TA Review Flashcards
4 Basic Properties
-obligate parasite -composed of nucleic acids -small, pass through filters -cannot be directly observed
Lytic vs. chronic vs. latent
Lytic –> Virus is replicating, with symptoms Chronic –> Virus is replicating, asymptomatic presentation Latent –> Virus is not replicating, asymptomatic
General Stages of Replication Cycle
- Attachment and penetration 2. Uncoating 3. Fusion 4. Replication/translation/maturation 5. Assembly 6. Budding
Ebola Replication Cycle
- Attachment 2. Macropinocytosis 3. Fusion at endosome 4. Negative strand with RNA virus transcription –> translation into viral proteins. 5. Negative strand RNA virus replication 6. Assembly of parts from 4 and 5 7. Budding
RNA Virus classification card
DNA Virus Classification Card
What are DNA Viruses
HHAPPPP(y)
Hepadna (HBV), Herpes, Adeno, Pox, Parvo_, P_apilloma, _P_olyoma
Characteristics of DNA Viruses
- Double-stranded (except parvo – it’s only “ part of” a virus)
- Replicate in nucleus (except pox – it’s weird)
- Are Icosahedral (except pox – it’s weird)
Geography of Ebola
West Africa
Transmisison of Ebola
Direct Contact: Blood, secretions, organs, & other body fluids –
Indirect Contact: Contaminated environment –
Airborne Transmission: During aerosol generating procedures –
Individuals are Infectious as long as Ebola virus present in blood, breast milk, and other secretions.
Diagnosis of Ebola
Presenting Symptoms: ELISA; PCR; virus isolation –
Late in Disease or After Recovery: IgM and IgG antibodies
Ebola incubation period
2-21 days
Ebola presenting symptoms
- Acute Onset: Fever, Myalgia, Headache
- After 5 days: N&V, Abdominal pain, Diarrhea, Chest pain, Cough, Pharyngitis
- Other Symptoms: Photophobia, Lymphadenopathy, Conjunctivitis, Jaundice, Pancreatitis, CNS Symptoms (decreased mental status, delirium, coma)
Ebola disease progression
Erythematous maculopapular rash: face, neck, trunk, arms with desquamation
- Bleeding Manifestations: petechiae, ecchymosis, & hemorrhage (less common).
- Fatal Progression: Shock, DIC, liver & renal failure. Death between 6-16 days.
- Protracted Convalescence: Arthralgia, orchitis, uveitis, transverse myelitis
Tx Ebola
Current: Supportive
Investigational: Zmapp (3 monoclonal antibodies) after onset of treatment; Vaccines
Pathogenesis of Ebola
Infects macrophages and dendritic cells –> Leads to supression of Type I IFN, and systemic dissemination –> Causes direct tissue injury in liver, spleen, and adrenals–> Host IR causes damage also via cytokines.
Influenza Virus A/B/C family
Orthomyxoviridae
Influenzae Morphology
Enveloped
Single Strand RNA virus
Negative sense
Segmented
Helical Capsid
Influenzae pathogenesis/infectious properties
Hemaagglutin (HA) –> Binds Sialic Acid which leads to endocytosis into respiratory endothelium and agglutination of RBCs
Neuroaminidase (NA) –> Cleaves HA sialic acid bond and allows for spread of viral copies
M2 –> forms a proton channel, facilitates uncoating
Standard clinical manifestation of influenzae
Primarily: “flu symptoms” including malaise and myalgia
Clinical complications of Influenzae
pneumonia/secondary bacterial pneumonia
otitis media
Reye’ s syndrome (w/aspirin in peds) –> Rash, vomiting, liver damage due to swelling in liver and brain
Encephalitis
myositis/cardiac involvment
Diagnosis of Influenzae
Often made on clinical grounds
Rapid antigen, culture, serotyping are available
GO back to lecture for this!! more info on slides.
Influenzae Antigenic Shift
(major reassortment, Flu A only). Responsible for Pandemics, happen every 50 years
Antigenic Drift Influenzae
(yearly changes/mutations). Three strains: A, B, and C. Responsible for yearly outbreaks
Treatment of Influenzae
NA Inhibitors (Tamiflu/Oseltamavir) and M2 Channel Blockers (Amantadine) Vaccines (live + inactivated)
Virus in family paramyxoviridaie
Parainfluenzae
RSV
hMPV
Adenovirus morphology
Nonenveloped
linear
dsDNA
Icosahedral capsid
Adenovirus infectious properties
HA (hemaglutinin) –> binds sialic acid and mediates endocytosis
Transmission of Adenovirus
Fecal Oral
*(TA Review is wrong when it says Fomites, Droplet, contact)
Epidemiology of adenovirus
Outbreaks in congregate settings, different serotypes target different tissues
Clinical presentation of adenovirus
• Pharyngitis, pneumonia, & other respiratory tract infections •
Common Cold (#3 cause) •
Conjunctivitis (“pink eye”) •
Gastroenteritis (#2 viral cause of diarrhea), hemorrhagic cystitis (hematuria & dysuria)
Adenovirus diagnosis
DFA (direct fluorescent antibodies); PCR; culture
Not routinely done –> check on this in lecture
Tx and Prevention of adenovirus
Supportive. Live attenuated vaccine used in military (congregate setting)
Cidofovir used in immunocompromised hosts
Coronavirus morphology
Enveloped,
(+) ss RNA;
helical capsid (RNA genome + N protein)
Coronavirus infectious properties
E2 glycoproteins form “halo-like” projections surrounding the envelope (crown!)
