a structural precursor protein.
Pol: Polymerase. Encodes the Reverse Transcriptase.
Env: Envelope-protein. Encodes glycoproteins that become a part of the viral envelope.

ONCOVIRUS PARTICLES: Retroviruses become proviruses and can cause transformation by several mechanisms. They can induce host-genome mutation (insertional mutagenesis), and they can act as transposable elements.

Four major types recognized.

A-Type: Non-infectious
B-Type: Budding through plasma membrane with eccentric core. MMTV.
C-Type: Most Common. Budding through plasma membrane with central core. Includes HTLV, RSV (Rous-Sarcoma), MuV.
D-Type: Some primate viruses.

Two Categories:

Acute: v-onc⁺ viruses have genes homologous to host proto-oncogenes. They are defective in that they can't replicate -- replication-deficient transformation-competent v-onc⁺ viruses.
Chronic: Not in themselves v-onc⁺ genes, but rather they cause transformation long after infection by insertional mutagenesis. Usually cause leukemia.

Specific Viral Oncogenes: v-onc genes.

arc: Role in Rous Sarcoma. It encodes a Tyrosine Kinase.
erbB: Encodes a receptor for Epidermal Growth Factor (EGF-R).
sis: Encodes PDGF.
ras: Encodes GTPase activity. v-ras (oncogene) differs from c-ras (protooncogene) by one codon.
myc: In Burkitt's Lymphoma, it is involved with an Ig gene in a 8:14 translocation.
abl: Involved in 9:22 translocation with bcr to form the Philadelphia chromosome, in Chronic Myelocytic Leukemia (CML).
erbA: A thyroid-hormone receptor in birds. It blocks the differentiation of proliferating erythroid precursor cells.

Tumor-Suppressor Genes:

Retinoblastoma (Rb) Gene:
Wilms Tumor Gene:
p53:

REPLICATION: Via reverse transcriptase

Cytoplasmic Stage: Particle is not immediately uncoated. RNA genome utilizes Reverse Transcriptase to make a double-stranded copy of DNA (RNA ------> cDNA ------> dsDNA). Then the RNA is degraded.

It utilizes a hydrogen-bonded host-cell tRNA as a primer.

Nuclear Stage: ds-DNA copy enters nucleus. It becomes integrated as a provirus, with the aid of the nuclease activity of Reverse Transcriptase. If integration fails, then the virus can't survive. Thus it's a potential drug target.

Transcription then ensues and viral mRNA is made. The unspliced transcripts serve as progeny genome.
Gag, Pol, and Env proteins are translated, glycosylated, and incorporated with the genome as a new virion particle is formed.

Endogenous Proviruses: Human have a few silent endogenous proviruses: EREV1, and ERV3. They are both defective and produce no symptoms.
HUMAN T-LYMPHOMA VIRUS (HTLV-1): (ONCOVIRINAE)

STRUCTURE: Type-C Oncovirus particle.
MANIFESTATIONS: Adult T-Cell Leukemia / Lymphoma (ATL). The virus infects CD4⁺ T-Cells, causing proliferation.

tax/rex gene is the single viral gene that is implicated in oncogenesis. HTLV virus is integrated into the infected cell as a provirus (no replication occurs). The mechanism of transformation is unknown, but they think it is acute and that the virus has v-onc⁺ genes.
Symptoms: Skin manifestations, hypercalcemia, leukocytosis, hepatosplenomegaly.
Bad prognosis.

Rous Sarcoma Virus (RSV): (Oncovirinae). Causes sarcoma in birds.
HUMAN IMMUNODEFICIENCY VIRUS (HIV): (LENTIVIRINAE)

SUBTYPES:

HIV-1: Human HIV.
HIV-2: More closely related to SIV and infects monkeys.

STRUCTURE:

Gag, Pol, and Env proteins.
Accessory Proteins:

vpu protein is required for maturation and budding.
tat (transactivator of transcription): Activates transcription of the major viral mRNA's.

Glycoproteins: Encoded by the Env genes. gp160 is the precursor glycoprotein, which is then cut in two:

gp120: Also called the 'Secretory Subunit." High antigenic variability.

