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BIOM30002 - M2M > Lecture 14 - HIV - Natural History, Treatment, Prevention > Flashcards

Lecture 14 - HIV - Natural History, Treatment, Prevention Flashcards

1
Q

What is the clinical hallmark of HIV infection?

A

CD4+ T cell depletion

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2
Q

When is HIV first seen in plasma?

A

After a couple of weeks

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3
Q

What is the virus doing during clinical latency?

A

Steady state: virus production is equal to virus loss

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4
Q

Describe the changes in CD4+ T cell number

A

Primary infection: acute depletion
Seroconversion: increases somewhat
Clinical latency: gradual loss
AIDS: less than 200 cells per mm3

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5
Q

Describe the changes in the GIT mucosa during HIV infection, and how this leads to immune activation

A
  • Mucosal depletion of CD4+ T cells in the Peyer’s patches
  • Increased microbial translocation, due to decreased defences
  • These bacteria activation TLRs, and thus trigger the immune system
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6
Q

What illnesses are seen at the various stages of HIV infection?

A
  1. Primary infection
    • Features of normal viral infection (fever, myalgia)
  2. Clinical latency
    • Autoimmune disorders
    NB these are not disorders that signal to GPs that the patient may have HIV infection
    • Tuberculosis
  3. AIDS:
    • Disorders that are only really seen in people who are highly immunosuppressed (PCP, Kaposi sarcoma, non-Hodgkins Lymphoma)
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7
Q

Describe CD4+ T cell homeostasis

A
  1. Production in bone marrow
  2. Development in thymus
  3. Proliferation of naïve cells
  4. Differentiation into effector cells and memory cells
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8
Q

How does HIV infection lead to decline in CD4+ T cells?

A
  1. Increased destruction
    a. Direct infection kills the cell
    b. Indirect effects
    “SAIL”
    • Syncitium formation
    • Apoptosis
    • Immune activation
    • Lymph node fibrosis
  2. Impaired production
    • in the thymus
    • progenitor cell suppression / loss
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9
Q

Describe Syncytium formation

A

Virally infected cell expresses viral proteins and glycoproteins on the cell surface

Many uninfected CD4+ T cells start to gather around the infected cell and fuse membranes

This is called syncytia.

These huge fusion of cells dies, and a single virion has killed many CD4+ T cells by infecting only one cell.

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10
Q

Describe the indirect killing of CD4+ T cells by HIV

A 
"SAIL"
 • Syncytium formation
 • Apoptosis
 • Immune activation
 • Lymph node fibrosis
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11
Q

Why is CD4+ T cell depletion variable?

A

Viral factors
• CXCR4 virus → accelerated T cell loss
• Nef deleted virus

Host factors
• Genetic: CCR5 del32 heterozygote
• Age: thymic function dependent on age
• Immune response: HLA type

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12
Q

What is the effect of Nef deleted virus?

A

No HIV infection in the host

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13
Q

Describe the effect of HLA on HIV infection

A

Certain HLA alleles are associated with good progression, whilst others are associated with poor progression

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14
Q

What happens to CD8+ T cells in HIV infection?

A

Great number stimulated during acute phase

Later on, decline, because they are exhausted

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15
Q

What happens to NK cells in HIV infection?

A

Decreased numbers

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16
Q

Describe HIV-induced immunopathology

A
  • Depletion / dysfunction of immune cells

* Chronic immune activation

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17
Q

What is the CMV-specific response?

A

Expansion of the memory T cells for CMV
This is seen in response to HIV infection

Part of aberrant immune activation in HIV infection

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18
Q

What happens to Tregs in HIV infection?

A

Depleted

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19
Q

Which monkeys develop AIDS when exposed to HIV?

A

Rhesus Macaques:
• develop AIDS when exposed to SIV

Sooty Mangabeys:
• have very high levels of the virus, but remain healthy

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20
Q

Compare CD4+ T cell decline in the various monkeys

A

RM: depletion
SM: no depletion

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21
Q

Compare immune activation in the various monkeys

A

RM: yes
SM: no

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22
Q

Compare LPS level in the various monkeys

A

RM: increased
SM: low

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23
Q

Compare CD4+ T cell depletion in the GIT in the various monkeys

A

RM: depleted
SM: normal

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24
Q

Describe HAART

What are some of the classes of anti-retroviral drug?

