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week 2 Flashcards

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1
Q

HIV1

A
  • Lentivirus met envelop
  • 2 ssRNA
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2
Q

AIDS

A
  • CD4 under 20 cells per ul
  • Opportunistic - canditis
  • Cancers – lymphoma, karposi sarcoma
  • Dementia
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3
Q

What determines rate of HIV1 infection

A
  • Virus
  • Immune response
  • Genetic background
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4
Q

HIV1 diversity

A
  • Reverse transcription RNA to dsDNA. Lacks proofreading
  • Knipt host DNA en plakt eigen er in
  • Increased fitness through escape ctl, neutralizing ab, antiviral drugs. Selection pressure
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5
Q

Relevance hiv diversity

A
  • Clinical course; viral fitness and coreceptor use, excape ctl
  • Effctivity antiretroviral therapy
  • Diagnostics (primer binding, antibody
    binding)
  • Envelop based vaccine design
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6
Q

Binding HIV1 to T cel

A
  • CD4
  • CXCR4 or CXCR5 (alleen op macrofaag) as co receptor. Has v3 loop. Negative charges then ccr5 use, positive charges then cxcr4 use
  • Can also infect macrophages
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7
Q

Difference x4 and r5 hiv expression in disease progression

A

If you have x4 then you have r5 virus aswell (shown by evolution). Having both lead to increase disease progression by accelerated loss of cd4, because naive T cells can be infected aswell.

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8
Q

CCR5 genetic variation

A

32 base base pair deletion. Cannot get infected if homozygous normally, only a few found. Heteozygous not any difference in infection, but difference in disease outcome.

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9
Q

Host genetics in HIV infection

A

using SNP detection in typical and fast progressors. Grootste verschil in HLA; b57/27 langzaam, B35 rapid disease

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10
Q

Loss of immune control in hiv1 infection

A
  • Escape ctl; TL9 epitope mutation at beginning affects presentation. TL9 epitope mutation in middle affects recognition.
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11
Q

Natural control of hiv1 -

A

Protective HLA alleles
HLA B57 (for positive immune control HIV)
* Presentation of viral epitopes from conserved regions of the virus
* High affinity recognition of presented peptides by TCR at low amounts
* Viral escape occurs in immune dominant epitopes -> viral attenuation (milder)
* Strong immune response by cd8
* Escape from cd8 occurs and is associated with viral attenuation

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12
Q

Humoral immunity HIV with neutralizing Ab

A

Nab response is not associated with disease progression
HIV1 sensitivity to autologous Nab – HIV1 escapes

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13
Q

Search for hiv vaccine

A

Sterilizing immunity – preventing virusses coming in and establishing infections.

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14
Q

Why we don’t have a vaccine for HIV

A
  • Viral sequence, antigenic variation
  • Env defense against neutralizing Ab – complex has 6 subunits, noncovalently bound, unstable
  • Viral defenses against cellular immunity
  • (e.g., MHC Class I down-regulation by Nef).
    4. Infection of immune cells, high replication rates and rapid development of
    viral reservoirs
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15
Q

Common epitopes are recognized by roadly neutralizing antibodies – why not use this as a vaccine

A

but in vaccination not usefull because you need to vaccinate for a long time, maybe see response in 25%

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16
Q

Overview aids vaccine design

A
  • Best option for working durable response – normally inactivated or life attenuated because this can reactivate, too dangerous.
  • Subunit vaccine – first monomeric with no protection at all, then recombinant dimer did not work
  • Recombinant viral vector – best platform to induce T cell response. Ad5 with structural proteins. More infections in vaccine group. HVTN505 made no difference
  • Combination subunit and viral vector – first induce T cell response then boost. Results are better, sig difference, 31% lower chance of infection. Follow up no difference
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17
Q

Why no response – research using reverse vaccinology

A
  • Tried gp120, uncleaved gp140 (more subunits), gp140Fd (bound together), SOSIP664 gp 140
  • SOSIP664 gp 140 in animals could elicit neutralizing antibodies in animals
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18
Q

Future HIV vaccine - Strategies to induce braodly neutralizing Ab

A
  • Scaffold to prime, then recognise whole protein
  • Overcoming viral diversity by using engineerd protein
  • Mimicing natural infection
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19
Q

What HIV learned from sars cov

A

now focussing on HIV

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20
Q

Passive vaccination for hiv

A

adding Ab instead of eliciting them
* Would have to give every 2-3 weeks, maybe alter so that they circulate for 6 months
* Didnt see big difference, but Ab used was also not very broad.
* Suppresion of viral load when given 3 different Ab

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21
Q

antiretroviral drugs – stop viral replication. classes

A
  • First class; Entry inhibitors – block interaction CD4/cxcr5
  • Reverse transcriptase inhibitors – block viral replication in early steps
  • Integrase inhibitor – blocks enzymatic protein of virus
  • Second class; Protease inhibitors – stops particle formation
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22
Q

Development of drug resistance

A

due to variability and mutation rate
* Drug will only leave resistant HIV particles
* Combination of classes of treatment is necessary and high treatment adherence

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23
Q

Persistence of HIV reservoir

A

Active reservoir; residual viral replication
o Virus integrates in host genome, ongoing replication and infection of new cells despite ART. In macrophages, and T cells in brain, lymph nodes, genital tract, gut

Latent reservoir; transcriptionally inactive integrated virus
o T cell will not be activated upon infection, macrophages and memory T cells can survive over 10 years, keeping the reservoir in place
o Proliferation – memory T cells divide to maintain immune memory pool and reservoir
Clearance of HIV on ART will take 73 years

24
Q

Strategies to cure HIV infection

A
  • Eradiction of functional reservoir
  • Functional cure; induction immune control
    Prevention;
  • Vaccination
25
Q

