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BIOM30002 > Pandemics (A) > Flashcards

Pandemics (A) Flashcards

HIV

1
Q

What is a Pandemic

A

Global outbreak of infectious disease

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2
Q

What are the major current pandemics?

A

HIV/AIDS, Tuberculosis, Malaria

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3
Q

HIV/AIDS causes of death globally in 2007 vs 2017

A

2007: 5th, 2017: 13th

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4
Q

Global burden of HIV

A

36.7 million people living with HIV globally, 30% don’t know their status

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5
Q

When did AIDS related deaths start declining globally? Why?

A

Early 2000s
Because of availability of antiretroviral therapy (ART) through global advocacy and large donor effort, became available in low income countries

50% now have access to treatment, but about 1 mil still die of AIDS per year

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6
Q

What is the definition of AIDS?

A

HIV+ve (+ve HIV antibody test) and sick from virus/complications related to the virus

+

Low CD4+ T cell count <200/350

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7
Q

HIV/AIDS related deaths are not declining everywhere.

In Eastern Europe and Central Asia, AIDS-related deaths are increasing because:

A

There, HIV is primarily transmitted through drug use - drugs are illegal and clean needles are not available

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8
Q

AIDS related deaths decline as treatment coverage increases.

How are low or middle income countries able to access ART?

A

From early 2000s, increasing global effort to fund antiretroviral therapy

Low/middle income countries don’t need to abide by patent laws and can get access to generic versions of ART drugs

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9
Q

New HIV infections declining but not quick enough.

A

New HIV infections peaked in mid 90s largely due to uptake in testing

Numbers of new HIV infections are decreasing, but as of last year 1.8mil new HIV infections per year

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10
Q

What are the two global targets of reductions of HIV infections?

A

1) Reduce new HIV infections to 500,000 per year by 2020,

2) Global target of 90:90:90

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11
Q

Explain 90:90:90

A

90% in country should be tested and aware of their status
90% on treatment
90% on EFFECTIVE treatment = undetectable viral load

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12
Q

What is U = U?

A

Once someone is on ART, the virus in their blood declines to undetectable levels by standard assays and you can no longer transmit the virus sexually

Undetectable = untransmissable

The more people that are on treatment, the less transmission in the community

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13
Q

Risk factors for HIV: Globally

A

Globally more women than men affected by HIV

Key populations affected by HIV are very different across the globe

  • Eastern Europe and Central Asia: 51% People who inject drugs
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14
Q

New HIV diagnoses in indigenous and non-indigenous populations are:

A

Very similar, only about 6x higher rates of HIV infections in indigenous people, compared to 100x that of other STDs like Syphillis

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15
Q

How do we track number of newly acquired HIV infections by risk category (HIV negative test within 6 months)?

A

Track number of people who have had positive test and also had a negative test in the last 6 months
- tells you who has HIV now, tells us where the virus is being transmitted

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16
Q

What is the normal CD4+ T cell count?

A

> 500

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17
Q

Late HIV diagnosis and symptoms start at what CD4+ cell count?

A

<350

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18
Q

If someone has CD4+ T cell count <350 at diagnosis, they:

A

Have probably already been infected for about 5-10 years, about 50% of new diagnoses are in people who have a late HIV diagnosis.

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19
Q

Why is the number of people living with HIV in Australia an aging cohort?

A

Number of people living with HIV dramatically increased over last 2 decades because of ART, allowing people to live a normal long life with normal life expectancy

Growing number of people over 50 living with HIV

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20
Q

HIV is a (complex) retrovirus of the ____ family?

A

Lentiviridae

Slow viruses - make you sick slowly
Can be infected and stay healthy (asymptomatic) for 10+ years

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21
Q

Retroviruses are:

A

RNA viruses with the capacity to copy itself into host DNA (reverse transcribing via viral reverse transcriptase)

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22
Q

Primate retroviruses do not ____

A

make the primates unwell.

The primate retroviruses are non-pathogenic in their own species but are pathogenic in other species.

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23
Q

HIV-1 virus originated from:

A

Chimpanzee (SIVcpz)

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24
Q

HIV-2 Virus originated from:

A

African Green Monkey (SIVagm)

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25
Q

Lentivirus properties:

A

Retrovirus family

HIV-1, HIV-2

Icosahedral capsid symmetry

Has envelope

Genome is diploid linear 10kb (+ve) sense ssRNA (2 strands of ssRNA)

Virus replicated in nucleus and assembly in cytoplasm

Slow disease onset of AIDS, neurologic, arthritis, pneumonia

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26
Q

HIV genome consists of:

A 
Structural proteins (gag)
Viral enzymes (pol - polymerase - encodes all viral enzymes)
Envelope glycoproteins (env)

All retroviruses share many of these genes

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27
Q

A high degree of ___ exists for gag and env proteins

A

variability

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28
Q

HIV and SIV differ by their ___ proteins?

