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GMS6121 - Infectious Diseases > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

polyoma genome structure

A

small, dsDNA (similar to papilloma)

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2
Q

what are the human polyomaviruses?

A

JC, BK, and Merkel cell

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3
Q

key features of JC and BK polyomaviruses

A

primarily infect the kidneys
persistently infect people but usually do not cause disease
generally are not a problem except in people undergoing transplants

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4
Q

key features of Merkel Cell polyomaviruses

A

non common
associated w a rare but deadly skin cancer

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5
Q

mononega genome structure

A

neg sense RNA nonsegmented
enveloped
highly conserved genome order
RdRp starts making mRNAs INSIDE the nucleocapsid after entry (3’ to 5’), sequential gene expression, terminating and releasing before reinitiating

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6
Q

what type of virus is rabies

A

Rhabdo (mononega)

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7
Q

what type of virus is ebola

A

Filo (mononega)

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8
Q

what type of virus is mumps

A

paramyxo (mononega)

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9
Q

what type of virus is measles

A

paramyxo (mononega)
binds SLAM/CD150

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10
Q

what type of virus is RSV

A

paramyxo (also pneumo), (mononega)

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11
Q

paramyxo genome structure

A

Neg RNA
No segmented
Enveloped
transcription begins inside nucleocapsid after entry
3’ to 5’
leader as initiation signals
has conserved intergenic sequences between ea ORF
order of genes is conserved
viral RdRp: sequential transcription, terminates and releases ea mRNA before reinitiating at some rate
allows virus to regulate amount of ea protein

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12
Q

paramyxo virion structure

A

roughly spherical
loose envelope
nucleocapsid is helical despite virion being spherical

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13
Q

paramyxo HN protein

A

hemaglutinnin-neuraminidase (not all, some have just H, no N)
note that F and HN are separate

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14
Q

paramyxo F protein

A

fusion protein
has F1 and F2 bound by disulfide bond
starts internal, needs to be cleaved to be functional
note that F and HN are separate

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15
Q

paramyxo N protein

A

nucleocapsid
helical
binds EXACTLY 6 nts in genome each
wound as left handed helix
packaged w P and L

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16
Q

paramyxo L protein

A

polymerase
packaged w N and P

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17
Q

paramyxo P protein

A

phosphoprotein
packaged w N and L

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18
Q

paramyxo SH protein

A

small hydrophobic
maybe function as ion channel (like M2 in influenza)

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19
Q

paramyxo M protein

A

matrix

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20
Q

rhabdo virion structure

A

bullet shape due to wrapping of helical nucleocapsid in supercoil
coiling mediated by M (matrix)
genome complexes to BOTH N and M

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21
Q

paramyxo receptors

A

terminal sialic acid residues on glycolipids on cell mem
paramyxo have HN, neuraminidase releases progeny virions that bind to surface of cell

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22
Q

what is the measles receptor

A

SLAM/CD150
found on activated BCs, TCs, DCs, and MO
killing imm cells leads to immunosuppression

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23
Q

rhabdo entry

A

only have one single glycoprotein (G) that does binding AND fusion (note rhabdo has one protein (G) but paramyxo has 2 (HN and F))
fuse in endosomes not plasma mem
G protein used in pseudotyping other viruses

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24
Q

what is pseudotyping

A

producing viruses or viral vectors in combination with foreign viral envelope proteins
using rhabdo G protein allows it to infect many more cells that don’t have its receptor

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25
Q

what are the two models of mononegra transcription and which is correct

A
  1. multiple promoter, 2. single entry
    single entry is correct - leader seq is only primer, pol (L) transcribes ORF, terminates at intergenic seq, at some freq can reinitiate at the intergenic seq
    we know this is correct bc introducing a mutation in one ORF affects all downstream ORFs (multiple promoters would have it only affect that one ORF)
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26
Q

paramyxo transcription

A

3’ to 5’
L (pol) binds leader at 3’ end, P (phosphoprotein) also binds and helps
L transcribes ORF then falls off, then at some percentage reinitiates, makes N

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27
Q

do paramyxo mRNAs have a 5’ cap

A

yes, methylated (typical cap) by L (pol)

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28
Q

do paramyxo mRNAs have a poly A tail

A

yes, obtained from stuttering on UUU repeats (transcribed into As)

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29
Q

how does paramyxo regulate its mRNAs and proteins

A

falling off/reinitiation leads to more 3’ proteins than 5’ proteins
this is why order is so highly conserved
5’ end has L (pol), doesn’t need a lot
low N (nucleocapsid) leads to transcription, high N leads to replication

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30
Q

how does paramyxo regulate transcription vs replication

A

Neg RNA is used for both transcription and replication
low N (nucleocapsid) leads to transcription
high N leads to replication

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31
Q

paramyxo assembly

A

After mRNAs are made, glycoproteins made
Glycosylated by ER and golgi, inserted into plasma membrane
Matrix not glycosylated, moves to plasma mem and associate w tails of G
N, P, and L all important for replication as well as secondary transcription (makes more mRNAs and more translation templates)

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32
Q

paramyxo P/C/V gene

A

only paramyxo mRNA that makes multiple proteins
multiple start sites, TRANSLATION machinery can uses any of them
P/V/W are most favorable, P is primarily made (longest form)
P is phosphoprotein, subunit for pol
Can also result in V or W
Caused by stuttering on As (DURING TRANSCRIPTION), that can add an additional 1 or 2 Gs (makes V or W)
Gs loated between poly A tail and GC rich region
Y and C are also important

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33
Q

paramyxo differences between transcription and genome replication

A

Full‐length RNA is encapsidated by N whereas mRNAs are not
when N present, pol starts transcribing, nascent RNA becomes associated w N
N may sequester/hide intergenic seq –> block transcription, drives RNA rep

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34
Q

paramyxo assembly and release

A

envelope glycoproteins insert into ER and glycosylated in glogi
(most) F proteins cleaved by furin (ceullar protease) in trans-golgi right before insertion in plasma mem (prevents fusion during intracellular transport)
M (matrix) associates w cytoplasmic tails of envelope
nucleopcapsids in cytoplasm migrate to plasma mem and interact w matix
bud through plasma mem
Fusion is competent on cell surface (causes cell-cell fusion (syncytia) and tissue destruction)

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35
Q

what is different in hendra and nipah F proteins

A

F NOT cleaved by furin
Moves through ER and golgi and is glycosylated, expressed on plasma mem but REPLICATION INCOMPETENT (F0)
Reendocytosed from plasma mem into endocytic vesicle
Cathepsin L cleaves into competent form (F1 and F2) and then F recycled back to plasma mem

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36
Q

what is F0

A

replication incompetent fusion protein, found in hendra and nipah mononegraviruses before reendocytosis

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37
Q

measles transmission

A

aerosol droplets (remains infectious for a few hours)
transmission days before rash, hard to control
one of the most contagious viruses ever studied
primarily in childhood bc so contagious
lifelong immunity
prevalent where there is no vacc

