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Zpath term 2 > HIV persistence > Flashcards

HIV persistence Flashcards

1
Q

HIV virus family

A

Belongs to lentivirus family, along with SIVs, FIV, equine infectious anaemia virus and bovine immunodeficiency virus.

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2
Q

Establishment of virus

A

Level of persisting virus established early determines subsequent progression to AIDS. High setpoint  rapid progression. Low setpoint  slower progression.

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3
Q

Steps in establishment of HIV

A

From SIV models.
• Infection of founder cells. Establishment of small foci.
• Active replication within permissive cells and local infection spread.
• Dissemination to lymphoid tissues
• Spread throughout the body, with substantial deletion of CD4+ T cells.

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4
Q

What determines levels of persisting viral load in early infection?

A
  1. Properties of infecting virus
  2. Host genetics
  3. The efficiency of control of viral replication by the early host immune response
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5
Q

Properties of infecting virus determining persisting viral load in early infection.

A

CXCR4-utilising viruses (rarely transmitted) are highly pathogenic
viruses bearing deletions in Nef exhibit reduced pathogenicity

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6
Q

Host genetics determining persisting viral load in early infection.

A

a. may affect viral entry/replication capacity eg. the CCR5-D32 allele is protective vs infection.
b. may affect host immune response The only SNPs found to be associated with variation in setpoint viral load in genome-wide association studies are in the MHC region. They include SNPs that are proxies for the “good” HLA alleles HLA-B5701 (in Caucasians) and HLA-B5703 (in Africans)

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7
Q

Efficiency of control of viral replication by early host immune response.

A 
Cytokines and IFN
NK cell response
Antibody response
CD4 T cell response
CD8 T cell response.
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8
Q

Cytokines early in HIV infection.

A

Beneficial effects
Detrimental effects
HIV evasion.

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9
Q

Efficiency of control of viral replication by early host immune response.

A 
Cytokines and IFN
NK cell response
Antibody response
CD4 T cell response
CD8 T cell response.
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10
Q

What determines levels of persisting viral load in early infection?

A
  1. Properties of infecting virus
  2. Host genetics
  3. The efficiency of control of viral replication by the early host immune response
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11
Q

Beneficial effects of cytokines early in HIV infection.

A

Direct antiviral activity of type 1 IFNs Adjuvant effects – activation of other innate and adaptive responses

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12
Q

Detrimental effects of cytokines early in HIV infection.

A

Chemokines recruit CD4 T cells to mucosal transmission site to fuel virus replication Proinflammatory cytokines promote immune activation and drive viral replication Pro-apoptotic effects of eg IFNa/TNFa may contribute to CD4 cell loss.

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13
Q

HIV evasion of cytokines.

A

o Counteracts cytokines in later stages, not early.

o Accessory proteins evade some ISGs.

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14
Q

Effects of IFN in early establishment of SIV

A
  • Block IFNR while inoculating with SIV –> Reduced antiviral gene expression, Increased reservoir size, faster CD4 T cell depletion and progression to AIDS despite reduced immune activation
  • Gave IFN before inoculation. –> Antiviral gene expression increased, infection blocked
  • Gave IFN over longer period up until inoculation –> Negative feedback of type 1 IFN response (Foxo3a upregulation), antiviral gene expression decreased, infection with increased SIV reservoir size, immune activation and faster CD4 T cell loss
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15
Q

NK response to early HIV infection. Evidence that they contribute to viraemia.

A

o Genetic studies show associations between efficient control of viraemia over time and
o co-expression of KIR3DS1 (an activating NK receptor) with HLA-Bw4 Ile-80 alleles –
o co-expression of highly-expressed, highly inhibitory KIR3DL1 alleles and HLA-Bw4 Ile-80 alleles
o expression of more copies of KIR3DS1 & KIR3DL1 NK cells can control HIV replication in vitro HIV has evolved strategies for evasion of NK control

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16
Q

HIV avoidance of NK cells.

A

Happens in chronic (MHC, KIR and NCR), less in acute.

In chronic, Tat may have a role.

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17
Q

Tat and NK cells.

A

Tat may inhibit NK cell lysis by blocking Ca2+ influx and preventing degranulation

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18
Q

Early antibody response to HIV.

A

• Early antibody response correlates with decrease in viral load.
o Via ADCC?
o C’ fixation?
• Delayed production of neutralizing antibodies.