A

Combination of several (3) different classes of retroviral drugs

Classes:
 • Cellular chemokine receptor antagonists
 • Fusion inhibitors
 • RT inhibitors
 • Integrase inhibitors
 • Protease inhibitors

It is very important that several classes are used in combination.
This ensures that the virus does not rapidly evolve resistance to the treatment

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25
Q

Describe what happens to:
• HIV levels
• CD4+ T cell levels
after cART

A

HIV: Levels drops rapidly

CD4+ T cells: count increases
NB this is actually quite variable between individuals

26
Q

Compare life expectancy:
• pre-HAART
• early HAART
• Late HAART

A

Pre-HAART: very unlikely to reach 50
Early HAART: much better outcomes
Late: only live 10 years less that non-infected people

27
Q

Describe the changes in HIV therapy access around the world

A

Over the last 3 years access has increased greatly across low and middle income countries

28
Q

How many HIV+ people globally know they’re infected?

A

50%

29
Q

What are people with HIV infection dying from nowadays?

Why is this?

A

non-AIDS deaths
• Disease seen without HIV, but are increasingly prevalent in HIV+ people

  • Malignancy
  • Cardiovascular disease
  • Renal disease
  • Liver disease
  • Metabolic disorders

Because:
• Immune dysfunction
• cART toxicity
• HIV infection, virus is still present at low levels

30
Q

Why is CD4+ T cell recovery due to therapy actually quite variable?

A

(similar to variable infection outcome)
Viral factors

Host factors:
• genetic
• age; thymus function
• CD4+ T cell count when treatment was started

31
Q

Describe the immune abnormalities seen in HIV+ patients on cART

A
  1. Similar to those seen in normal ageing
  2. Don’t get better with cART and HAART
    •Observed whether or not the HIV+ individual is receiving cART

This is why the diseases that kill people with HIV infection are similar to those seen in old age

32
Q

What are the various strategies for HIV prevention?

A

Behavioural:
• Testing
• Condoms

Biomedical:
 • Vaccines
 • Circumcision
 • Microbicides
 • Treatment of STIs
 • PREP
 • Anti-retroviral treatment
→ treatment as prevention
33
Q

Which responses are vital for a clinically effective HIV vaccine?

A
  1. T cell based, CTLs
    • very quick detection of infected cells
  2. Neutralising Abs
    • virus can never infect cells
34
Q

What was the response to recombinant protein vaccines?

A

Poor response

35
Q

What was the response to DNA vaccines?

A
  • Good T cell responses

* Poor antibody responses

36
Q

What was the response to live vector vaccines?

Give an example

A

• Good T cell responses, but this didn’t translate to good protection

STEP trial
• found to be not effective, possible even increased risk of infection

37
Q

What was the response to live attenuated vaccines?

A

Potentially unsafe

Never trialled

38
Q

What are prime boost vaccines?

What was the response to prime boost vaccines?

A

DNA + protein / vector

  • Thai trial
  • decreased probability of infection (30%)
  • 30% is not as much as desired
39
Q

What was the response to bnMAbs vaccines?

Describe how this works

A

Look very promising, but not yet in human trials

  • can neutralise a large number of viral strains
  • directed against regions of the envelope that are often hidden by glycan shields
40
Q

What happened in the Ad5 prime boost study?

A

Stopped prematurely due to lack of efficacy

The vaccines can induce good T cell responses, but do not prevent infection

41
Q

Describe CMV vector vaccines.

Describe how this works

A
  • There has been a trial in Macaques
  • The vaccine group showed protection against infection, whereas the placebo group wasn’t

The vaccine induced a very unconventional response:
• Unconventional CD8+ T cells that also recognise peptide in MHC II
• Unconventional CD8+ T cells can recognise more infected cells than a normal one
• They are more promiscuous: they can recognise the same epitope in the context of different MHC class II
• Can recognise many more epitopes than normal

42
Q

What is the effect of male circumcision?

Why?

A

Reduced by 70%
• There are many DCs in the epithelium under the foreskin that capture the virus, which leads to infection
• By removing this, it decreases infection

43
Q

Describe treatment as prevention of HIV

A

There was a trial undertaken in discordant (for HIV+) couples

• 96% prevention of infection of the unifected partner when infected partner was on ART

There is the potential for cART to eradicate HIV infection.
The only problem is logistics.