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38
Q

measles spread in body after infection

A

enters through resp tract
rep in many cells bc of SLAM receptor
First cells infected are lung/aveloar cells and MO and DCs (migratory)
Allows spread when MO and DCs drain to lymph nodes, allows virus infect B and T cells
BCs and TCs circulate through blood, virus can spread to 2’ infection sites (skin and more)
Pantropic bc so many cells susceptible
Entering skin causes rash
Rarely enters brain

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39
Q

measles cell tropisms

A

MO, DCs, TCs, BCs, epithelial, endothelial, neurons

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40
Q

measles tissue tropisms

A

pantropic
lungs, lymph nodes, spleen, liver, kidney, GI tract, thymus, skin, rarely CNS

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41
Q

what is viremia

A

virus in blood

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42
Q

measles disease progression

A

lymph entry, initiates viremia > reaches skin and other 2’ tissues > rep in skin (no symptoms) > signs of infection (prodromal like resp disease) > can make Koplik’s spots > dec virus in bloodstream as Abs are made > rash develops
Rash – starts as viremia dec and Abs inc
Starts at hairline and moves down (toes and fingers last)
5-6 days
Resolves from top down as well
Infectious period before symptoms and thorough onset of rash (long time)

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43
Q

Koplik spots

A

red dots on mucosal surfaces, cheeks, and tongue
associated w measles

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44
Q

what causes measles rash

A

Why rash so late in disease progression?
Not caused by virus rep, caused by immune complex formation
Ab binds virus, forms imm complex, targeted by imm sys
Infectious period before symptoms and thorough onset of rash (long time)

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45
Q

what is an imm complex

A

a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen of its own with a specific epitope (think affinity vs avidity in imm class where one Ab binds multiple Ags or 1 Ag binds multiple Abs)

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46
Q

measles outcomes

A

most resolve symptoms in 1-2 wks
in order of increasing rarity: ear infections (1/10, and possible deafness), pneumonia (1/20), encephalitis (1/1000), death (1 to 2/1000, due to pneumonia, worse where malnutrition is problem), SSPE (1/10,000)

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47
Q

what is SSPE

A

subacute sclerosing panencephalitis
CNS degenerative, YEARS (6-15) after measles infection,
causes ataxia, seizures, death
neurons infected w measles virus develops persistent non productive infections (no imm resp but still pathologic to neurons)
Linked to mutation in viral genome
Bigger problem before vaccination

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48
Q

mumps transmission

A

aerosol transmission
similar parhogenic course to measles (resp tract > local lymph nodes> disseminate via viremia to virually all tissues > widespread inflamm)
most common 2’ infection in parotid glands (large salivary glands), CNS, gonads, kidneys, pancreas, heart, and joints
characteristic swelling in neck (spread to parotid glands)
CNS spread can cause meningitis
goand spread can cause sterility (rare)
vaccinated for w measles (MMR)

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49
Q

what is in the MMR vaccine

A

protects against measles, mumps, and rubella (pos sense togavirus)
99% reduction in measles (start in 1963)
US declared eliminated in 2000
2019 saw highest rates of measles in long time
MMRV becoming more common (V = varicella (chickenpox))

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50
Q

Andrew Wakefield (aka the asshole)

A

“linked” MMR vacc to autism and IBD, tried to push his own vacc series w components
no reproducible data bc he’s an ass

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51
Q

mumps outbreaks

A

2006 - midwest college students in dorms (mostly vaccinated)
spread made worse by slow diagnosis - Drs hadn’t seen mumps in long time
2015-16 in college campuses
2016-17 in NW Arkansas
2018 had lowest total of recent outbreaks, but in many places

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52
Q

RSV transmission

A

most common cause of pneumonia and fatal acture resp tract infections among infants
v common (2/3 of infacts infected by 1yr old)
v infectious
transmitted through aerosol droplets or fomites (stay long time)
no vacc

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53
Q

RSV pathogenesis

A

respiratory but v diff from measles and mumps
Spreads from one cell to another along endothelial cells of resp tract
Limited to lungs, no lymph node spread
Can cause severe pathology in the lungs tho (bronchitis and pneumonia)
can cause apnea and chronic lung disease later in life
Formulin inactivated vaccine made in 1960s but made it worse (withdrawn)
Repeated exposure over time, immunity wanes but repeat infections inc immunity again, only infants are symptomatically infected

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54
Q

Rabies (rhabdo) transmission

A

animal bites (usually bats in US, can also be foxes, or racoons)
domestic cats have it more than domestic dogs
1 case a yr in North America
causes encephalitis
once there is symptoms, nearly always fatal
long latent period between bite and symptoms allow for post exposure vaccination

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55
Q

how are wild animals vaccinated for rabies

A

editable baits dropped from planes that have an oral vaccine in them

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56
Q

rabies spread in body after infection

A

animal bite > virus rep in muscle at site of bite > virus infects nerve in PNS > virus spread via retrograde transport > virus rep in dorsal root ganglion > travel from spinal cord to brain > brain infected > virus travels from brain to other tissues (eyes, kidneys, salivary glands)

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57
Q

rabies symptoms

A

Headache, fever, general weakness
Cerebral dysfunction, anxiety, confusion, agitation
Delirium, abnormal behavior, hallucinations, insomnia
Mania and eventually coma
Primary cause of death – respiratory failure (brain stops telling you to breathe)

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58
Q

Milwaukee protocol

A

put patient in induced coma to ‘protect them from their brain’, buys imm sys time to clear infection
treat w antivirals and chemically induced coma
respirator keeps patient breathing
worked 3 times total with no rabies vacc, 5/30 times including rabies vacc
very long rehab

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59
Q

Ebola first outbreaks

A

1976 started in north Zaire (now Democratic Republic of Congo) then south Sudan
near Ebola river
outbreaks were back to back but they were 2 diff outbreaks w 2 diff strains
the first outbreaks were limited and sporadic bc of the isolated communities they happened in (until 2014)
Zaire - 88% fatality
Sudan - 53% fatality

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60
Q

Ebola 2014 outbreak

A

West Africa
initially looked same, within months it multiplied at a staggering rate
why? located in a much more dense city

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61
Q

Ebola 2018/19 outbreak

A

the next most impactful outbreak after 2014
Happening more in dense populations
(may be getting worse)

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62
Q

Ebola reservoirs

A

thought to be classic zoonotic
apes and humans susceptible but END HOSTS bc too deadly, not good spread (not reservoir)
reservoir believed to be fruit bats (not proven tho)
evidence: some bats have pos serology (Abs) for Ebola, migration patterns similar to outbreak locations, exposure correlated to outbreaks
bat exposure and consumption is common in these areas

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63
Q

ebola transmission

A

classical zoonotic
fruit bats to humans (maybe)
human to human (family, caretakers, medical staff, and funeral staff)
infects MO and DCs

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64
Q

Ebola genome structure

A

neg sense RNA
mononega order, filo family
enocodes 7 proteins, including 3 forms of glycoprotein: GP, sGP, and ssGP

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65
Q

Ebolavirus vs Ebola virus

A

Ebolavirus = family (one word)
Ebola virus = species (two words)
Family (one word) contains both initial strains (Zaire and Sudan)
Zaire stain – Ebola virus
Sudan strain – Sudan virus
Focusing on Ebola virus (Zaire)