High degree of antigenic shift. We make antibodies to gp120, but it is always changing its antigenic specificity.

Has V1-V5 Variable Regions. V3 is responsible for M-Tropism. The CD4 binding domain lies in between V4 and V5.

It is responsible for the binding of the virus to CD4⁺ receptors.

gp41: Transmembrane component. Less antigenic variability.

Responsible for the fusion of viral and cell membranes.
Also confers the tropism on the cell -- L-Tropic or M-Tropic.

Protease Inhibitors inhibit this cleavage.

Structural Proteins: Capsid proteins encoded by the Gag gene.

P55 is cleaved by protease into 5 substituents, including P24.
These structural proteins are required for viral replication.
Protease Inhibitors inhibit this cleavage.

VIRUS-TROPISM: Conferred by gp41 glycoprotein.

L-Tropic: Attracted to lymphocytes (CD4⁺ cells)

Infection of T_H cells accounts for depressed CD4 count.

M-Tropic: Attracted to macrophages or cells in macrophage lineage.

Infection of Alveolar Macrophages: accounts for HIV interstitial pneumonia.
Infection of CNS microglial cells: accounts for neurological symptoms and HIV encephalopathy.

DIAGNOSTIC TESTS:

ELISA Test: Detects antibodies to P24. It is highly sensitive but not specific. If positive, must confirm with a Western Blot.
Western Blot: Required confirmatory test. Highly specific. Must reveal antibodies to two viral proteins to be confirmatory.
Immunofluorescence, Flow Cytometry: Can be used to detect P24 viral antigen and thereby monitor disease and measure viral burden.

MANIFESTATIONS:

Primary Infection: A mononucleosis-like infection of fever, pharyngitis, lymphadenopathy. Leukopenia is present, but CD4 count returns to normal after initial infection.
Asymptomatic Phase: Can last from 1 to 15 years.

The virus continues to replicate throughout -- so it is not proper to call it a latent infection.
About 5% of CD4 cells are infected at any point in time.

AIDS / AIDS-Related Complex (ARC): Happens when CD4 count gets below 500, and then below 200.

What makes AIDS emerge?

Antigenic stimulation of the infected CD4 cell may cause it to undergo apoptosis, thereby setting off the symptomatic phase of the disease.
May need to wait for cytopathic variants of HIV to arise, by random mutations.

OPPORTUNISTIC INFECTIONS: Fungal, mycobacterial, viral, and parasitic infections that require CMI. They show up at 500 CD4-count, and then others show up at 200 CD4-count.
MALIGNANCIES: Kaposi Sarcoma, B-Cell Lymphomas in brain, invasive cervical cancer in women.

Kaposi Sarcoma: Probably sexually transmitted, and caused by HHV-8.

HIV Neurological Disease: Cognitive symptoms, behavioral symptoms, motor symptoms, due to infection of microglial cells by M-Tropic viruses.
HIV-Associated Nephropathy: 10-40% of infected patients. Renal failure and mesangial hyperplasia, due to infection of mesangial cells (nephritic macrophages) by M-Tropic viruses.
HIV Interstitial Pneumonia: Due to infection of alveolar macrophages. It is a giant-cell pneumonia.

TREATMENT:

Nucleoside-Analog Inhibitors of Reverse Transcriptase: AZT. It inhibits Reverse Transcriptase.

SIDE-EFFECTS: Bone marrow toxicity, nausea, myalgia, headache.
PROBLEM: Reverse Transcriptase acquires resistance by mutation. Resistance arises more rapidly in patients with advanced disease.
ddC and ddI are other analogs that are useful in combination with AZT. They also ameliorate side-effects.

Non-Nucleoside Inhibitors of Reverse Transcriptase:
Protease Inhibitors: They inhibit the cleavage of structural protein P55 into P24, thereby inhibiting replication. Promising drug.

The protease is an Aspartate Protease, thus any drug blocking that mechanism has promise.

VACCINES: Three types have been tried, all disappointing.

Humoral Immunity against gp120: it was unsuccessful.
Whole killed virus
Live attenuated virus: low success-rate and too risky.