A

Regulatory proteins - assist the virus to replicate in different settings

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29
Q

HIV regulatory proteins:

A

tat, rev, vpr, vpu, vif, nef

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30
Q

Envelope proteins are key to:

A

allowing the virus to enter the cell

bilipid layer envelope on the outside of the virus, thats where the env proteins sit within the bilayer like studs

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31
Q

The 2 HIV env proteins are:

A 
GP 120 (SU-surface; cell attachment)
GP 41 (TM-transmembrane; fusion domain)

GP120 is embedded in the viral lipid bilayer by GP41

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32
Q

The 3 HIV structural gag proteins are:

A

p17 (MA-matrix)
p24 (CA-capsid)
p7 (NC-nucleocapsid)

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33
Q

The 3 HIV enzyme pol proteins are:

A

p66/51 (RT-reverse transcriptase)
p32 (IN-integrase)
p11 (PR-protease)

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34
Q

The different strains of HIV globally within the HIV-1 group are called:

A

Clades

- defined on their genome sequence and how much they differ from other genome sequences

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35
Q

Then most globally important HIV-1 strain is:

A

Clade C (eastern and southern Africa, and India)

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36
Q

The most common HIV-1 clade in North America, South America, Europe and Australia is:

A

Clade B

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37
Q

Why are clades important to consider when designing new drugs/vaccines?

A

We need to design a drug/vaccine that works across all clades

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38
Q

Clades are defined by:

A

Phylogenetic trees

  • shows how related sequences are, whether they are close or clustered on a branch
  • HIV-1 M group (Clades A-F) have less sequence homology to each other, but as a group are more similar to SIVcpz, which is very different to HIV-2 (SIVagm)
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39
Q

List out the HIV life-cycle

A
  1. CD4 Binding
  2. Co-receptor binding
  3. Fusion (and genomic replication)
  4. Budding
  5. Maturation
  6. New HIV virion
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40
Q

Explain: 1. CD4 binding

A

HIV has to bind to receptor to infect
Main receptor is CD4
HIV mainly infects CD4+ T cells
Binds CD4 via GP120 (env protein)

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41
Q

Explain: 2. Co-receptor binding

A

GP120-CD4 binding leads to conformational change in the receptor which exposes another biding site within the envelope protein which binds a second receptor called a chemokine co-receptor

CCR5 or CXCR4

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42
Q

Explain: 3. Fusion

A

Virus membrane is brought into very close contact with the membrane of the cell, which results in fusion of the 2 membranes.

Viral ssRNA moves into host cell

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43
Q

Explain how virus genetic material replicates in host cell

A

Viral ssRNA moves into host cell (following fusion) and undergoes reverse transcription in cytoplasm to form viral DNA (proviral DNA)

DNA then moves in through nuclear pore into nucleus, and uses viral enzyme integrase to integrate into host genome (absolutely key step in viral life cycle - this is why we cant cure HIV, because the virus becomes part of our own DNA)

Once proviral DNA integrates into host DNA, it can basically be shut down and be silenced

  • persist there for long time
  • hiv latency (main reason why we cannot cure)
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44
Q

Explain: 4. Budding

A

In the right cell activation state, the latent virus starts to make copies of itself exactly like other genes do

  • DNA>RNA>protein
  • Packaged together
  • Bud from surface of cell
  • then undergoes maturation and a new HIV virion is formed to infect other cells
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45
Q

The 4 key features of HIV replication are:

A

1) Rapid

2) Error prone reverse transcriptase (p66/51)
- leads to rapid evolution of multiple quasispecies
- lots of errors every time the RNA is RT-ed into DNA
- advantageous feature for virus because it can lead to rapid evolution in setting of some sort of pressure
- if a single virus manages to cross the mucosal membrane, within weeks you get this expansion and multiple quasispecies
- no virus is identical because every time it copies itself, it makes these errors
- Single drug agent - virus can rapidly develop resistance in about 3 weeks
- immune pressure can also rapidly develop resistance

3) 10 bil particles produced per day
- someone not treated is producing 10bil viral particles per day
- also clearning 10 bil a day
- amt of virus is at steady state, but it doesnt mean virus isnt replicating

4) Impact on host cells
- CD4+ T cells are prime target for HIV
- If cell enters resting state - virus becomes latent, gives it a mechanism to survive indefinitely
- If cell is activated, will die > progressively lose CD4+ T cells in untreated HIV infection

  • Monocyte/macrophages also express CD4 receptor
  • slightly different life cycle of the virus which leads to long lived slow release of virus
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46
Q

Factors involved in attachment, co-receptor binding, and fusion are:

A

Attachment: Viral gp120 binds to CD4 on host cell

Co-receptor binding: gp120-CD4 complex binds to CCR5 or CXCR4 on host cell

Fusion: Viral lipid bilayer membrane duses with host cell membrane, facilitating viral ssRNA entry

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47
Q

R5 viruses are:

A

CCR5-tropic, virus enters CD4+ T cells via CCR5
(over 90% of HIV viruses use this co-receptor)

  • Nearly all infections are caused by R5 viruses (seems to have selective advantage for transmission across mucosal membranes)
  • R5 viruses cause less T-cell destruction
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48
Q

X4 viruses are:

A

CXCR4-tropic, virus enters CD4+ T cells via CXCR4

  • Rarely transmitted
  • Emerge late in the course of infection (almost not seen today because now we treat everyone as soon as they get diagnosed with HIV+ve status, but left untreated, virus will progress from R5 to X4)
  • 50% of AIDS patients carry X4 virus
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49
Q

D/M viruses are:

A

HIV viruses that can use either CCR5 or CXCR4 to enter CD4+ T cells (dual-tropic)

Viral populations containing a mixture of R5-tropic, X4-tropic, and/or dual-tropic HIV are called mixed tropic (D/M)

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50
Q

The Δ32 mutation in the CCR5 leads to:

A

deletion of 32bp and no expression of CCR5 on cell surface

  • 90% Wild type, 10% CCR5Δ32
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51
Q

CCR5 Normal Wt/Wt alleles lead to:

A
  • Normal CCR5 expression
  • Progression of HIV
  • Normal immune function
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52
Q

Heterozygote (Wt/Δ32) alleles lead to:

A
  • Decreased CCR5 expression
  • Delayed progression to AIDS/Death
  • Normal immune function
  • 10-15% of caucasians
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53
Q

Homozygote (Δ32/Δ32) alleles lead to:

A
  • No CCR5 expression
  • Rare infection by X4
  • Normal immune function
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54
Q

List the 4 innate anti-viral cellular factors (host proteins) and the HIV proteins that counteract them:

A

1) APOBEC3G - vif (regulatory protein)
2) TRIM 5alpha - capsid
3) Tetherin - vpu (regulatory protein)
4) LEDGF - Integrase

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55
Q

Describe the APOBEC3G-vif interaction

A

APOBEC3G - function is to edit/destroy foreign RNA

vif - inhibits APOBEC3G

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56
Q

Describe the TRIM 5alpha - capsid interaction

A

TRIM 5alpha - blocks uncoating of retroviruses

capsid - Human TRIM 5alpha is inactive against HIV capsin protein

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57
Q

Describe the Tetherin-vpu interaction

A

Tetherin - blocks budding/release of viral particles

vpu - inhibits tetherin to allow budding/exit of viral particles

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58
Q

Describe the LEDGF-Integrase interaction

A

LEDGF - tethers HIV to host chromatin (virus has taken advantage of this LEDGF to tether itself to our chromatin)

Integrase - facilitates integration of proviral DNA into host DNA

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59
Q

How do Antigen presenting cells (APCs) present foreign material, and to which cells?

A

APCs present foreign antigens to CD4+ T cells in the context of MHC II (major histocompatibility complex) and the T cell receptor (TCR)

  • same process for CD8+ T cells and MHC class I
  • both CD4 and CD8 make very robust response to HIV, its the over-exuberant immune response that makes people sick
60
Q

Describe the Immune response to HIV

A

HIV RNA that we can measure in the blood after exposure

  • after 2 weeks can start to detect an exponential increase in HIV RNA up to 1mil copies per mL, then immune response kicks in and a decline in HIV RNA as a combination of immune response and HIV runs out of target cells - start to see decline in HIV RNA and HIV reaches a set point
  • Rise in HIV-specific CD8+ T cells, and stays at high level, robust but ineffective response
  • By 4 weeks can already detect HIV antibodies (diagnostic of HIV +ve status)
61
Q

What is the HIV RNA set point?

A
  • Normal about 10-100,000 copies per mil of blood
  • Elite controllers -> undetectable levels of HIV RNA in blood, body produces fantastic immune response to HIV, 1% of people with HIV
  • dont bother with set point in diagnosis anymore because anyone with HIV just goes straight onto treatment
62
Q

How does the HIV virus evade the immune response?

1) Sequence Variation

A

1) Sequence variation

  • Reverse transcriptase constantly introduces new mutations into virus, allowing it to escape recognition of both CTL (CD8 cytotoxic mediated immune response) and Antibodies
  • Antagonism so CD8 T cell can no longer function effectively
63
Q

How does the HIV virus evade the immune response?

2) Altered antigen presentation

A

2) Altered antigen presentation

  • down regulation of MHC Class I molecules by Tat, Vpu and Nef (regulatory proteins in HIV)
  • Key protein is Nef (negative factor) which allows HIV to persist in presence of immune response
64
Q

How does the HIV virus evade the immune response?

3) Loss of effector cells

A

3) Loss of effector cells

  • Clonal exhaustion (continual dividing and expanding and now the cells no longer function properly - a common feature of many chronic viral infections)
  • Loss of CD4 T cell help (to have effective CD8 cytotoxic response, you need CD4 help, and HIV kills CD4 which eliminates CD8 response)
  • Replicative senescence (cells can no longer divide any further, drop in population of CD4+ cells)
65
Q

How does the HIV virus evade the immune response?

4) Latency

A

4) Latency

  • Virus enters and integrates into host genome of a resting T-cell
  • Replication cycle is not complete so cell doesn’t express any viral proteins, virus hides in DNA and can evade immune response
  • Particularly in resting T cells, macrophages and astrocytes
66
Q

How does the HIV virus evade the immune response?