Transmisison of coronavirus
Fomites, person:person
Clinical presentation/epidemiology/diagnosis of coronavirus
Common Cold (#2 cause) & other respiratory infections; –>Diagnosis is clinical picture, seen all over the world
Gastroenteritis
- Severe Acute Respiratory Syndrome (SARS): fever, respiratory distress & pneumonia, diarrhea; 10% mortality. Diagnosis is done via PCR/EM/Antibody Assay, seen in Asia did spread from China to worldwide.
- Middle East Respiratory Syndrome (MERS): fever, respiratory distress & pneumonia, diarrhea. Diagnosis is done via PCR/EM/Antibody Assay. Seen in Saudi Arabia.
SARS/MERS
Both caused by coronavirus
- Severe Acute Respiratory Syndrome (SARS): fever, respiratory distress & pneumonia, diarrhea; 10% mortality. Diagnosis is done via PCR/EM/Antibody Assay, seen in Asia did spread from China to worldwide.
- Middle East Respiratory Syndrome (MERS): fever, respiratory distress & pneumonia, diarrhea. Diagnosis is done via PCR/EM/Antibody Assay. Seen in Saudi Arabia.
TX coronavirus
All treated with supportive care
Parainfluenzae Virus morphology
Enveloped,
ss (-) linear,
non-segmented RNA;
helical capsid
Respiratory Syncytial Virus (RSV) morphology
Paramyxoviridae:
Enveloped,
ss (-) linear,
non-segmented RNA;
helical capsid
Human Metapneumovirus (hMPV) morphology
Paramyxoviridae:
Enveloped,
ss (-) linear,
non-segmented RNA;
helical capsid
Parainfluenzae Infectious Properties
HN protein functions with combined HA and NA activity: mediates fusion and endocytosis (H) and cleaving for spread (N)
Parainfluenza Transmission
Respiratory droplets & Contact
Parainfluenzae clinical presentation/epidemiology
Croup (laryngotracheobronchitis – barking seal cough) –> See the steeple sign on xray, the narrowing of the airway
seen in kids age 3-5, most people get it by age 5. Seen in Fall and Spring.
bronchiolitis Pneumonia in kids (URI + LRI);
Common cold in adults (URI only)
Diagnosis of Parainfluenzae
DFA and PCR and culture
Treatment of Parainfluenza
Supportive and corticosteroids to open up the airway
RSV infectious properties
G protein mediates attachment and release, instead of HA/NA in other parmyxoviruses (such as parainfluenze and hMPV)
Transmission of RSV
Fomites or direct contact with secretions
Clinical presentations of RSV
- Kids/Infants: Pneumonia & bronchiolitis
- Immunocompetent Adults: Common Cold
- Immunocompromised Adults: Pneumonia
Epidemiology of RSV
Most infected by 2 years of age. Reinfection throughout life is common.
- Risk Groups: Premature / Elderly, Congenital Heart Defects, Bronchopulmonary Dysplasia (BPD – formerly chronic lung disease of infancy)
- Outbreaks in winter & spring
Diagnosis of RSV
Rapid antigen test, DFA, PCR (not used clinically)
Treatment of RSV
- Supportive care.
- Prevention of severe RSV disease for high risk infants: palivizumab (vs F protein). High risk infants are pre-mes, congenital heart defect babies, infants with bronchopulmonary dysplasia
hMPV clinical presentation
Bronchiolitis Pneumonia in kids, elderly, and immunocompromised;
URI in healthy adults
Epidemiology/Transmission of hMPV
Outbreaks: Jan-April (winter).
Recurrent infections throughout life.
Highest risk: immunocompromised, preemies, transplant, cardiopulmonary disease.
Transmission by contact with contaminated secretions.
Clinical presentation of hMPV
Bronchiolitis Pneumonia in kids, elderly, and immunocompromised;
URI in healthy adults
Treatment of hMPV
Supportive
Diagnosis of hMPV
PCR/DFA, probably not used clinically at all
Measles is caused by
Rubeola, Morbillivirus
Measles/Rubeola morphology
single strand negative sense RNA genome
non segmented
helical capsid
enveloped
single serotype
Infectious properties of Measles
HA –> sialic acid binding, endocytosis
M protein –> assembly
Measles transmission
Aerosol, need ot keep under negative pressure isolation
Clinical Presentation of Measles
- Incubation: 10 days;
- Prodrome (pre-rash): 3 days of cough, coryza, conjunctivitis, photophobia (CCCP);
- Disease: Koplik’s spots in mouth, maculopapular rash starts at head moves to feet.
