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1

Viruses—A Little History

• Virus—Latin word meaning “___”

• Late 1800’s o Charles Chamberland in Pasteur’s lab made a filter that would hold back the ___ ___.

o Iwanowski (Russia) and Beijerinck (Holland) showed that a plant infection (___ ___ disease) could be transmitted by ____ that passed through Chamberland filter.

• Something smaller than the smallest bacteria that was known about back then

o ___ and ___ disease of cattle was also transmitted by bacteria-free filtrates.

o ____ seen with light microscope. • Largest of all the viruses

• 1928-1950’s

o Virus was grown in suspensions of minced ____  tissue.

o Virus was grown in developing __ ___.

o Discovery of antibiotics inhibited ____ of cell and tissue cultures. • So you could study viruses without contamination of bacteria

o Electron microscope developed (1939) and ___ of viruses was delineated.

• 1953—Watson and crick described the structure of DNA

Viruses—A Little History • Virus—Latin word meaning “poison” • Late 1800’s o Charles Chamberland in Pasteur’s lab made a filter that would hold back the smallest bacteria. o Iwanowski (Russia) and Beijerinck (Holland) showed that a plant infection (tobacco mosaic disease) could be transmitted by extracts that passed through Chamberland filter. • Something smaller than the smallest bacteria that was known about back then o Foot-and-mouth disease of cattle was also transmitted by bacteria-free filtrates. o Poxviruses seen with light microscope. • Largest of all the viruses • 1928-1950’s o Virus was grown in suspensions of minced kidney tissue. o Virus was grown in developing chick embryos. o Discovery of antibiotics inhibited contamination of cell and tissue cultures. • So you could study viruses without contamination of bacteria o Electron microscope developed (1939) and morphology of viruses was delineated. • 1953—Watson and crick described the structure of DNA

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Properties of Viruses

• Size: ___ nm to __ __ nm

• ___ ____ parasites

• Do not produce ___ or ___

• Genome is either ___ or ____

• Morphologic types • __ ___• ____

• Assembled from components

Properties of Viruses • Size: 20 nm to several hundred nm • Obligate intracellular parasites • Do not produce energy or proteins • Genome is either DNA or RNA • Morphologic types • Naked capsid • Enveloped • Assembled from components

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Viral Classification—Symmetry

• ____ o Capsid is ___ ___ ___

• Enveloped with helical nucleocapsid (influenza virus) o Envelope wrapped around ___ __ ____ o Contains important structures for ____ of other cells

•____ symmetry o ____ faces o Genome is encapsulated in there

• Enveloped with icosahedral nucleocapsid (herpesvirus)

• ____symmetry (poxvirus): Doesn’t match any other viral structures

Naked or Enveloped and then Helical or Icosahedral

Viral Classification—Symmetry • Helical o Capsid is wound around genome • Enveloped with helical nucleocapsid (influenza virus) o Envelope wrapped around host cell membrane o Contains important structures for infection of other cells • Icosahedral symmetry o Pentagon faces o Genome is encapsulated in there • Enveloped with icosahedral nucleocapsid (herpesvirus) • Complex symmetry (poxvirus): Doesn’t match any other viral structures Naked or Enveloped and then Helical or Icosahedral

4

Virus Classification—Type of Nucleic Acid

• Its either DNA or RNA but its __ ___

• Classified based on whether you ___ with DNA or RNA • No matter what you start with you need mRNA to make protein • _strand or _ strand

Virus Classification—Type of Nucleic Acid • Its either DNA or RNA but its not both • Classified based on whether you start with DNA or RNA • No matter what you start with you need mRNA to make protein • + strand or - strand

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Virus Properties

• naked capsid Ex) Polio

• ___ coat • Subunits of protein coat called____

• environmentally ___ • temperature • acid • proteases • detergents • drying

• generally released by __ ___ • Infect cell. turn it into viral making cell. Viral prodcuts build up in cell and it bursts.

Virus Properties • naked capsid Ex) Polio • protein coat • Subunits of protein coat called capsomeres • environmentally stable • temperature • acid • proteases • detergents • drying • generally released by cell lysis • Infect cell. turn it into viral making cell. Viral prodcuts build up in cell and it bursts.