HUMAN FOAMY VIRUS (HFV): (SPUMAVIRINAE). Causes foamy vacuolation of many different cell types. Apparently benign.

ORTHOMYXOVIRIDAE: The Influenza Viruses

STRUCTURE: ss (-) RNA, segmented, helical nucleocapsid, enveloped.

Cell envelope is acquired by budding through plasma membrane.
Hemagglutinin (HA) on viral envelope attaches to sialic acid receptor on host cells. One source of antigenic types.

There are 15 subtypes of HA. H1, H2, H3 exist in humans.

Neuraminidase (NA) is released from infected cells. Another source of antigenic types.

There are 9 subtypes of NA. Only N1, N2 are found in humans.

REPLICATION: In host nucleus. Cap-snatching transcription. Viral RNA's utilize portions of host-cell RNA to make their own 5' Cap in the host cell nucleus.
ANTIGENIC VARIATION:

Antigenic Shift: Major source of antigenic variation, due to re-assortment of the RNA genome segments. It leads to changes of subtype of the envelope glycoproteins.
Antigenic Drift: Minor changes in antigenic variation, due to point mutations in the genome.

INFLUENZA VIRUS-A: 8 segments.

DISTRIBUTION: Found in humans, aquatic birds, swine, horses, seals, whales.
EPIDEMIOLOGY: This is the major player in flu epidemics, because of its antigenic variation. Highly contagious, spread by person-to-person contact.
MANIFESTATIONS: It targets the epithelial cells of the respiratory tract, upper and lower.

Epithelial cells become ciliastatic as a result of infection, which can predispose to more serious bacterial infections.
Incubation Period: 1-4 days.
Symptoms: Soar throat, fever, chills, myalgia, headache.
Normally Self-Limiting infection, lasting 3-7 days. Cough may last 1-2 weeks.

INFLUENZA VIRUS-B: 8 segments

DISTRIBUTION: Found only in humans
EPIDEMIOLOGY: Less serious infection than Type-A. Generally found in children or adolescents.
Influenza-B does not undergo reassortments or antigenic shift.

INFLUENZA VIRUS-C: 7 segments.

DISTRIBUTION: Found in humans and swine.
EPIDEMIOLOGY: Rarely causes diseases. Ubiquitous, and we all generally have antibodies by early childhood.

INFLUENZA VACCINE: Constantly updated, as CDC keeps track of antigenic types of latest strains.

In the past they've used inactivated whole viruses.
This year they are using a trivalent subunit vaccine consisting of purified viral HA antigen: (1) Type-A H1N1 and (2) H3N2, and Type-B antigen.
Vaccine administered during the fall. Breakouts are in winter.

PARAMYXOVIRIDAE:

STRUCTURE: ss (-) RNA, enveloped.

Fusion Protein (F): Responsible for forming syncytia, multi-nucleated cells.
Hemagglutinin-Neuraminidase (HN): Single protein.
Has a Transcriptase, RNA-dependent RNA-Polymerase.

REPLICATION: Entirely cytoplasmic.

Primary Transcription occurs, and the RNA genome is replicated.
Syncytia (via F-Protein) allow for cell-to-cell infections. Virion doesn't need to go outside of cell to infect neighboring cells.

DETECTION: You can use hemadsorption (hemagglutination) to detect the cells, as they have the HN-Protein on their surface.
GENERAL PATHOGENESIS:

Infection by respiratory tract. Mucosal IgA is more important than serum IgG in preventing infection.
Infection occur in late winter, early spring.

PARAINFLUENZA VIRUS: (PARAMYXOVIRUS).

STRUCTURE: Four human serotypes. Types 1 and 3 are within the Paramyxovirus family, while types 2 and 4 are within the Rubivirus family.

Sendai Virus = Parainfluenza Type 1.

DIAGNOSIS: Culture. Detect by FA. Respiratory Panel available commercially can identify seven common respiratory viral pathogens.
MANIFESTATIONS: Infection often occurs in autumn.

Croup (Types 1 & 2): Laryngotracheobronchitis in young children is the Croup. Fever, cough, and respiratory distress due to bronchial obstruction.