Complications of Measles
- Bacterial Superinfection, Pneumonia, Encephalitis (1 in a thousand)
- Subacute Sclerosing Panencephalitis (1 in a million; occurs years later)
- Transient Immunosuppression: TB susceptibility in endemic regions
Measles diagnosis
clinical findings, direct fluorescent antibody (urine)
measles tx and prevention
MMR vaccine; pooled immunoglobulins (prophylaxis in unvaccinated)
Treatment: Supportive care. Vitamin A supplementation
mumps morphology
negative sense single strand RNA, non-segmented, helical capsid, enveloped
infectious properties/transmisison of mumps
HN does both entry and exit, like parainfluenzae
Respiratory transmission
Clinical manifestation of mumps
Incubation - 7-10 days;
Viremia - 15 days
Disease manifestations – 18+ days: Parotitis (swollen parotid gland), orchitis (testis pain), mastitis, aseptic meningitis, encephalitis (Mumps gives you bumps!)
mumps diagnosis
clinical findings, serology
tx/prevention of mumps
No tx, vaccine coverage not quite as good as it was with measles. See some outbreaks amongst the vaccinated
Rubella/German Measles morphology
Togaviridae- Rubivirus,
enveloped,
(+)ssRNA,
non-segmented,
Icosahedral,
single serotype.
Infectious properties of Rubella
Only Togavirus not transmitted by Arthropod
Clinical presentation of Rubella
Fever followed by descending rash (mild disease);
Congenital rubella (toRches)- if mother infected in 1st trimester:
fetal deafness,
cataracts,
heart defects (PDA),
mental retardation,
blueberry muffin rash.
Rubella Diagnosis
Detection of IgM Rubella antibodies
Rubella transmission
respiratory droplets
Treatment/prevention of German measles
No Tx, MMR vaccine
Enteroviruses
“PERCH”
Poliovirus
Echovirus
Rhinovirus
Coxsackievirus A & B
Hepatitis A
Polio morphology
Enterovirus, Picornaviridae
non-enveloped, (+)ssRNA, nonsegmented, icosahedral
Infectious Properties of Polio
Stable at low gastric pH,
hidden binding sites,
inhibits host ribosomes
Clinical Presentation of Polio
Replicates in lymph of GI –> viremia –> anterior horn of spinal cord
Can cause meningitis and paralysis
Diagnosis of Polio
Done on Serology
Epidemiology of Polio
Fecal Oral in developing countries
Treatment/Prevention of Polio
IPV – Salk vaccine (killed)
OPV – Sabin (live attenuated)
Echo and Coxsackie morphology
Enteroviruses, picorniveridae
very small, non enveloped
Positive sense single strand RNA
nonsegmented
icosahedral
Infectious properties of echo and coxsackie
Stable at low gastric pH, hidden binding sites
Clinical Presentation Coxsackie A
herpangina, vesicular lesions, hand-foot-and-mouth diseases, throat pain, anorexia
common cold, fever, rash, meningitis in summer
Clinical Presentation of Coxsackie B
myocarditis, pleurodynia (painful pleuritic chest pain), fever,
common cold, fever, rash, meningitis in summer
Clinical Presentation Echovirus
Neonatal Disease
common cold, fever, rash, meningitis in summer
Epidemiology of Echo/Coxsackie
Fecal oral transmission, kids = hand/foot/mouth
Treatment of Echo Coxsackie
Symptomatic
Different types of Meningitis, CSF analysis
Rhinovirus morphology
Enterovirus, picorniviridae,
very small, non enveloped
ssRNA positive sense
non segmented
icosahedral
Infectious Properties of Rhinovirus
Over 100 serotypes, so reinfection of same host
Clinical presentation of rhinovirus
Also - pharyngitis, otitis media.
Less common - bronchiolitis and pneumonia.
NUmber one cause of the common cold
Diagnosis Rhinovirus
Treatment Rhinovirus
Diagnosis clinical
Tx supportive
Rhinovirus epidemiology
Everywhere and everyone;
Transmitted by aerosols and fomites.
Hands thought to be major vector.
Early autumn and late spring.
Rotavirus morphology
non-enveloped;
inner and outer capsids
Segmented dsRNA genome
dsRNA –> unique to reovirus aka this family
Rotavirus infectious properties
Enterotoxin (“NSP4”) –> causes dirrhea
replication in host cytoplasm
Highly resistant to desiccation – can survive in feces for months!
Rotavirus Clinical presentation
Diarrhea (watery), fever, vomiting, dehydration;
worse in immunodeficient 48 hr incubation;
subsequent reinfections are milder thanks to imperfect antibodies.
Diagnosis of rotavirus
ELISA, latex agglutination in stool, PCR, EM
Epidemiology of Rotavirus
#1 cause of Diarrhea in kids in the US and worldwide;
almost everyone’s had it by age 4
Spread via Fecal-oral route;
patients shed virus both pre- and post-infection.