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19
Q

Avoidance of early antibody response by HIV.

A

Impair response

Avoid recognition

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20
Q

Impairing early antibody response.

A
  • Paucity of appropriate B cells in the pre-existing repertoire
  • Lack of CD4+ T cell help
  • Detrimental effects of infection-assoc’d cytokine production on B cells (eg driving polyclonal B cell activation)?
  • Detrimental effects of apoptotic microparticles on B cells?
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21
Q

Avoiding early antibody response.

A

Selection for neutralisation-resistant HIV variants during early HIV infection has been documented. Resistance often conferred through alterations in glycosylation – “glycan shield”.
There are only 4-5 main sites on the HIV-1 envelope glycoprotein to which broadly-neutralising antibodies can be generated

22
Q

Generating broadly-neutralising antibody responses.

A

20-30% of people chronically infected with HIV do eventually develop some antibodies with fairly broad neutralising activity

23
Q

CD8 T cell response - importance in early infection.

A

Strong HIV-specific CD4+ T cell responses are seen in the context of good control of HIV-1 replication in patients given early combination ART and patients who naturally control HIV replication well. Causal or effector?

24
Q

What causes weak CD4 T cell responses in early HIV

A

Infection and loss of HIV-specific CD4+ T cells.
Bystander apoptosis of uninfected HIV-specific CD4+ T cells.
Defects in induction and/or maintenance of HIV-specific CD4+ T cell response.

25
Q

What causes weak CD4 T cell responses in early HIV - infection and loss of HIV-specific CD4+ T cells.

A

Virus acquired by CD4+ T cells from APCs with which they interact (DCs carrying HIV-1 virions bound to DC-SIGN may transmit infection to CD4+ T cells) CD4+ T cells then destroyed by lytic viral replication, by Fas-triggered apoptosis, or by virus-specific immune response.

26
Q

What causes weak CD4 T cell responses in early HIV - bystander apoptosis of uninfected HIV-specific CD4+ T cells.

A

Fas and FasL can be induced on CD4+ T cells by exposure to gp120

27
Q

What causes weak CD4 T cell responses in early HIV - defects in induction and/or maintenance of HIV-specific CD4+ T cell response.

A

 Nef-induced internalisation of peptide-loaded MHC class II Gp120 interference with CD4-MHC class II interaction HIV infection-associated impairment of DC functions ?

28
Q

Direct evidence for importance of CD8+ cells against immunodeficiency lentiviruses.

A

o Depletion of CD8+ lymphocytes resulted in poor control of primary viraemia in SIV-infected macaques
o Selection for viral variants able to escape CD8+ T cell control during both SIV infection of macaques and HIV infection

29
Q

Indirect evidence for importance of CD8+ cells against immunodeficiency lentiviruses.

A 
o	Efficient control of viral replication by HIV-specific CD8+ T cells demonstrated in vitro 
o	Strong, highly functional HIV-specific CD8+ T cell responses in LTNP; loss of response associated with disease progression
o	 Inverse correlation between HIV-specific CD8+ T cell numbers and virus load seen in some but not all studies - Association between certain HLA class I alleles and rapid (B35- 02/3, B8) or slow (B27, B57) disease progression
30
Q

HIV against CD8+ T cell response.

A

Impairment

Avoidance.

31
Q

HIV against CD8+ T cell response - impairment.

A

Some but not all studies also suggest that HIV-specific CD8+ T cells from chronically-infected patients may have defects in antigen-stimulated cytokine production The decline in functionality is likely due to “exhaustion” Exhaustion is promoted by prolonged antigenic stimulation and poor availability of CD4+ T cell help

32
Q

HIV against CD8+ T cell response - avoidance.

A

Integration, replication in immunoprivileged sites.
Downregulation of MHC
Anitgenic variation - viral escape mutants.

33
Q

Viral escape mutants against CD8+.

A

• Amino acid changes in/around CD8+ T cell epitopes can confer escape from epitopespecific CD8+ T cell responses by affecting - epitope processing - peptide binding to MHC -TCR recognition (loss of binding or altered TCR signaling)
• Escape is affected by:
1. Response breadth
2. Epitope conservation

34
Q

Response breadth affecting viral escape mutants from CD8+.