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• enveloped

• ___ layer

• Derived from ___ ___ ____

• Just like the cell membrane

• ____ • Envelope similar to host cell membrane

• ____ made from virus • It will insert these into its envelope

• ____

• Environmentally ____ • Don’t survive very long outside of a cell in which they can replicate

• __ ___ modifications • They make modifications to the cell membrane

• Released by ________ • Budding one at a time • Many use combo of these two approaches

• enveloped • outer layer • Derived from host cell membrane • Just like the cell membrane • Lipids • Envelope similar to host cell membrane • Glycoproteins made from virus • It will insert these into its envelope • proteins • Environmentally labile • Don’t survive very long outside of a cell in which they can replicate • Cell membrane modifications • They make modifications to the cell membrane • Released by budding and cell lysis • Budding one at a time • Many use combo of these two approaches

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Steps in Viral Replication

1-7

Steps in Viral Replication 1. Absorption 2. Penetration 3. Uncoding 4. Tx 5. Tlation 6. Assembly 7. Release

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Virus Families

More ___ virus families than DNA virus families

Grouped based on their ___

Virus Families More RNA virus families than DNA virus families Grouped based on their structure.

9

Cytopathic Effects of Viruses: What do we see in viral infected cells

• ___ ___ o Sites of virus assembly are taking place in cytoplasm o ___ viruses typically replicate in cytoplasm

• ___ ___ o Viruses that are ___ viruses replicate in the nucleus

• Cytoplasmic/Nuclear Inclusions

• ___

• ____ ____ o Form giant cells

• ____  o Virus can cause cells to become transformed, replicate uncontrollably • Associated with cancer

Cytopathic Effects of Viruses: What do we see in viral infected cells • Cytoplasmic Inclusions o Sites of virus assembly are taking place in cytoplasm o RNA viruses typically replicate in cytoplasm • Nuclear Inclusions o Viruses that are DNA viruses replicate in the nucleus • Cytoplasmic/Nuclear Inclusions • Lysis • Multinucleated Syncytium o Form giant cells • Transformation o Virus can cause cells to become transformed, replicate uncontrollably • Associated with cancer

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Effects of Viruses on Host Cells

• Virus enters the host cell • It can go two ways depending on cell type. • Viruses have different tropisms for different cells

• 1) ____ infection: o virus replicates in the cell and __ __→____ infection.

• 2)____  infection: o virus gets into a cell in which it ___ ___ but it can carry out a few fcns (make some early gene products)→____ Infection.

• ___: Small amts of virus are released overtime. • Never completely cleared by the body

• ___: Virus sits quietly in cell and then something triggers it to replicate • Symptoms aren’t as bad subsequent times

• ____: leads to cancer

• ____: virus at low level with no signs or symptoms • After long period of time then the signs and symptoms will occur

Effects of Viruses on Host Cells • Virus enters the host cell • It can go two ways depending on cell type. • Viruses have different tropisms for different cells • 1) Permissive infection: o virus replicates in the cell and kills it→cytocidal infection. • 2) Nonpermissive infection: o virus gets into a cell in which it can’t replicate but it can carry out a few fcns (make some early gene products)→Persistant Infection. • Chronic: Small amts of virus are releasedovertime. • Never completely cleared by the body • Latent: Virus sits quietly in cell and then something triggers it to replicate • Symptoms aren’t as bad subsequent times • Oncogenic: leads to cancer • Slow: virus at low level with no signs or symptoms • After long period of time then the signs and symptoms will occur

11

Determinants of Viral Disease

Nature of disease

• ___ ___

•___ of  ___

• Virus ___ to ___ ___

• Tissue ____ of virus

• Cell ____ for virus ____

• Viral ___ (___)

What determines what will happen once you are infected with a virus

Determinants of Viral Disease Nature of disease • Target tissue • Portal of entry • Virus access to target tissue • Tissue tropism of virus • Cell permissiveness for virus replication • Viral pathogen (strain) What determines what will happen once you are infected with a virus

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Severity of disease

• ___ ability of virus • How easy to cause destruction of cells

• ___ status • ____ • Prior ___

• _______→Inclusion bodies

• ___ of ___ ___

•___ to_____ of infection • Longer it goes on, the more severe it is

• General ___ of person • Nutrition • Other diseases

• __ __ of person

•___

Severity of disease • cytopathic ability of virus • How easy to cause destruction of cells • Immune status • Competence • Prior immunity • Immunopathology→Inclusion bodies • Size of virus inoculum • Time to resolution of infection • Longer it goes on, the more severe it is • General health of person • Nutrition • Other diseases • Genetic makeup of person • Age

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Mechanisms of Viral Cytopathogenesis

• Inhibition of cellular ___ ___

• Inhibition and degradation of cellular___

• Alteration of ___ ___: ____ insertion, ____ formation, disruption of ____, _____ 

• ____ bodies

• ____ of virion components

Mechanisms of Viral Cytopathogenesis • Inhibition of cellular protein synthesis • Inhibition and degradation of cellular DNA • Alteration of cell membrane: Glycoprotein insertion, Syncitia formation, disruption of cytoskeleton, permeability • Inclusion bodies • Toxicity of virion components

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Viral Pathogenesis—Initiation of Infection

• ___ ___ must be able to initiate infection.