More common in winter months
Rotavirus treatment and prevention
Prevent with *Live* Vaccine;
Oral Rehydration therapy in active infection
Norovirus morphology
Calicivirus family.
Non-enveloped,
(+) ssRNA,
non-segmented genome
Infectious Properties of norovirus
Infects the upper GI tract, replicates there
Host creates antibodies against norovirus, but they have a short effective half life
Clinical presentation of norovirus
Watery diarrhea +/- fever, headache, and constitutional symptoms
More diarrhea in adults, more vomiting in kids
1-2 day incubation –> 1-2 day illness –> 2 weeks shedding
Diagnosis of norovirus
Usually from clinical picture
Epidemiology of Norovirus
1 cause of Adult watery diarrhea, often with large outbreaks (think cruise ships)
Fecal-oral spread; affects older children and adults
Some are asymptomatic carriers, some are totally immune (“secretor negative”)
Treatment of norovirus
Supportive
What does hepatitis look like clinically
upper right quadrant pain
nausea/vomiting
jaundice
itching
fatigue
Hepatitis Morphologies
Hep A - Picorniviridae, non-enveloped, (+)ssRNA, nonsegmented, icosahedral
Hep B - Hepadnavirus, circular dsDNA Enveloped, icosahedral (carries own reverse txase)
Hep C - Flaviviridae, Enveloped, +ssRNA, linear, icosahedral
Hep D - Circular genome, ss-RNA
Hep E - Hepevirus (calcivirus) non-enveloped, +ssRNA, icosahedral
Hepatitis Transmissions
Hep A - Fecal Oral
Hep B - Parenteral, Vertical, sexual (?)
Hep C - Parenteral (mostly)
Hep D - Parenteral, Vertical, Sexual
Hep E - Fecal Oral (waterborne)
Incubation/clinical presentation of Hepatitis
Hep A - Short –> Abrupt presentation.
Hep B - Long (months).
Hep C - Long
Hep D - Depends
Hep E - Short
Hepatitis Clinical Presentations
Hep A –> Mild/self limited disease. Rarely see hepatic failure secondary to host IR.
Hep B –> Acute (after the long incubation) OR
Chronic (latent carrier state possible) hepatitis: ALT > AST
Cirrhosis
HCC (hepatocellularcarcinoma) (DNA oncogene; don’t need cirrhosis)
Hep C–> 20% self limited 80% progress to asymptomatic carrier or chronic active Hep C (at risk for HCC or cirrhosis)
Hep D –> Co-infection with Hep B, causes Superinfection (worse outcomes)
Hep E –> Acute (short incubation), self-limited, NOT chronic
High mortality pregnant women in 3rd trimester
Hepatitis Infectious Properties
Hep A - Stable in the soil and water
Hep B - Targets hepatocytes, but it’s mostly the immune response that causes damage
Hep C - E2 mediated cell attachment, RNA polymerase= high mutation rate, NS3/4A protease prevents IFN-b induction
Hep D - Needs Hep B for envelope proteins or else no infectious
Hepatitis Diagnoses
Done with serology mostly
Hep A - anti HAV IgM (acute) anti HAV IgG (prior or vaccination)
Hep B - HBsAg – surface antigen, indicates current infection Anti-HBs – Immunity (either exposure or immunization) Anti-HBc – Indicates exposure (IgM: acute, IgG: resolved) HBeAg– Contagious
Hep C - anti-HCV Ab, PCR (HCV RNA), biopsy
Hep D - HBV and HDAg S and L
Hep E - Clinical
Epidemiology of Hepatitis
Hepatitis A - Fecal oral transmission - Shellfish outbreaks Endemic areas, crowding, military, children
Hep B - Endemic S. Europe, Africa, Asia
Hep C - HIV coinfection, IV drug use
Hep D - Pts with HBV
Hep E - Developing countries
Hepatitis treatments
Hep A –> Supportive/vaccine
Hep B –> Vaccine, IFNa, HBV LATTE (RT-I) which doesn’t really work that well
Hep C –> OLD: Pegylated IFN-a + Ribavirin (duration based on genotype)
Hep C –> OLD: PegIFN + Ribavirin NEW: PegIFN + Ribavirin + Protease Inhibitor (Telaprevir or Boceprivir). No Vaccine.
Hep D –> Treat Hep B
Hep E –> Supportive
All the herpes viruses
Herpes Simplex Virus –> HSV-1;
HSV-2;
Varicella Zoster Virus –> VZV;
Epstein Barr Virus –> EBV;
Cytomegalovirus –> CMV;
Human Herpes Virus –> HHV-6 & HHV-7;
HHV-8
HSV1 and HSV 2 morphology
dsdna, enveloped icosahedral
HSV 1 and 2 pathogenesis
Surface glycoproteins: attachment and fusion, bind complement, bind Fc of IgG.