5) Privileged sites of viral replication

A

5) Privileged sites of viral replication

  • Sites traditionally not exposed to the immune system
  • Brain (BBB prevents T cells moving into brain), Testes (BTB), GIT (no specific barrier, but the volume and amount of HIV replicating there makes it a privileged site for replication)
67
Q

HIV disease: Define “Primary infection”

A

Acute phase of CD4 depletion, 0-3 weeks

CD4+ lymphocyte count drops to ~ 500 cells/mL
- because of HIV replicating and killing off CD4 cells

HIV RNA copies per mL in plasma spikes to 10^6

68
Q

HIV disease: Define “Acute HIV syndrome”

A

3-9 weeks post infection

HIV RNA copies spike to 10^6 then drop down to about 10^3/10^4 at the end of 9th week

CD4+ Lymphocyte count reaches 500

Wide dissemniation of virus

Seeding of lymphoid organs

69
Q

HIV disease: Define “Clinical Latency”

A

Chronic phase of CD4 depletion

Marker of HIV is CD4 T cell count - normal is > 500

Some recovery after initial drop in CD4 levels, but CD4 count doesnt go back to normal levels, but can get back up to about 500, and usually lose about 50 cells per year in absence of ART

Clinical latency is a bad term
- implies nothing is happening, but in fact, while the viral load is at steady state, there is still viral replication going on at the same rate of clearance

70
Q

When do constitutional symptoms of HIV occur?

A

After about 5-10 years when CD4 level reaches 200, start getting sick with constitutional symptoms of fever and diarrhea, weight loss, may even get opportunistic diseases.

Will eventually die if not treated because this is when HIV RNA copies per ml plasma start increasing again

71
Q

What happens in the gut of a HIV+ patient?

A

Massive depletion of CD4+ T cells from GIT in acute infection

  • GIT is main target for replication and CD4+ depletion, where only 1% of our lymphocytes are circulating
  • Depletion of Peyer’s Patches in GIT (lymphatic tissue in GIT ileum) - big driver for many complications seen in HIV
72
Q

Explain the Chronology of CD4 T-cell loss and disease

A

0-10 Weeks

  • Primary Infection
  • CD4 cell count per uL drops to 500 by 6th week
  • Glandular fever like illness, fever, rash, myalgia, myopathy, meningo-encephalitis

0-5 Years

  • Early Immune Deficiency
  • CD4> 500
  • Still number of complications, largely autoimmune because of the dysregulation of immune system in this early phase, even with normal CD4 count

5-10 Years

  • Intermediate Immune Deficiency
  • 500 > CD4 > 200
  • Mix of both autoimmune and infectious disease e.g. Herpes zoster, TB (not AIDS defining diseases but more common in people with impaired T cell function)

10+ Years

  • Advanced Immune Deficiency (AIDS)
  • CD4 < 200
  • PCP, CMV, MAC, Oral candidiasis, Herpes simplex, Hairy leukoplakia
73
Q

Describe CD4+ T-cell Homeostasis

A

Bone Marrow > Thymus > Lymph Node > Periphery

Bone Marrow
- CD34+ progenitor cells move into thymus

Thymus
- Complex process of positive and negative selection for T cells

Lymph Nodes

  • Naive T cells that are not self reactive
  • Constant homeostatic proliferation to replenish numbers

Upon exposure to antigen, Naive T cells expand and become

1) Effector T Cells (move into periphery to effect)
2) Central Memory T cells (Once antigen exposure is complete, Effector T cells will revert to Central Memory cells)

74
Q

Causes of CD4+ T-cell decline

1) Increased Destruction
a) Direct Infection

A

1) Increased destruction of CD4+ T cells
a) Direct infection

  • GIT&raquo_space;> blood
  • Incomplete reverse transcription in Naive T-cells (incomplete reverse transcripts can trigger apoptosis of CD4 T cells)
75
Q

Causes of CD4+ T-cell decline

1) Increased Destruction
b) Indirect Effects

A

1) Increased Destruction
b) Indirect Effects
- Contribute to far more CD4 loss than direct effects

  • Syncitium formation
    (CD4 cells become coated in HIV antigen which will bind other uninfected CD4 cells to the infected CD4 cells)
  • Apoptosis
  • Immune activation
    (Drives immune activation, CD4 cells constantly replicating and eventually reach end of life and die)
  • Lymph node fibrosis
    (due to overactive immune response, cannot produce similar numbers of T cells, stop producing IL-7 which limits T-cell proliferation)
76
Q

Causes of CD4+ T-cell decline

2) Impaired production

A

2) Impaired production
- Thymus
- CD34+ progenitor cells

77
Q

Which HLA types indicate good HIV prognosis?

A

B13, B27, B51, B57

78
Q

Which HLA types indicate rapid disease progression?

A

A23, B37, B49

79
Q

Infected CD4+ T cells present HIV antigen to CD8+ T cells via ____

A

MHC Class I

80
Q

Some people have very good immune responses to HIV, which is largely driven by their ___

A

HLA type

  • Certain HLA molecules present HIV epitopes more effectively, which enhances the adaptive immune response
81
Q

Other than CD4+ T cells, what other 4 cells get Depleted/Dysfunctional due to HIV-induced immunopathology?