• Cells at the site of infection must be ____, ___ and ____ for the virus.

• Local host ____-___l defense systems must be __ or ___ ____. • Ex) sIgA

• Viruses can get into any opening in the human body. They can also shed from those sites.

Viral Pathogenesis—Initiation of Infection • Sufficient virus must be able to initiate infection. • Cells at the site of infection must be accessible, susceptible, and permissive for the virus. • Local host anti-viral defense systems must be absent or initially ineffective. • Ex) sIgA • Viruses can get into any opening in the human body. They can also shed from those sites.

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Diagnosis of Viral Disease

• ___ and ____ provide first clues; often allow ___ of bacterial and fungal infections

• laboratory studies are done to:

• ___ the clinical diagnosis by ____  the virus • Maybe you can trt it depending on the virus • define the disease process

• allow ____ ____.  Many viruses have to be reported to the centers for disease control

• methods

•___/___

•___ ___

• ___ ___

• _____/____ /____ • Using Antibodies to identify infection

• detection of viral ___ ___→PCR

• ____ • Look in serum for Ab to the virus

Diagnosis of Viral Disease • history and symptoms provide first clues; often allow exclusion of bacterial and fungal infections • laboratory studies are done to: • confirm the clinical diagnosis by identifying the virus • Maybe you can trt it depending on the virus • define the disease process • allow epidemiologic monitoring • Many viruses have to be reported to the centers for disease control • methods • cytology/histology • electron microscopy • cell culture • immunohistochemistry/immunofluorescence/immunoassays • Using Antibodies to identify infection • detection of viral nucleic acids→PCR • serology • Look in serum for Ab to the virus

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cytology/histology • ___ • Many nuclei in one cell • ___ ___ • ______s→ HPV infection

electron microscopy • ___ ___ stain of specimen • immunoelectron microscopy

growth in cell culture • Inoculation of ____cells

detection of viral proteins • ____ & immunohistochemistry • Fluorescent or enzyme labeled ___ 

detection of viral nucleic acids • ___• Gel Electrophoresis to detect amplified DNA • Real time PCR

Immunoassays Like a pregnancy test

serology • Detection in patient serum

cytology/histology • Syncytia • Many nuclei in one cell • inclusion bodies • koilocytosis→ HPV infection electron microscopy • direct negative stain of specimen • immunoelectron microscopy growth in cell culture • Inoculation of susceptible cells detection of viral proteins • immunofluorescence & immunohistochemistry • Fluorescent or enzyme labeled Ab detection of viral nucleic acids • PCR • Gel Electrophoresis to detect amplified DNA • Real time PCR Immunoassays Like a pregnancy test serology • Detection in patient serum

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Interferon--Induction of the Anti-Viral State

• Functions

o inhibition of ___ ___

o inhibition of ___ ___

o ______

• Types (Have different sources)

o α-interferon—___ interferon

o β-interferon—___ interferon

o γ-interferon—activated ___ cells and __ cells

• IFN is important for fighting viral infections

• Virus gets in the cell and induces production of ___

• ___ ____ NA are better at inducing IFN

• Cell dies from viral infection and IFN is ____

• IFN will signal

o uninfected cells to destroy the ___ and reduce __ ___ • So virus can produce protein in the cell

o ____ of infected cells

o Activation of ____ cells

• Alpha and Beta produced in response to ___ infection and then Gamma comes in to ____

Interferon--Induction of the Anti-Viral State • Functions o inhibition of viral multiplication o inhibition of cell division o immunomodulation • Types (Have different sources) o α-interferon—leukocyte interferon o β-interferon—fibroblast interferon o γ-interferon—activated T cells and NK cells • IFN is important for fighting viral infections • Virus gets in the cell and induces production of IFN • Ds NA are better at inducing IFN • Cell dies from viral infection and IFN is released • IFN will signal o uninfected cells to destroy the RNA and reduce protein syn • So virus can produce protein in the cell o Apoptosis of infected cells o Activation of immune cells • Alpha and Beta produced in response to viral infection and then Gamma comes in to fight