Latent in CNV ganglion (HSV-1) or sacral ganglion (HSV-2)
Transmission HSV 1 and 2
HSV 1: Respiratory secretions, saliva, HSV 2: Sexual, perinatal
Clinical Presentation of HSV 1 and 2
Many asxatic. Oral/genital lesions- crops of small, painful blisters that ulcerate. Encephalitis.
In neonates: diarrhea, recurrent infections. (ToRCHES).
Diagnosis of HSV 1 and 2
Culture, DFA, PCR, Tzanck smear (scraping of ulcer for cells)
Epidemiology of HSV 1 and 2
HSV1 = most people have it,
HSV2: usually sexually transmitted
Treatment of HSV 1 and 2
Acyclovir, Valacyclovir
Varcicella Zoster Virus (“VZV,” or Human Herpes Virus-3) morphology
dsDNA, enveloped, icosahedral
Pathogenesis of VZV/Zoster
Similar to HSV 1/2
Surface glycoproteins: bind complement, bind Fc of IgG and enter cells. Latent in DRG
Clinical presentation/transmission of VZV/Zoster
Transmission: respiratory droplets
Primary (varicella): Chickenpox (“dew drop on rose petal” vesicles of different ages)
Reactivation (zoster): Shingles (vesicles & pain in dermatomal distribution from DRG) seen in Immunopromised /pregnant also with pneumonia or encephalitis
Diagnosis of VZV/Zoster
Made on history of chicken pox, clinical.
Epidemiology of Zoster/VZV
Primary disease worse in adults, reactivation in immunocompromised
Treatment of VZV and Zoster
VZV vaccines, (Val)Acyclovir, Human Pooled IgG
Epstein-Barr Virus (“EBV” or Human Herpes Virus-4) morphology
dsDNA, enveloped, icosahedral
EBV transmssion/pathogenesis
TM by saliva, requires close contact.
Infects B cells via CD21, causes B cell transformation
(immortalization), remains latent in B cells for life. Can cause via this immortilazation atypical lymphocytosis (T cells).
EBV clinical presentation
Mononucleosis: fatigue, fever, lymphadenopathy, pharyngitis, hepatosplenomegaly, rash (worse with amoxicillin). Resolves in 2-3 weeks. –> mono sucks, you feel really tired
Complications in immunosuppressed: lose control of transformed B cells, complications range from minor to malignancy
Diagnosis of EBV
MONOspot test- IgM heterophile (nonspecific) antibody
*Not sensitive for children under 5 yrs old
Epidemiology of EBV
50% of children infected, 70% of US by age 30
African endemic Burkitt’s, HIV-associated lymphomas, Hodgkin’s
Treatment EBV/mono
Rest, reduce immunosupression
CMV human herpes virus 5 morphology
dsdna
icosahedral
enveloped
Pathogenesis of CMV
Infects lymphocytes,
Downregulates MHC I, Contains UL97 and UL 54.
Clinical presentation of CMV
EBV negative Mono
Congenital infection –> (hearing loss) TORCHES CMV is the most common congenital infection
Severe disease in immunocompromised (pneumonia, retinitis, etc)
Other: Guillain-Barre syndrome
Shed in secretions, blood transmission
TORCHES congenital infections
T – Toxoplasmosis / Toxoplasma gondii
O – Other infections (see below)
R – Rubella
C – Cytomegalovirus
H – Herpes simplex virus-2 or neonatal herpes simplex
The “other agents” under O include:
Coxsackievirus
Chickenpox (caused by varicella zoster virus)
Chlamydia
HIV
Human T-lymphotropic virus
Syphilis
Diagnosis of CMV and
Owl’s eye inclusions, biopsy and culture, PCR, urine cultures
Epidemiology of CMV
Most people are CMV positive, but disease is bad in immunocompromised.
Treatment of CMV
Treatment is reserved for immunocompromised. Can treat prophylactically
1st Line: (Val)Gancyclovir.