A

1) CD8+ Cytotoxic T-Lymphocytes (CTL)
- Abnormally high during acute phase
- Decline at later stages

2) Natural Killer (NK) cells
- Impaired numbers
- Impaired function

3) Monocytes/Macrophages
- Defects in chemotaxis
- Inability to promote T-cell proliferation
- Defects in Fc receptor function

4) B Cells
- HIV doesnt infect B-cells
- Increased production of IgG and IgA = hyperactive B cells
- Hypergammaglobulimia, but decreased antibody responses

82
Q

HIV causes C____ I____ A___

A

Chronic Immune Activation

  • opposite of what you would expect in an immunodeficiency disease
83
Q

Name some markers of immune activation that are elevated in HIV infection (T-cells)

A

Cellular markers

  • HLA-DR (one of the key markers to measure immune activation)
  • CD38

Soluble Markers

  • sCD26
  • sCD30
  • sCTLA-4
84
Q

What are the 4 factors that lead to immune activation, despite the knocking out of CD4+ T cells?

1) Mucosal depletion of CD4 T-cells

A

1) Mucosal depletion of CD4 T-cells

  • Increased microbial translocation
    (fragments of microbial products can cross GIT wall)
- Activation of TLR4 by bacterial products (LPS)
(TLR4 = toll-like receptor class 4, expressed on monocytes and macrophages - leads to chronic activation even without viral infection)
85
Q

What are the 4 factors that lead to immune activation, despite the knocking out of CD4+ T cells?

2) Activation of innate immune response (pDCs)

A

2) Activation of innate immune response (pDCs)
- Plasmacytoid Dendritic Cells

  • pDCs express TLR7/8
  • HIV ssRNA is a TLR7/8 ligand
  • Increased plasma INF-alpha
86
Q

What are the 4 factors that lead to immune activation, despite the knocking out of CD4+ T cells?

3) Cytomegalovirus (CMV)-specific responses

A

3) Cytomegalovirus (CMV)-specific responses

  • characteristic feature of aging and immune activation
  • shows dysregulated immune response to other pathogens that people with HIV are infected with
  • Expansion of CMV-specific activated CD4+ and CD8+ T-cells
87
Q

What are the 4 factors that lead to immune activation, despite the knocking out of CD4+ T cells?

4) Loss of T regulatory cells

A

4) Loss of T regulatory cells

  • Treg cells also express CD4, usually activated and important in dampening down immune cell response
  • HIV knocks them out, and leads to hyperactive immune response
88
Q

What classes of antiviral drugs are used for HIV?

A

1) Integrase Inhibitors
- few side effects
- prevent proviral dna from integrating into host dna

2) Protease Inhibitors
- Inhibit the HIV protease required to cleave proteins GAG and POL to block maturation of the new virion particle

3) Reverse Transcriptase Inhibitors
- Prevent viral ssRNA from getting transcribed into proviral DNA which would go on to become integrated

4) Fusion/Entry Inhibitors

89
Q

What was the breakthrough idea concerning antiviral HIV drugs?

A

Using multiple drugs put together

  • if you only treat with 1 drug, within 3 weeks the virus will become resistant
  • If treat with 3 drugs, you tackle it from different angles and it freezes viral replication
  • introduced in 1996
90
Q

Anti-Retroviral Therapy (ART) leads to ______ in HIV RNA and ______

A

Rapid decline in HIV RNA, and CD4 recovery

  • people on ART, HIV RNA drops rapidly to undetectable levels (<20-50 copies per mL)
  • Within 4 weeks can go from 1 mil copies of HIV RNA per mL to undetectable
  • Virus is always there but it stops virus from replicating, and T cells will recover
  • If you start treatment very late, T cell levels may not recover to normal levels
91
Q

What is the START study?

A

Key study that changed the way we looked at HIV

  • Don’t wait for CD4 count to drop below 350, just start immediately
  • Life expectancy is normal for people who start treatment early, but if you do wait, your life expectancy is reduced
  • Risk of serious illness or death reduced by 53% in immediate (CD4>500 cells/uL) vs deferred (CD4<250 cells/uL) ART
  • Survival benefit maintained across all subgroups
92
Q

What are the 5 current challenges of ART?

1) Life expectancy almost normal

A

1) Life expectancy almost normal

- still reduced if treatment started late

93
Q

What are the 5 current challenges of ART?

2) Life long adherence

A

2) Life long adherence

- New advances in long acting injected ART

94
Q

What are the 5 current challenges of ART?

3) Toxicities of medications

A

3) Toxicities of medications

- Hyperlipidemia, renal toxicity, bone disease

95
Q

What are the 5 current challenges of ART?

4) Drug resistance

A

4) Drug resistance
- Very rare if adherent
- Looking globally, about 10% of transmitted strains are drug resistant
- It is a problem of implementation i.e. if people stop taking the ART drugs for whatever reason

96
Q

What are the 5 current challenges of ART?