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New Test for Viral Infections

• ___ ___ ____ ___ 

• Use ___ ___ to express proteins of wide variety of viral proteins

• See persons ____ to wide variety of viruses

New Test for Viral Infections • Systemic viral epitope scanning • Use bact viruses to express proteins of wide variety of viral proteins • See persons immunity to wide variety of viruses

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Antivirals

• most viral diseases, except HIV disease, are ___ ___ and do not require treatment

• current antivirals target ____viruses, ____ viruses (B and C), ____ viruses, ____syncytial virus and ___

• field is rapidly evolving as viruses become ___ to ___ ___

Antivirals • most viral diseases, except HIV disease, are self-limited and do not require treatment • current antivirals target herpesviruses, hepatitis viruses (B and C), influenza viruses, respiratory syncytial virus and HIV • field is rapidly evolving as viruses become resistant to older drugs

20

Human Herpesviruses

• ___ and ___

____

____

_____

____

____
____

Human Herpesviruses • herpes simplex virus (HSV-1 and HSV-2) • varicella-zoster virus (VZV) • cytomegalovirus (CMV) • Epstein-Barr virus (EBV) • human herpesvirus 6 (HHV-6) • human herpesvirus 7 (HHV-7) • human herpesvirus 8 (HHV-8)

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• ____

NA: , ___ ___

• encode___ ___e and___ ___ • Distinct form those in mammals • Good targets for drugs

•___, ___, ___, ____ infections

• ___ infections and/or associated with orofacial tissues and saliva

• enveloped, ds DNA • encode thymidine kinase and DNA polymerase • Distinct form those in mammals • Good targets for drugs • lytic, persistent, latent, and immortalizing infections • oral infections and/or associated with orofacial tissues and saliva

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Pathogenesis of HSV Infection

• Initial Infection

o Often Occurs in ____

____ infection

o Oral mucosa becomes infected

o May have___ signs and symptoms or may have a ___ infection

o Virus transported to __ ___ ___ at the site of primary infection

• HSV1: ____ ganglia • HSV2: ___ ganglia, sexually transmitted

• Latency

o Sits in those ganglia and makes latency associated proteins but its ___ ____ o Can be maintained here for a long time

• Reactivation

o Can be triggered by variety of things: Hormone fluxes, exposure to sun, immunosuppression, stress

o Virus travels ___ ___ the nerve to __ ___ where it will replicate and you will see ___ caused by virus

• Transmission

o___ ____:Both 1 and 2

o This can lead to transmission→sexually, thru infected birth canal, exchange of oral fluids

Pathogenesis of HSV Infection • Initial Infection o Often Occurs in childhood o Oralfacial infection o Oral mucosa becomes infected o May have severe signs and symptoms or may have a subclinical infection o Virus transported to sensory nerve ganglia at the site of primary infection • HSV1: trigeminal ganglia • HSV2: Sacral ganglia, sexually transmitted • Latency o Sits in those ganglia and makes latency associated proteins but its not replicating. o Can be maintained here for a long time • Reactivation o Can be triggered by variety of things: Hormone fluxes, exposure to sun, immunosuppression, stress o Virus travels back up the nerve to mucosal surface where it will replicate and you will see lesions caused by virus • Transmission o Mucosal shedding:Both 1 and 2 o This can lead to transmission→sexually, thru infected birth canal, exchange of oral fluids

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HSV Disease Syndromes

Normally 1 infects ___ the waist and 2 is ___ the waist but can cross over

HSV Disease Syndromes Normally 1 infects above the waist and 2 is below the waist but can cross over

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Clinical Course of HSV Infection

Primary Infection

1. Incubation peiod: ____ days

2. ___ symptoms: ___ or ___

3. Systemic symptoms: __ ___ symptoms

4___  appear. New lesions for ___days Fluid in lesions is ___ with virus

5. Viral ____: ____ days

6. Vesicles __ ___

7. Healing in ___-___ days

Clinical Course of HSV Infection Primary Infection 1. Incubation peiod: 3-14 days 2. Prodromal symptoms: Tingling or itching 3. Systemic symptoms: Flu like symptoms 4. Vesicles appear New lesions for 5-6 days Fluid in lesions is full with virus 5. Viral Shedding: 10-15 days 6. Vesicles Crust over 7. Healing in 18-21 days