Barking cough is seen.
Crop = obstruction of larynx in young children.

Type-3: Bronchiolitis in infants. Severity correlates to IgE levels, indicating an immunopathogenesis for the disease.
Parainfluenza may also be the cause of the common cold.
Only short-term immunity is acquired.

MUMPS VIRUS: (PARAMYXOVIRUS).

STRUCTURE: Only one major serotype.
DIAGNOSIS: Culture, demonstrate hemadsorption, look for syncytia.

Will see multinucleated cells on cell culture.

MANIFESTATIONS: Generalized infection, with incubation period of 1-3 weeks.

Lifelong immunity is acquired.
Symptoms: Parotitis (parotid gland inflammation), Orchitis.

Infants may be subclinical due to maternal antibodies.

Complications:

Use to be most common cause of viral meningitis -- seen in the Winter and Spring (not Summer and Fall like Coxsackie A Virus).
May see pancreatitis or encephalitis.

MEASLES VIRUS: (MORBILLIVIRUS).

STRUCTURE: Only one major serotype.
Related Diseases: Distemper in dogs, Rinderpest in cattle are also a part of this family.
DIAGNOSIS: Culture, serology.

Koplik's Spots on buccal mucosa.
Will see multinucleated cells on cell culture

MANIFESTATIONS: Generalized infection, with incubation period of 1-3 weeks.

Lifelong immunity is acquired.
Symptoms:

Early Symptoms: Fever, cough, coryza, conjunctivitis.
Late Symptoms: maculopapular rash.
Flat macules that coalesce to form large blotches, and fade in 5-6 days. Rash spreads from head, down to rest of body.

Severe Complications: Otitis media, viral or bacteria pneumonia which is possibly fatal.

Post-Infectious Encephalomyelitis: 1:1000 cases. 15% fatality rate. Appears to be an autoimmune pathogenesis. This is the most important complication.
Subacute Sclerosing Panencephalitis (SSPE): 1:1 million cases. Follows the acute measles by several years.

Patients afflicted with this lack antibodies against the measles-virus M-Protein. The virus is being produced without an envelope in these cases, and that results in this fatal complication.

Pneumonia occurs especially in developing countries where malnutrition is common. It can be fatal.

TREATMENT: Vitamin-A for infants. Passive immunity.
MMR VACCINE: Live-attenuated vaccine.

Primary dose at 12-15 months.
Booster shot in elementary school.
Vaccine should not be given to immunodeficient children -- except for HIV children, for which it is recommended.

RESPIRATORY SYNCYTIAL VIRUS (RSV): (PNEUMOVIRUS)

STRUCTURE: Has a G-Protein and F-Protein, but lacks NA and HA activity.
DIAGNOSIS: FA, Respiratory Panel of viruses.

Will see multinucleated cells on cell culture.

MANIFESTATIONS: Acute infection, with incubation period of 3-5 days.

Only short-term immunity is acquired.
Serious respiratory infection in neonates (0 - 6 months). Only mild disease in older folks.

TREATMENT: Ribavirin, aerosolized, may have limited effectiveness, for hospitalized babies.
VACCINE: Passive immunization is available for infants at high risk.

Newcastle Disease Virus (NDV): Avian virus, can produce conjunctivitis in humans.

RHABDOVIRIDAE: RABIES VIRUS

STRUCTURE: ss (-) RNA, helical capsid, enveloped, bullet-shaped.

Transcriptase, RNA-dependent RNA Polymerase is present.

REPLICATION: Cytoplasmic.

Primary transcription ------> genome replication ------> more transcription and translation occur post-replication.
Nucleocapsids bud through host cell-membrane to form new particles.

EPIDEMIOLOGY:

Racoons are the most common animal carrier today.
Bats are most common carrier in U.S. to actually result in infection.
Also skunks, wild mammals, and unvaccinated domestic mammals.

DIAGNOSIS: Look for Negri bodies in the animal tissue.
MANIFESTATIONS:

PATHOGENESIS:

Virus replicates in striated muscle at site of bite. Then it travels up nerve endings to spinal cord and brain.
Virus hooks to Acetylcholine receptors at neuromuscular junction.