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66
Q

Ebola virion structure

A

filamentous
enveloped
helical capsid
“knot” or loop at end
diameter about 80nm (normal), length up to 14,000nm (insanely large for a virus)

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67
Q

ebola GP protein

A

glycoprotein
GP is transmem, embedded in envelope, facilitates virus entry

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68
Q

ebola NP protein

A

nucleoprotein, encapsidates the neg RNA genome and protects it
Genome + nucleoprotein = nucleocapsid
Filamentous helical structure – irregular proteins individually, but tightly buttress to ea other to form helical shape
Genome is completely protected by the nuceloprotein

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69
Q

ebola VP30, VP35, and L

A

replications proteins that associate with nucleoproteins
L is RdRp

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70
Q

ebola L protein

A

pol (RdRp) associated w capsid

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71
Q

ebola VP40 protein

A

matrix that forms filamentous structure and connects to envelope

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72
Q

ebola sGP and ssGP

A

secreted glycoprotein
slows host Ab response to virus by binding Abs in place of binding to actual virus

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73
Q

how does ebola get its envelope

A

‘stolen’ from host cell, contains viral glycoproteins (GP important for entry)

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74
Q

ebola entry

A

binds target (DCs or MOs)
entry via macropinocytosis (enters in endosome)
Normally endosomes degrade conents bc low pH, Ebola uses it
Acid activates host proteases, cleave GP, opens receptor binding domain (RBD), binds receptor inside of endosome
NPC1 is receptor
Membrane of virus fuses w mem of endosome, nucleocapsid release to cytoplasm

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75
Q

what is NPC1

A

receptor inside of endosome that ebola uses to fuse to vesicle mem and release into host cell cytoplasm

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76
Q

ebola genome replication

A

Need to make pos from the neg genome
Pos works as mRNA for translation and templates to make more neg (for progeny)
As more nucleoprotein is made it encapsidates genome, join w rep proteins, bud out of cell through mem
‘steals’ lipid envelope and viral GPs that have inserted themselves on the plasma mem
Bud vertically (most of them) or horizontally (occasionally in some types of cells)
Makes solube GPs, slows host Ab resp to virus
v fast rep, large titer in 4-5 days (before imm resp can stop it)

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77
Q

ebola pathogenesis

A

onset 7-9 days
can be asymptomatic in beginning
early symptoms nonspecific while virus is at high titers (fever, aches, etc)
nonspecific symptoms lead it to be confused w malaria, yellow fever, and dengue (missing it allows for more spread)
progress to multi-organ involvement (bleeding everywhere, coughing, vomiting, etc) leads to dehydration and hypovolemic shock which can cause death
not all patients get all symptoms
progress to late peak (blood in tissues, oozing from punctures, disseminated intravascular coagulation)
now it is Ebola Hemorrhagic fever (EHF)

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78
Q

ebola early symptoms

A

Fever, Headache, Chills, Malaise, Myalgia (joint/muscle pain), Nausea, stomach pain, Macropapular rash (flat red lesions) in some cases

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79
Q

ebola multi-organ symptoms

A

Systemic (prostration)
Gastrointestinal (vomiting and diarrhea with blood)
Respiratory (coughing w blood, chest pain, cough, shortness of breath)
Vascular (conjunctival injection, bloody nose, edema, hypotension)
Neurological (headache, confusion, coma)
Dehydration and hypovolemic shock
Without hospital intervention (fluids), die

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80
Q

what are the key symptoms of ebola infection

A

bloody nose and blood in whites of eyes (conjunctival injection)
not all patients develop all symptoms

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81
Q

ebola late / peak symptoms

A

Petechiae (small red spots)
Ecchymoses (blood into tissues)
Hemorrhaging from mucosal sites
Visceral hemorrhagic effusion (hemorrhaging into lining of lungs)
Uncontrolled oozing from venepuncture sites
result from “disseminated intravascular coagulation” (DIC)
called “Ebola Hemorrhagic Fever” (EHF)

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82
Q

what is DIC

A

disseminated intravascular coagulation
abnormal clotting in blood vessels that uses up all clotting factors, leading to massive bleeding in other complications

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83
Q

what causes DIC

A

Cannot clot, loss of blood even after transfusions
DIC - massive activation of coagulation factors in blood, clots all over body, used up and cannot respond to actual injuries
Leads to abnormal bleeding in other locations
result of abnormal reaction to infection
Aberrant bleeding also disrupts normal blood flow to organs (like kidney) which causes multi organ failure from lack of oxygen

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84
Q

ebola final stage symptoms

A

shock
convulsions
multi organ failure
death
Fatality rate can be higher than 80%

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85
Q

ebola spread in body after infection

A

Contact to skin (or mucosal sites) > infect resident MO and DCs > drain to regional lymph nodes > induce inflamm resp > cytokine release (causes inflamm resp and depletion of lymphocytes by recruiting more to infect) > rep to high titers > enter blood > disseminate to all peripheral 1’ organ systems > rep in peripheral organs (liver) > dec coagulation factor production > rep in lung, kidney, heart, brain > multi organ failure
Virus cannot infect TCs but induces TC death
Liver is especially important bc virus in liver severely reduces amount of coagulation factors made
coagulation factors are used up (imm resp) and more cannot be made (liver)

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86
Q

ebola immunopathology

A

infection of DCs and MOs induce cytokiens (massive inflamm resp), recruits more DCs and MOs, pos feedback loop
infection of DCs block costim molcules that TCs need, TCs cannot activate, die, lymphocyte apoptosis
massive inflamm resp uses up coagulation factors and causes vascular leakage

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87
Q

what part of the imm sys does ebola VP24 block

A

IFN type 1 (innate)

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88
Q

what part of the imm sys does ebola VP35 block

A

IFN type 1 (innate) and DC maturation (adaptive bc cannot stim TCs)

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89
Q

what part of the imm sys does ebola sGP block

A

anti-GP neutralizing Abs (humoral)

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90
Q

the role of coaggulation factors in EBOV

A

inflamm resp uses up coaggulation factors
ebola in liver prevents synthesis of new coaggulation factors
widespread and uncontrollable internal and external bleeding

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91
Q

ebola treatment

A

short window between severe disease and death
hospital support (fluids, electrolytes, other organ complications, etc) extends window, buys time for imm sys
two approved treatments: Inmazeb (REGN-EB3; combination of three monoclonal antibodies)
and Ebanga (MAb 114; single monoclonal antibody)
Both therapeutics use antibodies that bind to Ebola glycoprotein, preventing infection of cells

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92
Q

ebola vaccines

A

approved in 2019 (rVSV-ZEBOV (Ervebo) )
single dose
safe and protectve for Zaire
use in outbreaks in ring vaccination method - vacc population surrounding outbreak, contain outbreak

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93
Q

reo genome structure

A

dsRNA (only dsRNA we are focusing on)
segmented
dsRNA is fully complementary (right hand helix)
nonenveloped but have protein layers (have some enveloped properties)
mRNAs synthesized and capped inside cores and extruded through channels to cytosol
dsRNA made and maintained in core-like subvirion particles –> protected from antiviral resp
RdRp packaged in virion