2nd Line: Foscarnet or Cidofovir if viral TK (UL97) resistance. 2nd line drugs are very toxic, esp. Cidofovir (nephrotoxic)
HHV-6 (and HHV-7) morphology
dsDNA, enveloped, icosahedral
HHV-6 (and HHV-7) pathogenesis
Infects lymphocytes; Persists in Macrophage
HHV-6 (and HHV-7) clinical presentation
Sixth Disease or Roseola
Roseola (Exanthema subitum): Child with 2 days of fever, then fever disappears and total body rash suddenly appears. Febrile seizures (benign condition)
Diagnosis of HHV-6 (and HHV-7)
Made on clinical presentation:
Roseola (Exanthema subitum): Child with 2 days of fever, then fever disappears and total body rash suddenly appears. Febrile seizures (benign condition)
Epidemiology of HHV-6 (and HHV-7)
Most children have it by age 3 (95%)
Treatment of HHV-6 (and HHV-7)
Treating Sixth Disease or Roseola
Gets better on its own, supportive
HHV-8 is also called
(Kaposi Sarcoma Associated Herpesvirus)
Morphology of HHV-8
(Kaposi Sarcoma Associated Herpesvirus)
dsDNA, enveloped, icosahedral
Pathogenesis of HHV-8
Infects B cells primarily, encodes growth and anti-apoptotic factors
Clinical presentation of HHV-8
Kaposi Sarcoma: Vascular lesions w/bleeding and hemosiderin deposition
Primary effusion lymphoma –> lymphoma in body cavities
Castleman’s disease –> proliferation of lymph nodes
Diagnosis of HHV 8
History of Aids, Clinical presentation:
Kaposi Sarcoma: Vascular lesions w/bleeding and hemosiderin deposition
Primary effusion lymphoma
Castleman’s disease
Epidemiology of HHV-8
In the US: associated with HIV/AIDS, MSM, and drug users
Endemic in Africa, Mediterranean
Treatment of HHV-8
Antiretrovirals for HIV (or chemo if invasive)
Human Papilloma Virus (HPV) morphology
Unenveloped, circular dsDNA
HPV virulence factors
– Does not infect APCs–>limited immune detection
– Viral proteins E6 and E7 inhibit tumor suppressor genes –> oncogenicity
Clinical presentation of HPV
– Most asymptomatic
– Strains 6, 11 –> Genital warts (condyloma accuminatum)
– Strains 16, 18 –> Cervical cancer
Diagnosis of HPV
– Cytology (“Pap smear”): look for characteristic changes (koilocytes)
– Biopsy (if abnormal cells seen on pap): look for degree of cervical endothelial dysplasia
Epidemiology of HPV
– Exposure is EXTREMELY common; sexually active are at risk for high risk strain
infection.
– 99% of all cervical cancers assoc with HPV infection (also anal cancers
Treatment/Prevention of HPV
Bivalent (16, 18) and tetravalent (6, 11, 16, 18) vaccines available for women and men ages
Treat malignancy with chemoradiation
HIV morphology
- Enveloped, with 2 copies of + sense ssRNA
- Carries its own reverse transcriptase, a protease, and “integrase –> targets for drugs
Infectious properties/pathogenesis of HIV
- A retrovirus: Inserts its genetic material into the host’s genome
- Selects for immune cells: CD4+ Helper T-Cells & Macrophages
- Evades effective immune response due to hyper-variability of envelope proteins & downregulation of MHC
Clinical course of HIV without HAART (aka AIDS)
- Acute Infection (~2-4 weeks) –> Asymptomatic Period (avg ~8 yrs) –> AIDS (~13 yrs)
- Opportunistic infections, increased risks of cancer, dementia, kidney disease, more.
Diagnosis of HIV
- ELISA for anti-HIV antibodies,
confirm with Western blot;
PCR for plasma viral RNA
Epidemiology of HIV
In US, highest risk is in MSM, IV drug users, and Immigrants from endemic areas
- Most new infections are in Blacks & Latinos; increasing % through heterosexual contact
Treatment of HIV
- Highly Active Anti-Retroviral Therapy (“HAART”)
will go into specifics on other cards
Specific important proteins/genes of HIV virus
p24 –> capsid protein encoded for by gene gag
gp41 --> fusion and entry
gp120 –> attachment to host T cell
gp41 and gp120 are both envelope proteins (outermost layer, surrounding capsid) encoded for by gene env
Reverse transcriptase –> encodes dsDNA from (+) ssRNA encoded for by gene pol
Integrase –> inserts dsDNA into host genome
Time course of HIV infection
Primary Infection –> Low viral load, High T cell count
Acute HIV syndrome (wide dissemination of virus and seeding of lymphoid tissue) –> High viral load and mid-low T cell count. Three weeks after primary infection.
Clinical Latency –> Can last months to years. Viral load drops after acute HIV syndrome and then starts rising slowly. T cell count starts dropping slowly.
Constitutional symptoms –> Happens when T cell count gets low enough/viral load gets high enough
Opportunistic Infections –> When T cell count gets really low. Viral load very high.
Death –> Usually due to an opportunistic infection/other sequealae.
Common opportunistic infections
Principles of HAART
- Strongly recommended for all pts at time of dx
- Required for pts CD4 count <500 cells/mm3, or AIDS-defining illness
Use exactly 3 drugs:
- Use at least two different classes of drugs
- Usually: 2 NRTI + 1 integrase inhibitor
Lack of maintenance –> breeding resistance to drugs.
Life Cycle and linked Drugs
- Attachment (Maravoric)
- Fusion/Uncoating (Enfurvitide)
- Reverse Transcription (NRTIs Exs: Abacavir, Tenofovir), NNRTIs Exs: NeVIRapine, EfaVIRenz, and EtraVIRine )
- Integration (Integrase Inhibitor, Ex: Raltegravir)
- Assembly
- Maturation (Protease Inhibitors ex: idinavir all ___-navir)
NRTIS mechanism of action and names and toxicities
Molecules that look like a normal nucleosides and competitively inhibit reverse transcriptase.