Eradication of viral reservoir

A
  • Shock and kill; activate latently infected CD4 (shock) so that viral proteins are presented again by adding latency reversing agents. Killing of activated reservoir is next challence
  • Block and lock; permanently silence reservoir
26
Q

Functional cure

A

Induction of immune control. Is possible but very rare

27
Q

Only some people have shown a functional cure after stop ART

A

Escape mutation of cd8 T with robust gag specific cd8 T cell response – shifts the balance to the immune system. Caused by a single point mutation

28
Q

PREP

A
  • ART taken to prevent infection
  • Not 100% protective; mostly due to low adherence. However, PREP resistant variants are circulating, and infection despite PREP use can occur.
29
Q

Anelloviruses –

A
  • pathogenicity never found. Found in humans and several animals, no mouse model
  • Small, -ssDNA
  • Circular
  • All people infected, present in blood
  • Large diversity in one person, infected by multiple
30
Q

Human anellovirus – differ in size

A
  • Torque teno virus TTV
  • Torque teno Midi virus TTMDV
  • Torque teno Mini virus TTMV
31
Q

Anelloviral proteins function

A
  • One mRNA, makes one big potein
  • ORF1 - Functions as viral capsid
  • ORF2 – essential for virion assembly a potential regulatory function, suggested to interfere with immune responses of host
  • TAIP – apoptosis inducing in some variants
  • Other splice variants functions are unknown
32
Q

Possible functions of anelloviruses

A
  • Training immune system
  • Compete with other viruses, infect other viruses
  • Inhibit tumorformation (apoptotic function)
  • Dampen immune reaction
33
Q

Needed to discover the function of virus –

A

which cannot be done for anelloviruses due to variation, except for anellome stability
* Culture system
* Compartmentalization
* Anellome stability (or continuous infection)
* Replication mechanism
* Host cells
* Immunity

34
Q

Study anellovirusses how

A

look at blood under different conditions, using qPCRs. Also rolling circle amplification and illumine sequencing possible to look at annelome (how many viruses), create a heatmap

35
Q

Anellovirusses in different age categories

A
  • Children are born without anelloviruses – TTMDV grows first
  • Mothers barely carry the virus (become negative again), positive after 6 months post partum
  • Infection with interferon treatment decreases anellovirusses, same for covid NAKIJKEN
  • Immunodeficiency affects TTV, low in beginning, more couple of months later, then lower than ever
  • Old age TTV concentrations increase’
36
Q

Can anelloviruses be healthy

A

difficult to conclude, cancer patients with chemo have depleted levels of immune cells.

37
Q

Proteins influenza surface

A
  • Hemagglutinin binds sialic acid, tears surface open, pulls inside
  • Neuraminidase is opposite, for coming out of cell to cut bonds sialic acid and hemagglutinin
    New class H or N - if it has no cross reactivity with other H or N
38
Q

Pandemic flu –

A

novel virus usually from animals, spreads from human to human

39
Q

Seasonal flu

A

always in humans, 5-15% of human population, evolution

40
Q

Sialic acid difference in different species

A

has different conformations in different animals – makes certain species more susceptible.

41
Q

Virus can disappear and reappear how

A

in humans by circulating in animals in the mean time, or laboratory mistake

42
Q

What can avian viruses bind to in the human body

A

Avian like sialic acids only in lungs and eyes. In trachea is not deadly, deep in lungs is very fatal

43
Q

Why 1918 pandemic so servere

A
  • Virus itself
  • Secondary pneumonia
  • War
44
Q

h5n1 reservoir

A

H5N1 in birds is spreading, but declining in humans

45
Q

Which compound of flu activates immune system most, which are vaccines based upon

A

hemagglutinin activates immune system most, is what vaccines are based upon

46
Q

Antibody escape of hemagluttinin –

A

normally attach to globular head, more easily accessible than stick part. Mutations reduce antibody cross reactivity.

47
Q

Antigenetic variation in influenza –

A

antigenic similarity is measured as seen by antibodies. The population level selection is strong.

48
Q

Barrier to create new influenza virus

A

A single substitution can be sufficient, there are only 7 positions that matter

49
Q

Potential explanations ermerging new influenza

A
  • Neutral networks of substitutions. At any moment you can make a substitution, but you have to wait for other substitutions
  • Deleterious mutation load – carry mutation that are bad. However, those are not tolerated and should be kicked out
  • Antigenic mutations themselves are deleterious
50
Q

Constraining evolution Assumptions;

A

Antigenic evolution is constrained by virus, immunity comes form strong constant Ab response

51
Q

Within host variation influenza

A

vaccinated in same year then pretty good response to virus

52
Q

How can we reconcile strong population level selection when this isn’t seen in individuals

A

influenza virus evolution is limited by the
asynchrony between virus replication and
antibody selection pressure.
interaction between host and virus. First response no antibodies, no strong selection of virus. Second infection cascade events to produce Ab again, only starts around day 3, then virus already replicated. Every replication it makes mistakes, only late in infection

53
Q

What if we would have constant Ab response

A

new variants in every host

54
Q

Bottlenecks for viruses

A
  • Excretion bottleneck – see which viruses survive and get excreted
  • Inter host bottleneck – which viruses reach other people
  • Mucus bottleneck – stops infection in first place
  • IgA bottleneck – in mucus, also stops virusses
  • Cell infection bottleneck – cell cycle dependent
  • From 10^7 viruses to <10
55
Q

Why punctuated

A

timing and nature of selection , only large differences matter
Slow - timing of antibody selection rarely coincides with virus replication. Accumulation of population takes time

56
Q

virus evolution in host how

A

Immunocompromised people could be key for virus evolution

advanced medical microbiology (4 decks)

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