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94
Q

reo genome segments characteristics

A

10-12 segments
dsRNA, fully complementary, right‐handed dbl helix
mostly monocistronic (some have alt translation start sites)
Virion has 1 copy of ea segment (must have mech for packaging)
Arranged in parallel and equivalent distance
can reassort during co‐infection –> adaptation
Segments may be linked??Conserved 5’ and 3’ ends
5’ caps but no poly A tails
subterminal regions conserved among homologous genes of diff strains
UTRs v short –> may have role in packaging and transcript/rep initiation

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95
Q

reo genome segments subterminal regions

A

at both 5’ and 3’ ends
include UTRs and beginning (or end) of ORFs
highly conserved among homologous genes of diff virus strains –> selective pressure to maintain independent of protein-coding functions

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96
Q

what type of virus is rota

A

reo

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97
Q

what is the main difference in the rotavirus virion compared to most other reovirus virions

A

it has 3 proteion chells instead of 2

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98
Q

orthoreovirus disease

A

aka reovrisues
cause uppper resp and GI infection, gennerally asymptomatic

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99
Q

where does the name reo come from

A

respiratory enteric orphan
porhan bc no onvious symptoms at first
now known that rota is major cause of diarrhea

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100
Q

rotavirus disease

A

major cause of childhood gastroenteritis

101
Q

orbivirus disease

A

Transmitted by arthropods (arboviruses); little human disease; important pathogen of domesticated ruminants (bluetongue disease)

102
Q

coltvirus disease

A

Arboviruses; Colorado tick fever can cause fatal encephalitis/hemorrhagic fever in humans

103
Q

rota virion structure

A

non enveloped 2 or 3 (rota) layered structure
8 viral proteins, no cellular proteins
inner capsid/core: genome + rep complexes, surrounds tightly packed dsRNA segments
outer capsid: 12 spikes project from core through to outer capsid at 5-fold axis of symm (RNA pol complexes at base of ea spike)
only rota has intermediate capsid

104
Q

turreted vs non-turreted virions

A

reo
infectious virions have spikes, during rep process spike is lost –> transcriptionally active subviral particle
Turreted – during rep has large protruding proteins
Nonturreted – Smooth (rota)

105
Q

viroplasm

A

reo
location of genome replication, able to sequester dsRNA away from host antiviral resp
not at mem like many other viruses
made up of VP2 and 5

106
Q

subviral particle

A

reo
transcription competent

107
Q

reovirus replication

A

Binds host receptors, receptor mediated endocytosis, in endocytic vesicle, outer layer degraded, makes infectious particle into subviral transcription competent, can also escape vesicle and release core into cytoplasm, transcription in core (sequester away dsRNA), transcription makes mRNAs, mRNAs are extruded out, translated using host machinery (has 5’ cap), proteins assemble into viroplasms (genome rep, sequesters dsRNA), assembly, budding into ER lumen (remember non enveloped)

108
Q

reo attachment and entry

A

spike = sigma 1
tail of spike can bind sialic acid > scanning of virion along epithelial cell surface, scans until it finds JAM-A (at tight juncts) > JAM-A binds at head of spike >
receptor mediated endocytosis via beta integrins
Once in endosome, loss of outer layer –> ISVP
Transcriptionally active, cannot transcribe in endosome, escapes into nucleus, looses more intermediate capsid proteins, release of core
spike acts as channel where mRNA can be extruded out

109
Q

what is ISVP

A

infectious subvirion particle (reovirus)
transcriptionally active
transcription occurs inside the particle
spike protein acts as channel for mRNA to exit
spike looks bigger on ISVP bc loss of outer layer

110
Q

rota particle conformational changes during primary replication

A

virion enters w 3 layers, one RdRp complex at base of ea spike protein bound to one genome segment
looses outer layer to become transcriptionally active ISVP, loosing outer layer causes upward and outward movement of VP6 (intermediate) and 2 (inner), causes expansion of channel at spike protein, nt can enter, transcription occurs
can have 12 transcription events at same time (one for ea spike and genome segment)
mRNAs are extruded for translation, capped by their way out

111
Q

rota VP7

A

outer capsid layer

112
Q

rota VP 6

A

intermediate capsid layer

113
Q

rota VP2

A

inner capsid layer

114
Q

rota VP4

A

spike protein
acts as channel to extrude mRNA
caps mRNA (methyltransferase activity)
(λ2)

115
Q

rota VP1

A

RdRp
active after loss of outer capsid layer
found inside inner capsid
(λ3)

116
Q

rota VP3

A

supports pol
found inside inner capsid
(μ2)

117
Q

do rota mRNAs have 5’ cap

A

yes, acquired while exiting ISVP through spike channel
spike has methyltransferase activity

118
Q

what is the moving template model

A

rolling circle of replication, pol continues to transcribe RNA while finished mRNA is extruded from ISVP and new NTPs come in
happens bc the RNA is ds, uses neg RNA to make pos mRNA

119
Q

rota λ2

A

spike protein
can cap mRNA
(VP4)

120
Q

rota λ3

A

pol, RdRp
(VP1)

121
Q

rota μ2

A

RdRp cofactor (VP3)

122
Q

how does reo regulate translation

A

similar to host:
Length of mRNA (shorter = more)
Seq context around AUG initiator codons (how strong attraction to pol)
Diff in length and 2’ structure of 5’ NTRs
in host, poly A tail also regulates, reo does not have tail, may have seq that have similar functs

123
Q

what are intracytoplasmic inclusions

A

sites of 2’ transcription and replication
contains viroplasm (VP2 (inner capsid) and 5), dsRNA, virions at diff stages of maturation, and crystalline arrays of mature virions
associated w cytoskeleton
do NOT contain mem like other viruses
form rapidly (4 hpi)

124
Q

where does 2’ transcription and replication occur in reo

A

intracytoplasmic inclusions
in viroplasms

125
Q

what is DLP

A

double layered particle

126
Q

what are early replication complexes

A

one copy of ea 10-12 reo mRNAs assembled into subviral particles
located in inclusions

127
Q

what are replicase particles

A

dsRNA genomes in subviral particle (result of pos mRNA being copied by RdRp to form the 10 dsRNA genome segments)
2 downstream options: 2’ transcription (majority) or virion assembly (minority)
located in inclusions

128
Q

what happens in 2’ transcription

A

dsRNA genome in subviral particle made (back) into mRNA
the bulk of mRNA is a result of 2’ transcription not incoming genome

129
Q

two functions of reo RdRp (pol)

A

In cores, makes ss‐mRNAs using dsRNA template that remains intact and can be used multiple times (circling transcription)
In replicase particles, makes dsRNA genomes using ss‐mRNA template

130
Q

why do reovirus use 2 step (1’ and 2’) transcription

A

ensures one segment in every virion
segregates dsRNA within subviral particle away from host