Examples: Zidovudine, Lamivudine, Emtricitabine, Abacavir,and Tenofovir
Toxicity for Entire Class: mitochondrial toxicity, peripheral neuropathy, hepatitis, lactic acidosis, dislipidemia, insulin resistance
Abacavir: Hypersensitivity reactions in pts with HLA-B5701 (we can test for this). We can test for this and prevent a possible fatal reaction.
Tenofovir: Renal toxicity, esp. if underlying renal disease; osteomalacia
Zidovudine: anemia
NNRTIs mechanism of action, names, toxicities
Allosterically inhibit RT
NeVIRapine, EfaVIRenz, and EtraVIRine
Toxicities for entire class: Cytochrome p450 interactions, early resistance, rash
Nevirapine: Can cause severe hypersensitivity reaction with liver toxicity and rash, particularly in women with high CD4 counts.
Efavirenz: Teratogen, so avoid in pregnancy. Also causes neuropsychiatric symptoms like vivid dreams and/or depression; lipid elevation.
Protease Inhibitors mechanism of action, names, toxicities
- Messes up the maturation of the drugs because the proteins need to be cleaved in order to be assembled.
- Lopinavir, Atazanavir, Darunavir, Fosamprenavir, Tipranavir
- Can also act as a pharmokinetic booster –> Ritonavir +Cobicistat (cytochrome p450 inhibitors)
Toxicities entire class: Cause GI disturbances and metabolic syndrome (high cholesterol, diabetes, etc), lipodystrophy, CYP450 interactions.
Atazanavir: Can cause jaundice (without actually causing liver injury), kidney stones.
-
Prophylaxis for Pneumocystic jiroveci
– CD4 count <200
– TMP-SMZ
• Prophylaxis for Mycobacterium avium- complex
– CD4 count <50
– Azithromycin
Immunology: Extracellular Bacteria
Innate Response:
– Phagocytosis
– Complement activation
Adaptive Response:
– Ab neutralization of pathogen
– Ab potentiation of innate response
- Opsonization
- ADCC (antibody dependent cell-mediated cytotoxicity)
Immune evasion extracellular bacteria mechanisms
- Inhibition of complement (all)
- Resistance to phagocytosis (Strep. pyogenes)
- Biofilm (Staph. epidermis)
- Clot formation (Staph. aureus)
Immunology intracellular bacteria adaptive and immune response
• Innate response: Transient control for a short period of time
– NK cells
– Phagocytes
• Adaptive response: Infection eradication
– Th1 cells –> IFN gamma
– IFN gamma–> phagocytes to destroy endocytosed bacteria
Immune evasion intracellular bacteria
- Intracellularity!
- Inhibition of phagolysosome fusion (TB, Legionella)
• Destruction of phagosome membrane (Listeria)
Immunology viruses
- Innate response: Link to adaptive*
- Adaptive response: Potential eradication**
– Th1 cells –> IFN gamma
– IFNs –> “antiviral” state
• Alpha/Beta: Recruit uninfected cells to put their defenses up, activate NKCs to kill viral infected cells.
• Gamma: Increases MHC I, II expression in all cells
Immune evasion: Viruses
- Intracellularity!
- Inhibition of antigen presentation
• Manipulation of cytokine environment
– IL-1 blockade (all)
– Cytokine receptor decoys (poxvirus)
– Secretion immunosuppressive cytokines (EBV)
• Lysing of immune cells (HIV)
Common immune evasion strategies
- Neutralization ROS (many bacteria)
- Multiple serotypes (bacteria & viruses)
Viral vaccines: killed
Hepatitis A: Killed whole virus
Hepatitis B: Recombinant protein subunit (HBs)
HPV: Recombinant protein subunits
Rabies: Killed whole virus, Given as part of PEP
Influenza: Killed whole, Injected form only
Polio (Salk): Killed whole, Injected; 4 doses before school entrance. No mucosal immunity.
Viral vaccines live
Measles/Mumps/Rubella: Live attenuated; Contraindicated in pregnant women, HIV pts with signs of immunodeficiency.
Yellow fever: Live attenuated; Given to those traveling to endemic areas
VZV: Chickenpox: Live attenuated
VZV: Shingles: Live attenuated; Given to pts >60 y/o, 10x dose of chickenpox
Polio (Sabin): Live attenuated, 3 doses provide optimal immunity; 1 provides 50%
Rotavirus: Live human-bovine reassortant (Rotateq) OR Live human attenuated (Rotarix), Rotateq is pentavalent; Rotarix is monovalent but provides cross-protection. Both multi-dose.
Viruses we provide passive immunity for
- Hepatitis A (IVIg)
- Hepatitis B (Hepatitis B Ig)
- Rabies (Rabies Ig)
- Varicella (Varicella Ig)
- RSV (palivizumab)
…and breast feeding!