5) Persistent immune activation

A

5) Persistent immune activation
- More common if you start ART late rather than early
- Multiple drivers and consequences

97
Q

HIV causes ______ risk of diseases of aging

A

Increased

  • Stroke, malignancy (non AIDS), renal disease, liver disease, fracture/osteoporosis, dementia, type 2 DM, COPD, Frailty

in an aging cohort globally

  • myocardial infarc
    (issue around inflammation that drives heart disease)
  • Virus-associated cancer
    (very common in untreated HIV infection, but rates decline with progression in ART, still 10x more common in people with HIV)
98
Q

T-cell activation on ART is still_____

A

Higher than without HIV, but lower than without ART

T-cell markers of immune activation are CD38+ and HLA-DR+

99
Q

What mechanisms drive Immune activation on ART?

A

Drive immune activation:

  • microbial translocation
  • persistent HIV
  • Co-infections: CMV, HCV
  • Activation of pDCs
  • Altered Treg/Th17

Immune activation
(Off ART&raquo_space; On ART&raquo_space; HIV Negative)

100
Q

What mechanisms drive disease on ART?

A

Drive Disease (due to immune activation)

  • Lymph node fibrosis
  • T-cell exhaustion
  • Local inflammation

Leads to:

  • Impaired CD4 T-cell recovery
  • End-organ disease e.g. CVD, liver, dementia
  • We see less and less of these problems as people start treatment earlier and earlier
101
Q

What are the 3 Key 2020 fast track Global Targets for tackling HIV?

A

1) 90(aware of HIV status):90(on HIV treatment):90 (virally suppressed)
2) 30 million people on treatment
3) Fewer than 500,000 new HIV infections annually

102
Q

What is the future of ART?

A

Injections rather than tablets

  • 12 injections over a year instead of 365 tablets
  • wont suit everyone
103
Q

Explain the concept of the Combination Prevention Toolbox in treating HIV

A
  • Blood Supply Screening
  • Condoms
  • Education/Behavior modification
  • Clean Syringes
  • Treatment/Prevention of Drug/Alcohol Abuse
  • STI Treatment
  • Mainly rely on behavioural compliance
  • Over the last few years, seen many new biomedical strategies to prevent HIV - rely on antiviral therapy
104
Q

List the prevention modalities built on antiviral therapy

A

1) Prevention of mother-to-child transmission
(we now use full ART with pregnant women and dramatically reduce transmission, from 600,000 to 220,000)

2) Pre-exposure prophylaxis
(Preventing getting infected with HIV)

3) Post-exposure prophylaxis
(Treatment early within 72h of exposure can prevent infection)

4) Treatment as Prevention
(when you treat someone who has HIV with ART, their viral load becomes undetectable and they can no longer transmit HIV)

105
Q

Treatment as Prevention (TASP):

A

ART reduces infectiousness by 96%

  • undetectable = untransmissable
106
Q

Pre-exposure Prophylaxis (PREP):

A

PREP is highly efficacious in MSM
-taken daily
- taken intermittently
- Truvada contains 2 reverse transcriptase inhibitors
- Event driven PREP
(2h before sex and 24 and 48h after > about 95% effective in preventing transmission)

  • PREP activity lower in women (probably because takes longer time for antivirals to accumulate in vaginal mucosa)

Adherence, effects on condom use, STIs and cost are the main concerns

107
Q

Reported failures to PREP are _______

A

Extremely rare

  • Over 500,000 people globally on PREP
  • 6 reported cases of infection while on PREP (just not 100% effective)
  • Infection with drug resistant virus
  • Infection with drug sensitive virus
  • Inadequate dosing
  • Event driven PREP x1
108
Q

Uptake of PREP globally is still _____

A

Limited

  • Most of the world still doesnt have access to PREP
  • Costs a lot of money
  • Are you better off putting infected on treatment, or preventing infection?
109
Q

How does a Dapivarine Vaginal Ring work?

A

Dapivarine = non-nucleoside reverse transcriptase inhibitor

  • 2 large Phase III studies using the ring monthly
  • ASPIRE, 2600 participants, 56% reduction in new infections
  • The Ring Study, 1959 participants, 31% reduction

Both studies showed poor effect in young women (18-21) most likely due to poor compliance

110
Q

Circumcisiton reduces the risk of HIV acquisition by 70% becuase

A

of removal of langerhan cells in the foreskin

  • inner foreskin frenulum is a prime area rich with dendritic cells which is a prime first cell that HIV infects
111
Q

Circumcision for HIV prevention

A

Implemented across many parts of the world as a strategy to reduce HIV transmissions

112
Q

What 2 components are needed for an effective vaccine response to HIV?