131
Q

reovirus assembly

A

NSP4 may interact w VP4 (spike) to recruit dbl layered particle (DLP) and VP7 (outer) in ER mem
Induces ER mem to wrap around particle and bud into lumen
NSP4 and ER mem are removed, allowing VP7 to assemble onto the DLP (3 layers total in rota)
NSP4 is in virion but needs to be removed (non structural protein)
NSP4 lost w ER mem (not well understood)
Also allows VP7 to associate w dbl layer
Nonenveloped virus but has envelope at this stage bc of ER mem

132
Q

rota epidemiology

A

gastroenteritis most severe in v young (6mo to 2yrs) and developing countries
ubiquitous (90% have Ab by 3yrs old)
clearance does not give full protection but repeated exposure results in adults being resistant to infection
has seasonality (peak in winter, possibly more stable at cool temp but not certain)
passed on fomites or direct exposure

133
Q

rota symptoms

A

1-2 days post exposure, 2-3 days fever and vomit, then 1-5 days diarrhea
can cause severe dehydration (dehydration can be lethal)

134
Q

villus enterocytes

A

ADSORPTION
near tip of villi
mature nonproliferating cells covering villi that are digestive/absorptive (absorption); express digestive enzymes on apical surface

135
Q

crypt cells

A

SECRETION
near base of villi
progenitors of villus enterocytes; lack well‐defined microvilli and absorptive functions; actively secrete Cl‐ ions into intestinal lumen (secretion)

136
Q

villi vs microvilli

A

Large projections on gut wall = villi
Small projections on surface of cells = microvilli
microvilli have actin as anchor

137
Q

brush border enzymes

A

expressed along MICROvilli
digestion of sugars, nucleotides, and proteins
act as transporters

138
Q

rota pathogenesis

A

small intestine
infects mature enterocytes in mid and upper villous epithelium
leads to cell death and villus atrophy (shortens bc of cell death)
v few mature villus cells are infected (and no crypt cells)
mild inflamm
results: reduction in absorptiion, toxigenic effects of enterotoxin (NSP4), stimulation of enteric nervous sys, disorganization of brush border actin cytoskeleton causes impaired apical targeting of digestive enzymes

139
Q

rota pathogenesis: direct effects of cell damage

A

kills mature enterocytes at tips of vili
reduction in absorptive surface
crypt cells try to replace dead cells
diarrhea can precede blunting of villi

140
Q

rota NSP4 pathogenesis

A

coordinates assembly by interacting w DLP and VP7
enterotoxin - can use small fragment, inc intracellular Ca w/o rest of virus
able to mediate diarrhea w/o major cell damage
can be secreted by infected cells to affect neighbors
enterotoxin alone can cause necrosis (w/o virus)
doesn’t need high infectivity bc enterotoxin is mediating disease
binds integrin to inc intracellular Ca
breaks tight juncts –> water leaks
ENS can also change Ca lvels in crypt cells

141
Q

enterotoxin

A

toxin that stimulates net secretion in intestinal segments in the absence of histological alterations
usually bacterial, viral are rare

142
Q

enteric nervous sys (ENS) in rota infection

A

Stimulation of ENS causes intestinal secretion of fluid
block ENS –> attenuate rotavirus‐induced diarrhea
causes secretion in crypt cells (they are uninfected)
might be triggered by NSP4, chemokines, and prostaglandins

143
Q

brush border in rota infection

A

Disruption of actin filaments via VP4 (spike)
needs to disrupt actin cytoskeleton to release virus

144
Q

rota dissemination

A

viremia and 2’ spread but no associated disease diff from normal infection
transient detection of rotavirus Ag and viral RNA in blood of infected children in fatal cases
Virus can repl in DCs, MOs, and BCs – possible mech of dissemination

145
Q

rota transmission

A

fecal-oral
v high shedding in stool
require v low number to transmit
v easy to spread

146
Q

rota vaccines

A

1998 - 1st vaccine, tetravalent, mix of monkey and human segments
associated w intestinal intussusception –> withdrawn
2006 - 2 vaccines, high efficacy
RotaTeq - human-bovine reassortant (pentavalent)
Rotarix - human live attenuated
may still cause inc intussusception but not withdrawn (benefit outweigh risk)
vaccines seem less effective in developing countries

147
Q

retro genome structure

A

pos RNA, RT to dsDNA
small genome
TWO GENOME COPIES PACKAGED
Repeat (R) at both ends
U5 and U3 at respective ends adjacent to R
3 ORFs: Gag, Pol, and Env
complexed w NC (nucleocapsid)
has 5’ cap and poly A tail
5’ and 3’ splice sites

148
Q

retro virion structure

A

spherical
enveloped
capsid can be icosahedral or conical (HIV1)
bud at plasma mem
RT, PR, and IN packaged in virion
gp120 and gp41 are envelope glycoproteins
kissing loop - two copies of genome in head-to-head conformation
PBS bound to cellular tRNA (5’ end)

149
Q

retro kissing loop

A

seq in U5 that mediates association of two copies of genome in head‐to‐ head configuration
makes dimer of genomes

150
Q

what is a provirus

A

DNA copy of retrovirus genome
can be integrated into host chromosome
can cause cancer depending on where it integrates and the genes it disrupts

151
Q

retro oncoviruses

A

alpha
beta
gamma
delta
epsilon

152
Q

retro lentiviruses

A

slowly progressing, wasting disease
HIV1

153
Q

HIV Gag

A

group specific Ag
includes structural, MA (matrix), NC (nucleocapsid), and CA (capsid)

154
Q

HIV Pol

A

enzymes
includes protease (PR), RT, and integrase (IN)

155
Q

HIV Env

A

envelope glycoproteins
includes gp120, gp41, and Vpr

156
Q

retro genome 5’ to 3’

A

cap, R, U5, PBS, Gag, Pol, Env, ppt, U3, R

157
Q

retro SS

A

splice sites, important for packaging

158
Q

retro ppt

A

polypurine tract, important for RT

159
Q

HIV nonstructural proteins

A

Vif
Vpu
Tat
Rev
Nef

160
Q

retro life cycle: early phase key steps

A

binding, fusion, release NC, RT converts ssRNA to dsDNA, integrates into host genome

161
Q

retro spike protein structure

A

spike has 3 gp120 (surface of spike) and 3 gp41 (stalk of spike)

162
Q

retro attachment and entry

A

gp120 (surface of spike) binds CD4 (TCs and MOs)
conformational change in gp120, exposes 2nd binding site for coreceptor
coreceptor binds (CCR5 or CXCR4, they are chemokine receptors)
another conformational change, this time in gp41 (stalk of spike)
mediates fusion w plasma mem
nucleocapsid is released into cytosol

163
Q

retro RT protein

A

dimer
two activities: Polymerase (RdDp or DdDp) and RNase H(hydrolyses RNA part of RNA/DNA hybrid)
makes DNA INSIDE virion core
error prone –> results in quasispecies and adaptibility

