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

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Flashcards in Lecture 14 - HIV - Natural History, Treatment, Prevention Deck (61):
1

What is the clinical hallmark of HIV infection?

CD4+ T cell depletion

2

When is HIV first seen in plasma?

After a couple of weeks

3

What is the virus doing during clinical latency?

Steady state: virus production is equal to virus loss

4

Describe the changes in CD4+ T cell number

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

5

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

• 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

6

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

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)

7

Describe CD4+ T cell homeostasis

1. Production in bone marrow

2. Development in thymus

3. Proliferation of naïve cells

4. Differentiation into effector cells and memory cells

8

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

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

9

Describe Syncytium formation

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.

10

Describe the indirect killing of CD4+ T cells by HIV

"SAIL"
• Syncytium formation
• Apoptosis
• Immune activation
• Lymph node fibrosis

11

Why is CD4+ T cell depletion variable?

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

12

What is the effect of Nef deleted virus?

No HIV infection in the host

13

Describe the effect of HLA on HIV infection

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

14

What happens to CD8+ T cells in HIV infection?

Great number stimulated during acute phase

Later on, decline, because they are exhausted

15

What happens to NK cells in HIV infection?

Decreased numbers

16

Describe HIV-induced immunopathology

• Depletion / dysfunction of immune cells
• Chronic immune activation

17

What is the CMV-specific response?

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

Part of aberrant immune activation in HIV infection

18

What happens to Tregs in HIV infection?

Depleted

19

Which monkeys develop AIDS when exposed to HIV?

Rhesus Macaques:
• develop AIDS when exposed to SIV

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

20

Compare CD4+ T cell decline in the various monkeys

RM: depletion
SM: no depletion

21

Compare immune activation in the various monkeys

RM: yes
SM: no

22

Compare LPS level in the various monkeys

RM: increased
SM: low

23

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

RM: depleted
SM: normal

24

Describe HAART

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

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

25

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

HIV: Levels drops rapidly

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

26

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

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

27

Describe the changes in HIV therapy access around the world

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

28

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

50%

29

What are people with HIV infection dying from nowadays?

Why is this?

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

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

(similar to variable infection outcome)
Viral factors

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

31

Describe the immune abnormalities seen in HIV+ patients on cART

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

What are the various strategies for HIV prevention?

Behavioural:
• Testing
• Condoms

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

33

Which responses are vital for a clinically effective HIV vaccine?

1. T cell based, CTLs
• very quick detection of infected cells

2. Neutralising Abs
• virus can never infect cells

34

What was the response to recombinant protein vaccines?

Poor response

35

What was the response to DNA vaccines?

• Good T cell responses
• Poor antibody responses

36

What was the response to live vector vaccines?
Give an example

• 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

What was the response to live attenuated vaccines?

Potentially unsafe
Never trialled

38

What are prime boost vaccines?

What was the response to prime boost vaccines?

DNA + protein / vector

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

39

What was the response to bnMAbs vaccines?
Describe how this works

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

What happened in the Ad5 prime boost study?

Stopped prematurely due to lack of efficacy
The vaccines can induce good T cell responses, but do not prevent infection

41

Describe CMV vector vaccines.

Describe how this works

• 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

What is the effect of male circumcision?
Why?

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

Describe treatment as prevention of HIV

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

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

Accelerated depletion

45

Which cell types experience dysfunction in HIV infection?

• CD8+ T cells
• NK cells
• Monocytes & macrophages
• B-cells

46

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

• 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

What is the effect of HIV on monocytes and macrophages?

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

→ chronic, low level inflammation

48

Why is keeping viral load suppressed important?
How widespread is suppressed viral load?

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

What were the various types of vaccines tested for HIV?

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

Not yet tested:
• Broadly neutralising Abs

50

What are the 'unconventional' T cells?
What special things can they do?

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

Describe the use of microbicides.

What is the efficacy?

Which drug is contained in it?

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

What is PREP?

What is the efficacy?

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

Can universal cART end HIV?

It has the potential to, the only problem is logistics

54

Describe the immune activation seen with HIV infection

How is the immune activation detected?

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

Describe what happens to CMV specific T cells in HIV infection

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

Describe what the innate immune response is doing in HIV infection

Why is the innate immune response stimulated?

Innate immune response is overactive

HIV stimulates pDCs through TLR7/8 (RNA ligand)

pDCs produce lots of IFN-α

57

For which TLRs is HIV a ligand?

TLR-7 and TLR-8

58

What factors contribute to the accelerated ageing in HIV?

• Immune activation
• cART toxicity
• HIV infection

59

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

Original CD4+ T cell count when HAART is commenced

60

What is the most effective HIV vaccine trialled to date?

Thai Trial

Prime/Boost vaccine
30% protection

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

61

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

Treatment as prevention: 96%

Male circumcision: 70%

Microbicides: 40%

PREP: 40-70%
(depending on compliance)

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