Symptoms: Fatal encephalitis. Hypertonic muscle contraction, convulsions, coma, death.

Hydrophobia happens as swallowing would precipitate a spasm of throat muscles.

TREATMENT: No treatment known.

PREVENTION: Post-exposure immunization, both passive and active, should be given prophylactically in cases of possible infection.

Human Rabies Immune Globulin (HRIG) administered on same day as first vaccine dose, but at a different site.
Human Diploid Cell Vaccine (HDCV) is the new active vaccine (inactivated virus), grown in human diploid fibroblast cells. Given in 6 doses.

VESICULAR STOMATITIS VIRUS (VSV): Arbovirus causes disease in cattle and horses. Can cause mild disease in humans. Has been utilized as a model virus in research.

REOVIRIDAE: Respiratory-Enteric-Orphan viruses.

STRUCTURE: Non-enveloped, double-stranded segmented (-) RNA, in 10-12 segments. Contains concentric inner and outer capsids.

VP4: Viral glycoprotein neutralization antigen.
VP7: Viral glycoprotein neutralization antigen, derived from host-cell ER.
RNA-dependent RNA-Polymerase can make messenger RNA's out of the double-stranded viral genome.
Rigid capsule makes fecal-oral transmission possible.

REPLICATION: The inner capsid always remains intact.

The outer capsid is removed upon entry into the cell.
Inside the capsid, the RNA-dependent RNA-polymerase makes subgenomic (+) mRNA's. These mRNA's are transported into host-cell cytoplasm and translated into proteins.
Inside the capsid, the (-) RNA's are used as templates to make new ds-RNA genomes, which are then released outside the capsid.
The new genomes are assembled along with the viral proteins to make new infectious particles.

EPIDEMIOLOGY: Fecal-oral transmission.

Infection occurs in 6 months to 2 years old. Neonates, older children, and adults are usually asymptomatic. Breast-milk IgA probably provides protection for neonates.
Prevalent in winter, but throughout year in tropical climates. Unexplained west-to-east trend in seen in its incidence: Nov ------> Feb as you go from West ------> East in United States.

REOVIRUS: (ORTHOREOVIRUS)

STRUCTURE: 3 serotypes.
MANIFESTATIONS: Commonly infects, but asymptomatic, hence they are orphan viruses.

ROTAVIRUS: Group-A Rotavirus has 4 serotypes, based on the VP7 antigen.

MANIFESTATIONS: Gastroenteritis, which can be life threatening. It is the major cause worldwide, in infants and young children.

MECH is believed to be decreased absorption at brush border, but not sure.

IMMUNITY: Serotype-specific, and incomplete.
DIAGNOSIS: ELISA of stool samples
TREATMENT: IV-fluid replacement. Oral rehydration therapy.
VACCINE: In clinical trials are re-assortment-viruses containing genomes that encode VP4 or VP7. These are human viruses that infect the cell and reassort with the segmented genome of the rotavirus, rendering it non-pathogenic.

ORBIVIRUS: All are arboviruses. Most are asymptomatic. 10 segments.

COLORADO TICK FEVER VIRUS:

MANIFESTATIONS: Standard common viremia symptoms: fever, myalgia, rash, vomiting. May see maculopapular rash.
STRUCTURE: Has 12 segments, not 10.

ARBOVIRUSES: Not a genus. General Properties.

EPIDEMIOLOGY: Insect spread.

Mosquito-born viruses: prevalent in summer generally.
Tick-born viruses: Prevalent year-around.

MANIFESTATIONS: Usually asymptomatic, but may be severe disease. 4-7 incubation period for clinical symptoms.

Initial Infection: Viruses will replicate in vascular endothelial cells, in subclinical infection.
VIREMIA: Most common mild disease. Fever, arthralgia, rash, nausea, vomiting.

Dengue Fever: Most common cause
Sindbis virus
Colorado Tick Fever

HEMORRHAGIC FEVER: Extensive hemorrhages from almost any epithelial surface. Can lead to CV collapse and death. Fatality rate ranges from 2% - 50%.