164
Q

retro tRNA

A

cellular
acts as primer for DNA syn
binds PBS on viral RNA

165
Q

steps of reverse transcription: overview

A
  1. syn of minus-strand strong stop DNA
  2. RNAse H digestion
  3. first strand transfer
  4. syn of full length genome
  5. RNAse H digestion
  6. Syn of plus-strand strong stop DNA
  7. RNAse H digestion
  8. second strand transfer
  9. extension of both DNA strands
    result: proviral DNA
166
Q

retro preintegration complex

A

proviral DNA (dsDNA) associated with components of the virus core

167
Q

retro nuclear import

A

done w preintegration complex
most retroviruses can only integrate in dividing cells (breakdown of nucleus)
Lenti (like HIV1) has specialized proteins: MA, Vpr, and IN

168
Q

HIV MA

A

matrix
encodes classical nuclear import signal that interacts w importin

169
Q

HIV Vpr

A

mediates preintegration complex passage through nuclear pore

170
Q

HIV IN

A

catalyzes viral DNA integration
brings 2 ends of linear DNA together and in close proximity to cellular DNA
seems to integrate at random sites
LTRs are integrated as well
mediates preintegration complex passage through nuclear pore

171
Q

Trim5alpha

A

promotes degradation of capsid –> no RT
monkeys but NOT HUMAN work on HIV1

172
Q

2 retrovirus integration outcomes

A

latent infection: Does not contributed to disease but the largest hurdle to treatment and cure
Mem TCs and MOs are the ones w the proviral DNA, act as reservoir
HAART targets RT and IN, but if integration already happened, it has no effect
Latently infected cells are also not recog by imm sys
If taken off of HAART, cells will undergo lytic infection
active infection: virus proceeds with late phase of replication and progeny virus is made

173
Q

what is ‘shock and kill’ treatment

A

Shock and kill  activate all cells to undergo lytic replication and treat w massive amounts of antivirals

174
Q

retro translation

A

TATA box upstream of U3/R junct –> mRNA w/o U3 bc of where TATA box is, R at 5’ end now
U3 has enhancers
PolyA signal at R/U5 junct –> mRNA w/o U5 bc of PolyA tail
mRNA is IDENTITCAL TO INCOMING GENOMIC RNA OF VIRUS
Provirus has U3RU5 at both ends, while incoming genome only had R U5 and U3 R at either end
Gets capped and polyadenylated
Makes Gag and gag-pol poly proteins

175
Q

LTR conundrum: left

A

why only left LTR initiate transcription?
RNA pol at left hand LTR can dislodge pol on right side –> promoter occulsion
evidence: if left deleted, right can initiate cellular translation

176
Q

LTR conundrum: right

A

why only right LTR singla cleavage and polyA?
Some do it in U3 bc it is only in incoming RNA molecule, it is not in the RNA from the transcription, can’t happen on left hand side
Option 2 is to have it in R region but they have U3 seq that enhance recognition of the poly A signal or U5 seq that repress recog of poly A signal

177
Q

2 mRNAs made by retroviruses

A

Gag-pol
Env –> result of 5’ and 3’ ss that remove Gag and Pol, bringing two ends together
note that complex retroviruses have many diff splicing and donor sites to make many more mRNA

178
Q

retro exit

A

NC in Gag polyprotein binds viral genome and Gag forms multimers
Exposes myristate in MA, causes targeting of plasma mem
Env interacts w MA, P6 at opposite end interacts w host ESCRT machinery
ESCRT‐III scission between cell and immature virion mem –> release of virus
note: buds as IMMATURE virion, protease inactive until after polyprotein oligomerizes and budding (makes PR good antiviral target)

179
Q

HIV Tat and Rev

A

transactivator of transcription
regulatory
control vrial rep
upreg viral protein
ESSENTIAL
binds buldge (stem-loop), brings host proteins (Cdk9) which phos RNA pol –> inc processivity

180
Q

HIV Rev

A

regulator of expression of virion proteins
regulatory
control vrial rep
upreg viral protein
ESSENTIAL
shuttle viral mRNA into cytoplasm for translation
for the 9kb (unspliced) and 4‐kb (singly spliced) mRNAs
Both have cis-acting repressive seq (CRS)
Rev binds RRE in mRNA, interacts w host export proteins, overrides CRS, shuttles them out of nucleus to cytoplasm
Rev has NLS so it can be recycled

181
Q

HIV Vif

A

viral infectivity factor
Accessory (non essential in vitro, highly conserved in vivo)
binds APOBEC3G and degrades it, prevents it from bing packaged in progeny vrions –> virus can infect next cell
APOBEC3G (makes C into U), results in misincorporation of nt, inc mutations in viral genome (no proofreading)

182
Q

HIV Vpr

A

Virion protein R
Accessory (non essential in vitro, highly conserved in vivo)
active transprot of preintegraion complex into nucleus
arrests cells in G2 stage of cell cycle –> inc LTR transcription

183
Q

HIV Vpu

A

virion protein unique to HIV1
Accessory (non essential in vitro, highly conserved in vivo)
1. Degrades CD4
Why degrade own receptor?
Already infected, doesn’t need more
CD4 can interact w gp120 in ER lumen, retention of gp120 in cell, not as much at cell surface, needed for budding
Degrading CD4 allows for more gp at plasma mem
2. degrade tethrin
inc virus release from plasma mem by
Normally tetherin binds progeny virion, keeping them stuck to infected cell, taken back up and degraded
Same vibe as influenza getting stuck w/o neuraminidase

184
Q

HIV Nef

A

Accessory (non essential in vitro, highly conserved in vivo)
1. blocks expression of CD4 and MHC1
block CD4 by inc cycling
block MHC1 by blocking trafficking out of glogi
2. enhance infectivity (we don’t know how)
3. modify cell signaling
activating TC, promoting virus rep w/o proper imm resp

185
Q

Origins of HIV

A

Comes from monkeys
Probably derived from SIV, usually causes asymptomatic infections
Chimp infected w 2 diff SIV, rearrangement, then spread to humans
Know that it did come from primates and from 2 diff SIV that recombined and then infected humans

186
Q

HIV prevalence around the world

A

US –> 1%
subsaharan africa –> 1-5 to over 10% of population (worse more south)
why? Culture – safe sex
Access – HAART therapy

187
Q

HAART

A

Highly active antiretroviral therapy
not cure, just suppression
most antivirals target RT or PR
needs to stay on lifelong and take meds every day
need cocktail bc of 1. fast rep, 2. RT high mut rate, 3. ability to recombine
HAART inc CD4 TC numbers –> imm reconstitution
HAART has resulted in striking dec in HIV mortality (side effect is that more people have HIV bc they are not dying)

188
Q

HIV transmission

A

blood, semen, vaginal secretions, breast milk
exposure to mucous membranes
unprotected sex and needles in developed
almost eliminated: mother to fetus and blood products (transfusions)
DOES NOT DIRECTLY INFECT CELLS IN VAGINA OR GUT, NEED TO CROSS MUCOSAL BARRIER
facilitated by abrasion, inflamm, or ulcerations
can also be facilited by DCs

189
Q

HIV cell tropism

A

DCs and MOs - nonspecific (importnat for initial infection bc of sampling and spread)
TCs - specific imm cells (specifically ThCs)