44
Q

What is the effect on CD4+ T cell loss of CXCR4 virus

A

Accelerated depletion

45
Q

Which cell types experience dysfunction in HIV infection?

A
  • CD8+ T cells
  • NK cells
  • Monocytes & macrophages
  • B-cells
46
Q

What is the role of pDC in the immune response to HIV?

A
  • TLR 7 & 8 expressed in pDCs recognise ssRNA
  • HIV directly stimulates these TLRs on the pDCs

→ high, chronic levels of IFN-alpha

→ Downstream implications of this

47
Q

What is the effect of HIV on monocytes and macrophages?

A
  1. Activate monocytes and macrophages
  2. These cells then release many pro-inflammatory cytokines

→ chronic, low level inflammation

48
Q

Why is keeping viral load suppressed important?

How widespread is suppressed viral load?

A

25% of people living with HIV have suppressed viral load.

Suppressed viral load is important, as it means that people will not transmit the virus.

This is a potential mechanisms for eradicating HIV.

49
Q

What were the various types of vaccines tested for HIV?

A
  • Recombinant proteins
  • DNA vaccines
  • Live vector
  • Live attenuated
  • Prime boost
  • CMV vectors

Not yet tested:
• Broadly neutralising Abs

50
Q

What are the ‘unconventional’ T cells?

What special things can they do?

A

These are CD8+ T cells that recognise epitopes in the context of MHC II

Special features:
• Promiscuity: can recognise the same epitope in many different MHC molecules
• Can recognise a breadth of epitopes
• and of course, can recognise peptide in the context of MHC class II

51
Q

Describe the use of microbicides.

What is the efficacy?

Which drug is contained in it?

A
  1. Intercourse
    • up to 12 hrs before
    • again immediately after, up to 12 hours after sex
  2. Parturition
    • application to prevent infection of the newborn

Reduces female acquisition by 40%

Drug:
• Tenofovir; an antiretroviral drug

52
Q

What is PREP?

What is the efficacy?

A

Pre-exposure prophylaxis

Daily administration of anti-retrovirals
• Tenofovir or Truvada
• Orally or vaginally

Efficacy in gay men:
• 40%
• Up to 70% if compliance is high

53
Q

Can universal cART end HIV?

A

It has the potential to, the only problem is logistics

54
Q

Describe the immune activation seen with HIV infection

How is the immune activation detected?

A
  1. GIT MALT depletion
    • Many CD4+ T cells in GIT → die upon infection
    • Loss of Peyer’s patches
  2. Activation of innate immune response
    • RNA activates TLR7/8
    → IFN-α
  3. Cytomegalovirus (CMV) specific response
    • Expansion of CMV specific CD4+ T cells
  4. Loss of Tregs
    • Needed for dampening down of the immune response

Abnormal immune activation seen in HIV
• detected by elevated markers of immune activation

55
Q

Describe what happens to CMV specific T cells in HIV infection

A

CMV (cytomegalovirus) specific T cell expansion

  • CMV is a very common virus, and almost everyone has experienced it, and thus has:
  • CMV specific T cells in our memory repertoires
  • HIV infection can lead to expansion of these memory cells
56
Q

Describe what the innate immune response is doing in HIV infection

Why is the innate immune response stimulated?

A

Innate immune response is overactive

HIV stimulates pDCs through TLR7/8 (RNA ligand)

pDCs produce lots of IFN-α

57
Q

For which TLRs is HIV a ligand?

A

TLR-7 and TLR-8

58
Q

What factors contribute to the accelerated ageing in HIV?

A
  • Immune activation
  • cART toxicity
  • HIV infection
59
Q

Which factor is really important in CD4+ T cell recovery?

A

Original CD4+ T cell count when HAART is commenced

60
Q

What is the most effective HIV vaccine trialled to date?

A

Thai Trial

Prime/Boost vaccine
30% protection

This is better than the others, but 30% is still very low

61
Q 
Compare efficacy of the following prevention options:
 • Treatment as prevention
 • Male circumcision
 • Microbicides
 • PREP
 • Vaccines
A

Treatment as prevention: 96%

Male circumcision: 70%

Microbicides: 40%

PREP: 40-70%
(depending on compliance)

Vaccines:
• Most vaccines: 0%
• Thai trial: 30%

BIOM30002 - M2M (36 decks)

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