Dengue Virus: Dengue Shock Syndrome
Yellow Fever: Hemorrhagic fever with hepatitis.

ENCEPHALITIS:

From highest to lowest lethality:

Eastern Equine Encephalitis
St. Louis Encephalitis
Western Equine Encephalitis
California

Symptoms:

Starts with Meningitis -- fever, headache, vomiting, stiff neck.
Followed by lethargy, confusion, paralysis, and coma and death in most serious cases.
May see neuropsychiatric sequelae in non-fatal cases, such as mental retardation, paralysis.

IMMUNITY: Acquired and lifelong.
DIAGNOSIS: Must use serology. Acute:convalescent titers, or IgM.

TOGAVIRIDAE:

STRUCTURE: ss (+) RNA, spherical, enveloped, infectious.
REPLICATION: Polymerase is at the 5' end and structural proteins are at the 3' end.

First, the 5' end of the genome is translated, making some non-structural proteins and RNA-Dependent RNA Polymerase.
RNA-Dependent Polymerase then makes a minus-strand out of the plus strand, and then uses that to make more plus-strands.
Then the 3' end is translated, forming structural proteins that are packaged together with the new RNA strands.

ALPHAVIRUS: All are arboviruses, transmitted by insect-vector.

STRUCTURE: All share serological reactivity, i.e. cross-reactive for some internal viral antigens.
EASTERN EQUINE ENCEPHALITIS VIRUS (EEEV):

The deadliest of the encephalitis viruses.
The rarest of the encephalitis viruses.
Fatality: 30-50%

WESTERN EQUINE ENCEPHALITIS VIRUS (WEEV): The next deadliest.

TRANSMISSION: Horse-mosquito. Man is dead-end host.
Fatality: 3-5%

VENEZUELAN EQUINE ENCEPHALITIS (VEEV):
SINDBIS VIRUS:

MANIFESTATIONS: Standard common viremia symptoms: fever, myalgia, rash, vomiting. May see maculopapular rash.

RUBIVIRUS: RUBELLA -- not an Arbovirus (no arthropod vector)

STRUCTURE: ss (+) RNA, enveloped.
DIAGNOSIS: Immunofluorescence on cultured viruses in mammalian cell lines. MANIFESTATIONS: German Measles. Usually a trivial disease

Incubation Period: 2-3 weeks. Disease most prevalent in Spring.
Rubella is non-Cytocidal, as compared to the Arboviruses.
Symptoms:

Lymphadenopathy and mild conjunctivitis.
Maculopapular "Rubelliform" Rash that forms small discrete blotches, that do not coalesce, and disappear in 3-5 days.

Complications: Arthritis and, rarely, post-encephalitis.

MANIFESTATIONS: Congenital Rubella Syndrome (TORCH). Very few cases seen today, but an outbreak happened recently when people were lax about vaccines.

Do a Rubella titer for women of child-bearing age.
Greatest risk when maternal infection is early in pregnancy (first trimester).
Effects: Blindness, deafness, congenital heart defects, and brain defect are all possible. Rarely fatal (no spontaneous abortion).
DIAGNOSIS: Look for Anti-Rubella IgM in fetal cord-blood.

PESTIVIRUS:

FLAVIVIRIDAE:

STRUCTURE: ss (+) RNA, enveloped

Used to be classified with Togaviruses, but now is reclassified, because:

Nucleic acid sequences for Yellow Fever virus genome are different.
The virus does not utilize a subgenomic mRNA.
Alpha viruses bud mainly from the surface plasma membrane, whereas the Flaviviruses bud mainly into internal membranous structures (Golgi).

ST. LOUIS ENCEPHALITIS VIRUS: It has been the major cause of arboviral-born encephalitis over the last three decades.

TRANSMISSION:

Urban cycle of man-mosquito-man.
Natural cycle of bird-mosquito-bird.

JAPANESE ENCEPHALITIS VIRUS:

VACCINE: Vaccine available before travel to endemic area. Inactivated, purified vaccine given in three subcutaneous doses.