190
Q

HIV spread within body

A

infects DCs (mostly), MOs, and CD4 TCs in lamina propria > DCs activated, go to lymph nodes > virus rep and spread to other cells in lymph nodes > exit via lymphatics > dissemination to 2’ organs > 2’ amplification and peak shedding

191
Q

HIV peak shedding

A

causes imm activation CD8 TCs (diff than infected) and Abs control infection
HIV goes latent in CD4 TCs
Crazy amount of shedding during peak but then goes into clinical latency

192
Q

HIV diagnosis

A

Abs (3wks post inf), Ags (2 wks post inf), or viral mRNA (1 wk post inf)
Serology (Abs) most common - 20 min spit tests (lateral flow assay)

193
Q

lateral flow assay for HIV

A

20 min spit test
same set up as pregnancy/COVID tests
false neg - test too early after inf, no Abs yet
false pos - maternal Abs in babies up to 18 mo
can dbl check w PCR for viral mRNA or ELISA for Ag

194
Q

HIV progression to AIDS

A

3 phases:
1. Acute
2. clinical latency
3. AIDS

195
Q

Acute HIV phase

A

Median load is 10^6‐10^7 RNA copies/ml at peak, drops to 30,000 within 6‐12 mo
imm will shut down viral rep but level is maintained
if medicated can stay here
rapid (2-3 yrs), intermediate (vast majority, 8-10yrs), and slow (rare, non/slow) progression of AIDS determined by viral load at latency set point

196
Q

clinical latency HIV phase

A

variation in timing, 2yrs to decades
asumptomatic but virus is NOT DORMANT
gradual depletion of CD4 TCs and destruction of lymph nodes
‘asymptomatic progression’
TC depletion both from lysis and chronic imm activation
TC depletion > cannot control virus levels, release into circulation (progression to AIDS)

197
Q

asymptomatic progression

A

HIV clinical latency
disease is worsening, but no obvious symptoms
gradual depletion of CD4 TCs and destruction of lymph nodes
VIRUS IS NOT DORMANT IN CLINICAL LATENCY

198
Q

HIV exit of clinical latency

A

TC depletion > cannot control virus levels, release into circulation, leads to AIDS
start to have symptoms: fever, sweat, fatigue, diarrhea, weight loss, infections, neoplasia, neuro (dementia, NM disorders)

199
Q

HIV AIDS phase

A

AIDS is syndrome, HIV is virus
NEED DEFINING FEATURES:
CD4 count < 200 cells/ul (normal is 500-1000)
Appearance of either:
AIDS‐definining opportunistic infection
AIDS‐defining cancer

200
Q

AIDS cancers

A

opportunistic cancers
significant cause of death, even w HAART
KS, non-Hodgkins lymphoma, invasive cervical

201
Q

HIV monitoring

A

both CD4 TC levels (flow cytometry) and HIV1 RNA levels (RT-qPCR)

202
Q

HPV genome structure

A

dsDNA genome
circular genome
naked capsid
small genome, complexed w cellular histones in nucleosome structure
8 early (transcription and regulation) and 2 late (capsid) genes
LCR (long control region) contains Ori and cis-acting signals
2 promoters: E and L
L promoter can make some E genes

203
Q

HPV virion structure

A

icosahedral
nonenveloped
virion made of L1 and L2 proteins
72 capsomeres – each with 5 L1 proteins and 1 L2 protein
small relative to other DNA viruses

204
Q

HPV tropism

A

highly species specific highly tissue specific
virus that causes foot warts doesn’t cause warts in other areas
makes hard to study bc can’t use human to infect mouse
100% of cervical cancers linked to HPV

205
Q

koiliocytes

A

cells infected w HPV, have large gaps –> virus is rep in that area
identified on pap smears
proceed tumors

206
Q

HPV strain classification

A

High risk - 15 strains
HPV 16 and HPV 18
cause the majority of cancers
low risk - most others
HPV 6 and 11 cause the majority of genital warts

207
Q

HPV prevalence

A

most common STI in US
more than half of sexually active people have or have had HPV
43% of women have genital HPV, 7% of adults have oral
burden highest in developing countries - not just bc of cancer care, also bc lack of pap smears so no early detection

208
Q

HPV transmission

A

skin - direct contact w infected person or surface
genital - sexual contact, mucosal epithelial serve as reservoir
tissue specificity - skin OR genital

209
Q

HPV lifecycle through infected epithelium

A

infect epithelium live cells as basal layer
infected cells move up towards apical side as cells differentiate new skin is made
HPV requires hijacking host rep cycle, needs to be in live cells –> requires break in apical layer so virus can enter
basal cells show plasmid replication and early gene expression
keratinocytes have vegetative replication, late gene expression, assembly of particles
apical cells die and virus is released

210
Q

hyperkeratosis

A

piling of cells (keratinocytes) on ea other
warts

211
Q

HPV E7

A

activates cell cycle progression
Rb is tumor suppressor, cell at rest has RB bound to E2F –> no cell cycle
when Rb phosphorylated, release E2F –> cell cycle progression
HPV E7 binds Rb, Rb cannot inhibit E2F –> constitutively active cell cycle
HPV 16 and 18 have high affinity E7 and can degrade Rb over time (this makes them high risk for cancer)
low risk strains do not degrade Rb

212
Q

HPV E6

A

blocks apoptosis
p53 induces cell cycle arest and apoptosis as a response to overactivation (from E7 action on Rb)
E6 binds E6AP (host protein) which together degrade p53
prevent apoptosis and cycle arrest
high risk strains (like HPV16 and 18) do this at higher rates
E7 turns on cell cycle, E6 deals with the side effects

213
Q

how does HPV induce transformation

A

E7 and E6 block two key chk pts in cell cycle (Rb and p53)
uncontrolled proliferation and loss of ability to apoptose
combination is oncogenic
not an ‘objective’ of the virus, just wants to replicate itself
cancer only happens in small percent of those infected

214
Q

HPV to cervical cancer timeline

A

HPV incidence inc at start of sexual activity
Dec after marriage/monogamy
Peak of HPV infection happens in teenage years, peak of cancer doesn’t happen until 35-40 yrs old
Transformation after 10 to 15 yrs

215
Q

pathogenesis of cervical cancer

A

Millions of cases of HPV but only thousands of cancers
Majority are subclinical – low if any symptoms, imm clearance, 16 and 18 not as prevalent
High risk strains can hang on for longer, become more prevalent as time goes on (reverse pyrimid, ‘concentration’ of the virus in older population bc they are the long lasting ones and don’t go away as easily)
normal > low grade neoplasia > high grade neoplasia > cancer

216
Q

neoplasia

A

bengin tumor
HPV is integrated

217
Q

dysplasia

A

small bump caused by cells not dying
can be detected on pap smears
HPV is episomal (circular)

218
Q

progression of cervical cancer

A

normal > dysplasia > neoplasia > cancer
Mild dysplasia – small bump, caused by apical cells not dying, high levels of HPV produced
Moderate and severe – virus is no longer produced, higher levels of E6 and 7, integration of viral DNA into host chromosomes
Invasive carcinoma is the most severe outcome
PROGRESSION TO CANCER CORRELATED W INTEGRATION OF HPV GENOME INTO HOST CHROMOSOME
high risk strains have more integration