A

If the T cell response is directed at multiple viral epitopes, the virus will need to acquire escape mutations at more sites to escape from the whole response If more different T cell clones recognise each epitope (or if epitope-specific T cells have a functionally-flexible TCR) this will make it difficult for the virus to escape the response via effects on T cell recognition Overall, the fitness costs incurred in escaping from a broad response are also likely to be higher

35
Q

Epitope conservation in avoiding CD8+ T cells.

A

 T cell responses directed against epitopes in conserved regions of viral sequence (e.g. Gag) are difficult for the virus to escape and any escape mutations that are acquired usually reduce viral fitness.

36
Q

Responses to Gag antigens

A 
The association between HLA-B27 and HLA-B57 and good control of HIV replication partly because the dominant HIV-1 Gag-specific responses typically induced with these alleles. 
Gag-specific responses are good because Gag (and Pol) from input virions can be presented by infected cells very early after infection (2hrs) CD8+ T cell responses directed against proteins presented by infected cells early after infection have a greater antiviral efficacy than responses directed against proteins expressed later during viral replication - greater opportunity for T cell recognition of infected cells before Nef-induced MHC class I downregulation and virion production.
37
Q

Resistance to CD8+ T cell effector mechanisms.

A 
Intrinsic resistance (macrophages)
Resistance conferred by HIV (Nef inhibits apoptosis).
38
Q

Nef inhibiting apoptosis

A

Nef inhibits Fas and TNF-R-mediated apoptosis of infected cells by binding to and inhibiting ASK-1.
Nef also phosphorylates and inactivates the pro-apoptotic protein bad
Counterattack: - Nef induces FasL expression on infected cells - Gp120 binding to CXCR4 on macrophages up-regulates mbTNFa

39
Q

Virus eradication - smallpox

A

History
Eradication
Post-eradication issues
Bioterrorism fears.

40
Q

Virus eradication - smallpox in history.

A

o Fall of the Aztecs
o Biological warfare with North American Indians
o Smallpox and the House of Stuart. Pretty much wiped them out

41
Q

Smallpox: eradication dates.

A

• Eradication of disease predicted 1801, but only achieved and confirmed by 1980. Estimated cost of eradication - $250 million.

42
Q

Why was eradication of smallpox possible?

A

o No reservoirs or persistence
o Easily recognized
o Vaccine effective against all strains. Highly conserved capsid (unknown at time)
o Vaccine was efficacious, potent, cheap, abundant, stable and easily administered.

43
Q

Smallpox. Post-eradication issues

A
  • Collecting, cataloguing and centralizing the virus.
  • Destruction of the virus – postponed.
  • End of vaccination
44
Q

Smallpox. Post-eradication issues - collecting, cataloguing and centralizing the virus.

A

In Russia and in America.
o All work with live virus has to have WHO authorization.
o No genetic engineering allowed.
o No expression of variola virus genes in other orthopox viruses
o No lab holding more than 20% of genome
o No variola virus DNA in same lab as infectious orthopoxvirus.

45
Q

Smallpox. Destruction of the virus – postponed to allow development of…

A

o Diagnostic tests
o Anti-viral drugs
o A safer vaccine
o Debate about future postponing at the World Health assembly, 18-26 of May, 2015.

46
Q

Smallpox. Fears of bioterrorism

A 
engineering to make more virulent?
o	Old vaccine, in limited supply
o	Tg is 7-19 days
o	Highly infectious. 
o	Theoretical response to outbreak.
47
Q

Smallpox. Theoretical response to outbreak.

A

 Who would take care of patient? UK has 350 vaccinated staff, but does not vaccinate the population. Trained infectious disease physicians to differentiate from measles. Monitor immune response in vaccinees, and compare to new and safer smallpox vaccines.
 Is vaccine available?
 Would the UK close its borders with outbreak elsewhere?

48
Q

Important target proteins for VACV Lister vaccine.

A

o EEV protein: B5. Others for IMV

o Multiple vaccinations induce higher and longer lasting Abs.

49
Q

Engineering of orthomyxoviruses.

A

• Immunocontraceptive for mice
o Ectromelia virus
o Break immunological tolerance
o Enhance antibody response by co-expressing Th2 cytokines from the same virus.
 Surprise! Expression of mouse IL-4 suppressed cytolytic lymphocyte response, overcoming genetic resistance to mousepox.

50
Q

Rinderpest.

A
  • Disease of cattle, causing great plague in 1865, and mass starvation.
  • Walter Plowright vaccine. Last case Kenya 2001.

Zpath term 2 (14 decks)

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