YELLOW FEVER VIRUS:

TRANSMISSION: Monkey-insect-monkey cycle, with occasional transmission to man.

Can also have an Urban man-mosquito-man cycle.

MANIFESTATIONS: Hemorrhagic Fever with hepatitis. Yellow = jaundice.
VACCINE: Live attenuated vaccine is available, recommended before travel.

DENGUE FEVER VIRUS:

TRANSMISSION: Can have an Urban man-mosquito-man cycle.
SUBTYPES: Divided into Types 1-4.
MANIFESTATIONS: Dengue fever is the most common and (usually) least serious arboviral infection.

Fever-arthralgia-rash: Common symptoms of viremia -- Fever, chills, headache, myalgia, rash, nausea, vomiting.
Dengue Shock Syndrome: A form of hemorrhagic fever. Thought to be a hypersensitivity reaction with reinfection of a second subtype of Dengue virus.

Mechanism involves immune enhancement and extended tissue tropism -- i.e. infecting cells which are not normally infected.
Macrophages get infected by the virus whereas they normally are not infected.

HEPATITIS-C:

TRANSMISSION: Primary mode of transmission is parenteral route (blood). In the past has been associated with transfusions.
MANIFESTATIONS: Most often leads to chronic hepatitis.

BUNYAVIRIDAE: Hemorrhagic Fevers

STRUCTURE: ss (-) RNA, segmented, 3 segments. Enveloped. Spherical, helical nucleocapsid. There may be some ambisense (+/-) characteristics.

RNA-Dependent RNA-Polymerase is present.

DIAGNOSIS: Serology -- no culture.
BUNYAVIRUSES: Arboviruses

CALIFORNIA ENCEPHALITIS VIRUS:

Fatality: less than 1%

LA CROSSE VIRUS:

PHLEBOVIRUSES:

RIFT VALLEY FEVER VIRUS:

HANTAVIRUSES: Rodent-born viruses, not arboviruses. Transmitted by rodent urine and respiratory secretions.

HANTAAN VIRUS: First discovered member of this family. From 1950's Korea (Korean War).

MANIFESTATIONS: Korean Hemorrhagic Fever with Renal Syndrome (HFRS). Incubation period 2 - 4 weeks.

MUERTO CANYON VIRUS: Relative of Hantaavirus discovered in 1993 epidemic in New Mexico, U.S.

MANIFESTATIONS: Hantavirus Pulmonary Syndrome (HPS). ARDS-like syndrome with 70% fatality.
TRANSMISSION: Deer Mouse was newly discovered and found to be the vector. Direct contact with rodents or rodent-products required.
TREATMENT: Respiratory therapy. Ribavirin was once shown effective, but requires special permission to use.

SEOUL VIRUS:

FILOVIRIDAE:

STRUCTURE: ss (-) RNA, enveloped, long "filum."

Previously categorized with Rhabdoviridae, since reclassified.

MARBURG and EBOLA VIRUSES:

TRANSMISSION: Endemic to monkeys, and assumed to have a natural reservoir.
MANIFESTATIONS: Hemorrhagic Fevers. Hepatitis is prominent.

ARENAVIRIDAE:

STRUCTURE: ss (-) RNA, segmented, lipid-envelope and helical capsid.

Some ambisense (+/-) properties, like Bunyaviruses.
Viral RNA-dependent RNA-polymerase.
Name derives from a picture of sand on EM, which is cellular ribosomes accidentally packaged into the viral particles.

TRANSMISSION: Natural rodent reservoir. Transmitted by rodent respiratory secretions and urine.
LYMPHOCYTIC CHORIOMENINGITIS VIRUS: Causes meningitis.
LASSA FEVER VIRUS:

TRANSMISSION: Western Africa. Can be via rodent or human-to-human.
MANIFESTATIONS: Hemorrhagic fever with hepatitis.

MACHUPO VIRUS: Bolivian Hemorrhagic Fever. Epidemic in 1962-64 which resembles in many ways the Muerto Canyon epidemic of 1993. Rat population probably increased prior to the epidemic.
JUNIN VIRUS:

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