219
Q

HPV genome integration

A

Highly associated w cancer
During DNA rep, ds break, integration event
Can break anywhere in circle
In cancers:
Break in E2 gene, E4 and 5 removed, most of E2 removed
E2 is neg regulator of E6 and 7
Disruption in E2 cannot reg E6 and 7, they become even more active
Grow out of control

220
Q

HPV diagnosis

A

pap smear (most common)
immunohistochemistry, serology
nucleic acid detection done after previous detection to see if high or low risk strain

221
Q

HPV vaccines

A

targeted to the L1 of capsids
does not contain any actual virus
given before STI exposure
Gardasil: FDA approved; HPV 16, 18, 6, 11
Cervarix: FDA approval pending; HPV 16, 18

222
Q

HPV treatment (cervical cancers)

A

freezing, electro‐diathermy, cone biopsy
all to remove cancerous cells

223
Q

how are herpes families organized

A

cell tropism and genome organization

224
Q

how many human herpes in the family are there

A

8 or 9
depending on if you separate 6A and 6B

225
Q

chronic vs latent infections

A

chronic –> constant low level proliferation (HIV)
latent –> does not produce active virus (herpes)

226
Q

herpes virion structure

A

linear dsDNA
enveloped
icosahedral capsid 200nm
large genome

227
Q

HSV1 tegument

A

amorphous layer of 14 free proteins
Tegument proteins are released after entry and are crucial for establishing infection

228
Q

HSV1 capsid

A

icosahedral
6 proteins, VP5 is the major one

229
Q

HSV1 genome structure

A

dsDNA
Long and short unique regions
Flanked by inverted repeats (mirror ea other: a, b, UL, b’, a’ c’, US, c, a)
A – no ORFs, important for packaging
B - 4 ORFs
C - one ORF
two copies of B and C per genome
replication genes are conserved between diff viruses within the family
GENES ON BOTH STRANDS
some overlap on the same side

230
Q

HSV1 entry

A

gB and gC bind heparan sulfate proteoglycans on plasma mem
gD binds receptors nectin 1 (ICAM family) and HVEM (TNFR family)
triggers fusion of envelope w cellular membrane via gB, gH and gL
Tegument proteins and capsid are released into the cytoplasm
capsid detaches from tegument
capsid binds at nuclear envelope and insert DNA into nucleus
genome is circularized after entering nucleus

231
Q

HSV1 IE genes

A

transcribed quickly after infection
do not require new protein synthesis
most are **transactivators of E genes

232
Q

HSV1 E genes

A

transcribed within 4‐8 hrs
most involved in virus DNA replication
some are transactivators of L genes

233
Q

HSV1 L genes

A

Vast majority of genes
E‐L or gamma1 genes begin to be transcribed early, but are upregulated after DNA replication
L or gamma2 genes are transcribed only after DNA replication
**most are structural or packaging proteins

234
Q

HSV1 two methods of replication

A

plasmid (bidirectional) rep:
rolling circle rep:
Result: linear dsDNA in head to tail concatamer

235
Q

HSV1 rolling circle rep

A

happens 2nd
Head-to-tail concatemer
DNA pol goes in circles
Circle is nicked so that the strand can come off as you roll, allowing continuous rep
Makes long concatemer of linear genomes that are attached to ea other
Another pol comes in to make lagging strand
As more leading is made, more pol comes to make more lagging
Result: linear dsDNA in head to tail concatamer

236
Q

HSV1 plasmid (bidirectional) rep

A

happens 1st
circular dsDNA, Viral proteins bind strands of genome > ssDNA binding proteins bind to it, another set or proteins come and lay down RNA primer, DNA pol binds RNA primer, extends DNA in both directions, replicates entire circle
Makes more template for later rolling circle rep

237
Q

HSV1 assembly

A

Immature capsid is assembled by accumulation of VP5 and other proteins around a scaffold
Virus DNA entry into capsid is triggered by packaging sites (a’) within the genome
DNA packaging is complete when a full length genome is inserted and the machinery encounters another terminal (a) segment
scaffolding is dismantled and the scaffold proteins are ejected from the capsid
Capsid changes conformation, sealing the DNA inside the capsid

238
Q

HSV1 latency

A

hallmark of herpes infection
characterized by:
non‐productive infection (no production of infectious virus particles)
maintenance of the viral genome as an episome
few or no virus genes expressed
the ability to reactivate from latency
latency may be established in a diff cell type then primary infection

239
Q

HSV1 spread in body after infection

A

lytic rep in epithelial cells at site of inoculation
virus enters sensory neurons > retrograde transport
life long latency in neuron
reactivation via anterograde transport
virus reps and sheds from site of lesion (epithelial again)

240
Q

HSV1 vs 2

A

1 - oral lesions, leading cause of blindness in world (caused by herpes stromal keratitis (HSK))
2 - genital lesions

241
Q

major alphaherpes diseases

A

Chickenpox
Shingles
Herpes stromal keratitis Oral herpetic lesions
Genital herpetic lesions Encephalitis

242
Q

gammaherpes latency

A

in B cells
1’ inf in epithelial cells and oral cavity
transmitted to BCs in local lymph tissue
BCs circulate in blood, can reactivate at epithelium and be shed
Tibbetts will prob ask about EBV

243
Q

major gammaherpes diseases

A

(mostly cancers)
Mononucleosis Burkitt’s lymphoma (BL)
B‐cell lymphoma, AIDS‐related Lymphoproliferative disease (PTLD) Peripheral T‐cell lymphoma
Nasal T/NK cell lymphoma
Hodgkin’s disease (HD)
Lymphoepitheliomas (stomach, thymus) Gastric adenocarcinoma Nasopharyngeal carcinoma
Kaposi’s sarcoma
Primary effusion lymphoma
Graft rejection

244
Q

major betaherpes diseases

A

Birth defects: deafness, blindness, cerebal palsy, mental retardation, physical disabilities, seizures
graft rejection
Pneumonia

245
Q

pox virion structure

A

linear dsDNA
largest viral genome enveloped ovoid capsid
particle lined w many many proteins, form ridges
Very unusual bi‐concave core that is flanked by lateral bodies
MV = biconcave core + lateral bodies + envelope
EV = MV + extra envelope

246
Q

pox MV vs EV

A

MV = biconcave core + lateral bodies + envelope
better for cell to cell spread
EV = MV + extra envelope
better for person to person spread (more stable)
bind diff receptors bc EV envelope has diff proteins

247
Q

pox genome structure

A

dsDNA
v large genome
linear but NO FREE 5’ OR 3’ ENDS
ea end has terminal loop (hairpin)
genes at ends are repeated twice at the terminal repeats
NO overlapping genes
NO introns –> NO alt splicing
ea gene has its own promoter
genes in both directions
genes named based off of Hind III restriction enzyme digestion

248
Q

key features of vaccinia virus

A

acts as attenuated smallpox
used in labs (cannot study smallpox in lab)

249
Q
A

GMS6121 - Infectious Diseases (4 decks)

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