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Recurrent Infection

1. Reactivated virus travels to ___ or ____ surface

2. Prodromal symptoms

3.____  systemic symptoms

4. __ __ of vesicles New lesions for ___ days

5. Viral Shedding:___ days

6. Vesicles Crust over

7. Healing in___  days

Recurrent Infection 1. Reactivated virus travels to epidermal or mucosal surface 2. Prodromal symptoms 3. Minimal systemic symptoms 4. Small group of vesicles New lesions for 1-2 days 5. Viral Shedding: 3-5 days 6. Vesicles Crust over 7. Healing in 9-10 days

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HSV Infections

• ____: Oral

• ____: lesions on cornea, can go blind, autoinoculation from touching lesion on lip and then rubbing the eye

• ____: Can get lesions in nail bed, can autoinoculate yourself

• Herpes ____

• ____: usually only in immunosupressed

• ____s: Get into brain

• ___ Herpes: Infected birth canal, can be fatal

HSV Infections • Gngivostomatitis: Oral • Keratitis: lesions on cornea, can go blind, autoinoculation from touching lesion on lip and then rubbing the eye • Whitlow: Can get lesions in nail bed, can autoinoculate yourself • Herpes Gladiatorum • Esophagitis: usually only in immunosupressed • Enccephalitis: Get into brain • Neonatal Herpes: Infected birth canal, can be fatal

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HSV Infections—Epidemiology

• ___ infection

• ____ disease is source of ___

• ___ ____ (HSV-__ > HSV-__) o Have virus in absence of any lesions

• seroprevalence • 55% infected with HSV-1 • 17% infected with HSV-2 • rates increase with ___

• transmission • most often from an __ ___ • ___, ___ secretions, lesion___ on mucosa

• about one in six persons between ages of 14 and 49 years have genital HSV-2 infection in the U.S.

• transmission from an infected ___ to a ___ partner is more likely than from an infected female to her male partner

HSV Infections—Epidemiology • lifelong infection • recurrent disease is source of contagion • asymptomatic shedding (HSV-2 > HSV-1) o Have virus in absence of any lesions • seroprevalence • 55% infected with HSV-1 • 17% infected with HSV-2 • rates increase with age • transmission • most often from an active lesion • saliva, vaginal secretions, lesion fluids on mucosa • about one in six persons between ages of 14 and 49 years have genital HSV-2 infection in the U.S. • transmission from an infected male to a female partner is more likely than from an infected female to her male partner

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Genital Infections--HSV-1 vs. HSV-2

____ features of initial infection: 

____ genital lesion: 

days to ___ ___

avg ____s/yr

viral____

Genital Infections--HSV-1 vs. HSV-2

Clical features of initial infection: indisting

duration genital lesion: 1<2

days to first recurrence1<2

avg reccurences/yr 1<2

viral shedding 1<2

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HSV Infections—Treatment

• ___ or ___ the course of primary or recurrent disease

• does not eliminate___

• ____

• most prescribed anti-HSV drug

• Works on viral ___ ___

• Takes the acyclovir and converts it to a ___ that is incorporated into ___ ___ and prevents its synthesis

• highly ____; activation requires the __ __ ___

• valacyclovir (Valtrex); penciclovir (Denavir); famcyclovir (Famvir)

HSV Infections—Treatment • prevents or shortens the course of primary or recurrent disease • does not eliminate latency • Acylcovir • most prescribed anti-HSV drug • Works on viral thymidine kinase • Takes the acyclovir and converts it to a NA that is incorporated into viral DNA and prevents its synthesis • highly selective; activation requires the viral thymidine kinase • valacyclovir (Valtrex); penciclovir (Denavir); famcyclovir (Famvir)

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Pathogenesis of VZV—Chickenpox

• Spread by ___ ___→Then it gets into the ____s→ ___, ___ → start to get a ____ (flu like symptoms)→ go to ___ ___ or ___→ all the____ pop up→ latency in ____

• complications

o __ ___ of skin lesions

o___

o ____l varicella syndrome

o ____

Pathogenesis of VZV—Chickenpox • Spread by resp tract→Then it gets into the lymphatics→ Liver, spleen → start to get a viremia (flu like symptoms)→ go to mucous membrane or skin→ all the lesions pop up→ latency in neuron • complications o bacterial infection of skin lesions o pneumonia o congenital varicella syndrome o encephalitis