A

1) Develop better CTL (cytotoxic t-lymphocytes) that recognise an infected T-cell and eliminate it
2) Generate antibodies from B cells that will bind and neutralise HIV and prevent cells from ever getting infected

113
Q

The 4 different Vaccine approaches:

1) Recombinant proteins

A

1) Recombinant proteins

  • good antibody but poor t-cell responses
  • No protection
114
Q

The 4 different Vaccine approaches:

2) Live attenuated virus

A

2) Live attenuated virus

  • not possible with HIV because of potential risk of reverting to WT
  • potentially unsafe
115
Q

The 4 different Vaccine approaches:

3) DNA vaccines

A

3) DNA vaccines

  • we dont have DNA vaccines for any current viruses
  • Good t-cell responses but poor antibody responses
116
Q

The 4 different Vaccine approaches:

4) Live vectors

A

4) Live vectors
- not HIV as the vector, but maybe adenovirus or pox viruses or modified vaccinia Ankara (MVA) as good delivery systems for antigens
- Good t-cell responses but poor antibody responses

117
Q

Prime boost vaccine approaches
(a mix of standard vaccine approach strategies)

1) DNA + protein
(e. g. DNA + protein or vector)

A

1) DNA + protein
(e. g. DNA + protein or vector)

  • Thai trial, canary pox live vector + gp120
  • reduced risk of HIV acquisition by 30% (only study that showed reduced risk)
  • Most agree that you need 60% reduced risk to have an effective impact on the pandemic
118
Q

Prime boost vaccine approaches
(a mix of standard vaccine approach strategies)

2) DNA + live vector

A

2) DNA + live vector
- Non-replicating poxviruses expressing HIV-1 genes > good T-cell responses

  • Live vector of Ad5 (adenovirus 5)
  • STEP trial 2008
  • DNA vaccine + Ad5 boost
  • Possibly increased risk of infection because Ad5 induces activation of T cells which gave HIV more targets when person is exposed
119
Q

Prime boost vaccine approaches
(a mix of standard vaccine approach strategies)

3) Ad26 vector + Gp140

A

3) Ad26 vector + Gp140

- clinical trial underway

120
Q

Most promising HIV vaccine approaches:

A

1) Broadly neutralising antibodies
(only passive administration currently)

2) CMV vectors
(allow persistent antigen presentation)

3) Adenovirus (Ad) vectors
(Ad26 has minimal prior immunity)
- Chimpanzee (Ch) Ad virus

121
Q

What are bNABs?

A

Broadly neutralising antibodies

  • antibodies that some individuals make to HIV
  • can neutralise a large number of viruses
  • are directed against highly conserved regions of envelope that are “hidden”
  • Detected after 1-2 years of infection and of limited help to the patient
122
Q

If people make these bNABs, why dont they clear their own virus?

A

Because they make it too late

By the time they make it, the virus has already escaped that bNAB

123
Q

What are some bNAB targets?

A
  • N332 Glycan Supersite
  • V1 V2 Apex
  • CD4 Binding Site
  • Trimer Interface
  • GP41 (fusion protein) MPER
124
Q

How can bNABS be potentially used in HIV treatment, prevention and cure?

A

> HIV-infected individual who produces bNABs
clone HIV-specific B cells
Broadly neutralising anti-HIV antibodies: >200
Passive transfer of Abs
i.e. if you inject someone with bNABs, can you cure HIV

  • HIV prevention
  • Direct anti-HIV therapy
  • Prolonged suppression of viral rebound following interruption of ART
125
Q

Proof of concept of bNABs

A

Robust protection from SIV infection with multiple bNABs when monkeys were challenged with hybrid virus of SIV with HIV envelope

  • serum concentration of bNABs required to provide full protection from infection varies, and determines how we select antibodies to move into clinical trials
126
Q

Future directions and challenges for broadly neutralising antibodies as vaccines

A
  • Mono in combination, bi- or tri-specific bNABs enhance efficacy and reduce chance of resistance
  • Modification of the Fc tail of a bNAb to increase half life or activate Fc receptors
  • The biggest challenge is to generate bNAbs in vivo through vaccination (right now it is giving injections s.c.)
127
Q

CMV vectors promising in macaques

A
  • Induction of unusually broad HIV-specific T-cells
  • Peptides (in response to CMV vector) presented by HLA-E (instead of HLA-A and B)
  • Alternative antigen presentation triggered by CMV itself
128
Q

Ad26 virus + gp140 boost in monkeys and humans

A
  • Ad26 (common flu virus that many humans have not been exposed to)
  • Vaccine regimen: Ad26 (with mosaic antigen HIV) + gp140 (protein) + MVA
  • Immunogenicity in human (n=393) in a randomised double blind placebo controlled study. Identical vaccine in macaques and similar immune response
  • SHIV challenge of vaccinated monkeys gave 67% protection
129
Q

What happens when ART is stopped?

A

Rapid rebound in viral load (HIV RNA) within 2-3 weeks (virus is still present at low levels while on ART)

130
Q

Explain the two cases of HIV cure:

A

Berlin and London cases of HIV cure post stem cell transplantation

  • We would never use transplantation to cure HIV - high mortality of about 25%, these 2 patients received it because they needed the BM transplant for their blood cancer
  • This tells us that if you can knock out CCR5 and replace someone’s immune system with T cells that are no longer susceptible for HIV, we have a chance of the virus not coming back and maybe we have a chance of knocking out this receptor via much safer ways e.g. gene therapy to specifically excise the gene for CCR5
131
Q

How can we tell if someone is cured or in remission?