Diseases caused by prions
Humans: Creutzfeldt-Jakob Disease (CJD), Kuru.
Other animals: Scrapie, Bovine spongiform encephalopathy, chronic wasting disease
Infectious Properties seen in Prions
Infectious form of normal brain protein (PrP).
Domino effect: one misfolded molecule acts as template for other molecules to misfold.
Misfolded proteins are resistant to proteases. Accumulation leads to tissue damage and cell death.
Clinical presentation of prion diseases
Long incubation period, slow but progressive neurologic deterioration (dementia, myoclonus, etc.). Uniformly fatal; most patients die within 6 months of symptom onset.
Diagnosis of Prion diseases
Clinical; can perform EEG, MRI, CSF analysis.
Epidemiology of prion diseases
Most cases are sporadic. Brain eaters, exposure to animal form, rarely familial.
Treatment for prion diseases
none
Arboviruses (arthropod borne viruses) types and names
Need to Know bolded ones
Family: Togaviridae (ss +RNA) Genus: Alphavirus
Viruses: EEE*, WEE*, VEE
Family: Flaviviridae (ss +RNA) Genus: Flavivirus:
Viruses: Dengue virus, West Nile Virus, Yellow fever, SLE*
Family: Bunyaviridae (ss -RNA) Genus: Bunyavirus:
Viruses: La Crosse*, Hantaviruses (rodents)
* are causes of mosquito borne encephalitis. EEE has very high mortality.
Dengue Fever morphology/serotypes
Flavivirus, enveloped, (+)ss RNA, linear.
4 serotypes.
Dengue Fever Clinical Presentation
Less severe (Dengue Fever): aka “Break-bone fever” due to muscle & joint pain. Also: fever, rash, bone marrow suppression. More severe (Dengue Hemorrhagic Fever and Dengue Shock Syndrome): Severe hemorrhagic disease, leaky capillaries and multiorgan involvement.
What causes more severe presentation of Dengue Fever
(Severe disease usually occurs with second infection with a different serotype (four serotypes), due to antibody-mediated immune enhancement = exacerbated cytokine release.)
Diagnosis of Dengue Fever
Detection of anti-DenV IgM in serum, PCR
Epidemiology of Dengue Fever
Tropical Areas where there are mosquitos. S. America, parts of Africa, South Asia/ South East Asia
Vector of Dengue Fever
Aedes aegypti mosquitos. Human and Monkey host.
Treatment of Dengue Fever
Supportive care, vaccine trials ongoing
Yellow Fever Morphology
Flavivirus, enveloped, (+)ss RNA, linear
Yellow Fever Clinical Presentation
Majority: mild illness with fever, H/A, N/V, chills, back pain
Minority: enter a toxic phase with fever, jaundice (liver damage), GI hemorrhage
Epidemiology of Yellow Fever
Africa, S. America, Central America
Vector of Yellow Fever
Aedes aegypti mosquitos (same as Dengue)
Monkeys and Human reservoirs
Treatment of Yellow Fever
Live attenuated vaccine available.
West Nile Virus morphology
Flavivirus, enveloped, (+)ss RNA, linear
Clinical presentation of West Nile Virus
Most cases are asymptomatic (80%)
Rarely can progress to neuroinvasive disease: flaccid paralysis, aseptic meningitis or severe encephalitis (<1%)
Epidemiology of West Nile Virus
Has become more wide-spread over the years within the United States, from 2000 to now. Now see cases in every state. In 2000 saw just in the north east.
More severe infection with age and immunosupression.
Vector for West Nile Virus
Mosquito- Culex sp.
Human and Bird Host
Treatment of west nile virus
Supportive care. No vaccine available.
Prevention with good mosquito control.
Mosquito Borne encephalitis (other then west nile)
EEE (highest mortality) seen in Eastern NA, SA
WEE seen in Central and Western US, SA
SLE Americas. Seen in Urban epidemics.
La Crosse
Rabies morphology
Rhabdovirus, (-)ssRNA, linear, enveloped,
Helical capsid with “Bullet shaped” appearance
Rabies clinical presentation
Prolonged incubation in muscle (months to years).
Then, virus travels proximally to CNS via axons, causing acute encephalitis: mental status changes, delirium, paresthesias, pain, and death.
Onset of symptoms to death ~18days!
Diagnosis of Rabies
DFA (direct fluorescent antibody test) on nape of neck biopsy, PCR, Negri bodies in brain (viral sharply lined eosinophilic nucleocapsid inclusions in cytoplasm of some infected cells)
Epidemiology of Rabies
Rare in US, related to exposure to bats, raccoons, skunks, wild dogs
Transmission of Rabies
Exposure of non-intact skin to saliva of infected animal ~2 cases/ year in USA
Treatment of Rabies
Vaccine (prevention and as part of PEP)
IgG Post-exposure prophylaxis (administer w/in 72 hours)
Viruses with helical capsid
-Myxo’s (para,ortho)
- Corona
- Rabies
Mumps
Measles/Rubeola