A

Only way to tell is by stopping ART
> viral load will rebound within 2-3 weeks

We can only do this in the context of a clinical trial, not in a clinical setting

post-treatment controller as opposed to an elite controller

Goals of research: can we delay this rebound so it doesnt happen like with the berlin and london patients, or can we extend the rebound delay from 2-3 weeks to 2-3 years?

No biomarker available that can predict time to rebound or post-treatment control

132
Q

Rare cases of “remission”

1) Delay in viral rebound (months/years)

A

1) Delay in viral rebound (months/years)

  • Very very early treatment before the reservoir or the latency can be established
    (mississippi baby, san fransisco patient)
  • Stem cell transplantation (even without the CCR5 mutation, probably due to GVHD)
    (boston patients, minnesota patient)
133
Q

Rare cases of “remission”

2) Post treatment control (indefinite)

A

2) Post treatment control (indefinite)

  • Early treatment (6 months)
    (then after a few years on treatment, treatment stops, a higher number of people seem to be able to generate some post-treatment control)
  • Chronic treatment
    (melbourne patient, belgium patients)
134
Q

What barriers are there to a HIV cure?

A

1) Latently infected T cells
2) Residual viral replication
3) Anatomical reservoirs

135
Q

The two forms of HIV infected T-cells are:

A

1) Productive infection
- DNA positive (integrated virus)
- RNA positive (virus that comes out of cell)
- HIV protein positive
- DEATH (cell death, daughter virion goes on to infect new cells)

2) Latent infection
- DNA positive
- RNA negative
- HIV protein negative
- SURVIVAL (of host cell)

**its never one state or the other, not all or nothing, its a spectrum of activity between latency and full infection

136
Q

Latently infected cells are ____

A

RARE

  • 1 in 1 million T cells are latent
  • They dont express specific surface markers so big challenge in the field is to identify a marker to identify a latently infected cell
137
Q

How do infected cells survive on ART?

A

Latent infected cells

  • integrated pro-virus
  • doesnt express any foreign antigens
  • Therefore hidden from the immune system
  • gets into a long lived T cell (central memory and and naive t cells - designed to last a lifetime, its here that HIV establishes latency)
  • as long as the cell is not activated, it persists
  • Once cell becomes activated, active viral replication continues
  • Integration into DNA also allows for replication of viral DNA when the latent T-cells undergo proliferation
    (clonally expanded infected cells)
  • together, this forms the biggest barrier to a HIV cure
138
Q

Clonally expanded infected cells

A

Off ART = random integration

On ART = expanded clones (come from the same infected parent cell)

Can account for 50% of infected cells

Sites of integration may give the infected cell a survival advantage

139
Q

HIV persistence on ART

A

Residual virus production
“active reservoir”

  • Any virus coming out of this cell cannot infect a new cell because this person is on ART
  • for some reason, these cells survive and dont die, dribble out low levels of virus, not a problem for someone on treatment, but the moment you stop treatment, there is active virus in the system to rebound
140
Q

Concept of Tissue Reservoirs:

A

Tissues such as lymph nodes, GIT, brain are protected from drugs and immune system -> can find infected cells in lymph nodes and gut

  • B cell follicles in lymph node
    (HIV virus sits in the B cell follicle which is a sanctuary because cytotoxic T cells cant enter the follicles, and neither can the ART drugs, so B cell follicles seem to be very important source of active virus production)
141
Q

Clinical strategies to achieve remission off ART include:

A

1) Virus elimination
2) Gene therapy
3) Immunotherapy
4) Vaccines and antibodies

142
Q

Latency reversal involves what methods?

A

Shock and Kill

> latent cell
use latency reversing agent to activate the cell and cause productive infection
starts producing HIV daughter virions but they cannot infect new cells because of ART
immune mediated killing or pro-apoptotic drugs to kill off the productive infection cells

143
Q

Latency Reversing Agents (LRAs)

A

Most potent type of LRAs are the TLR agonists

  • Latency reversal possible in vivo
  • No induction of cell death (most likely need to combine latency reversal agents with another intervention that mediates cell death)
  • Future studies need more potent LRAs and/or combinations
144
Q

Permanent silencing: “Block and Lock”

A

Trying to push the virus into further latency so it will never reactivate

  • deep-latency
  • Tat-inhibitor or mTOR inhibitor silencing RNAs
  • this strategy has not yet reached the clinic
145
Q

Gene therapy to eliminate CCR5

A

> HIV+ on cART
Leukapharesis & CD4+ T-cell isolation
(mix of CCR5 pos and neg cells, collect large number of leukocytes)
ZFN modification of CCR5
(ex-vivo gene scissors (Zinf finger Nucleases) use to excise CCR5 gene)
CCR5 neg cells expanded ex-vivo and trhen re-introduced into patient

  • get 5-15% of cells to be CCR5 negative, but it doesnt seem to be enough to stop the virus coming back
  • Other ways looking at modifying stem cells

BIOM30002 (20 decks)

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