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BIOM30002: Molecule to Maladay > HIV > Flashcards

HIV Flashcards

1
Q

What is the number of people living with HIV globally?

A

38.4 Million
* 25.6 Million - Africa

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2
Q

What are the Risk Factors for HIV infections globally?

A
  1. Remaining Population
  2. Clients of Sex Workers & Sex Partners of Key Population
  3. Gay men & men-men sex
  4. Sex Workers
  5. People who Inject Drugs
  6. Transgender Women
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3
Q

Which groups are more commonly represented with new HIV infections?

A

Men who have sex with men (MSM)

Heterosexual Contact

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4
Q

What retrovirus family is HIV?

What are some features of this family?

A

Lentiviridae family

  • Cause disease slowly
  • Retrovirus
  • Capsid Symmetry: Icosahedral
  • Genome: Diploid linear 10kb + sense ssRNA
  • Genome replicated in nucleus
  • Virus assembly: cytoplasm - plasma membrane
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5
Q

Outline the HIV genome

A
  • ssRNA
  • (+) sense
  • 3 main genes:
    1. env
    – high variability exists
    – envelope glycoproteins
    2. gag
    – high variability exists
    – structural protein
    3. pol
    – viral enzymes
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6
Q

What are the HIV diversity (clades)?

A

HIV-1
* most common type of HIV globally
* further divided into several clades
– HIV-1 M = A-D, F-H, J, K = vast majority of HIV-1 infections globally = primary target
* US, Europe & Australia = share clade (B)
* Subsaharan Africa & India share clade

HIV-2
* less prevalant then HIV-1
* West Africa

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7
Q

Describe the life cycle of HIV

A
  1. CD4 - gp120 binding
  2. CoR binding
  3. Fusion
  4. Reverse transcription of viral genome into DNA
  5. Integration of proviral DNA into host genome
  6. Transcription of DNA into viral RNA
  7. Translation
  8. Assembly
  9. Budding
  10. Maturation into new HIV virion
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8
Q

What are the key features of HIV replication?

A
  • rapid
  • error prone RT = rapid evolution of multiple quasispecies
  • Impact on host cells
    – CD4+ T-Cells
    Activated = death, resting = latent
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9
Q

How does HIV enter the host cell?

A

1. Attachment
– Viral gp120 protein = binds to CD4 on host cell
2. Co-Receptor Binding
– gp120-CD4 complex = binds to CCR5 OR CXCR4 on host cell
3. Fusion
– Virus fuses with host cell membrane = viral entry

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10
Q

What are the main HIV chemokine receptors? And what type of HIV binds to it

A

CCR5 = R5 HIV
CXCR4 = X4 HIV

ON CD4+ T CELLS

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11
Q

Describe a case of natural resistance to HIV

A
  • mutation in CCR5 = CCR5 Δ32

Heterozygotes:

  • decreased CCR5 expression
  • delayed progression to AIDS/death

Homozygous for mutation:

  • no CCR5 expression
  • rate infection with R5

CCR5 Δ32 mutation does not affect immune function

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12
Q

What is APOBEC3G? What HIV protein inhibits it?

A
  • Host protein that edits RNA
  • vif Inhibits it
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13
Q

What is TRIM 5a?

A
  • Host protein that blocks uncoating of retroviruses
  • capsid = Human TRIM 5a = inactive against HIV
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14
Q

What is Tetherin? What HIV protein inhibits it?

A
  • Host protein that blocks release of virus
  • vpu = inhibits tetherin to allow exit
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15
Q

What is LEDGF?

A
  • Host protein that tethers HIV to host chromatin
  • Integrase HIV protein = facilitate integration

tethers= ties

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16
Q

What are the two major forms of HIV infected cells?

A

Productive infection

  • DNA positive
  • RNA positive
  • HIB protein positive
  • DEATH

Latent Infection

  • DNA positive
  • RNA negative
  • HIB protein negative
  • SURVIVAL
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17
Q

Describe the early events in HIV transmission

A
  1. Virion introduced in vaginal epithelium (hours)
    – microtears = allows virion to cross epithelium
  2. Local expansion (3-4 days)
    – HIV gp120 envelope protein binds to CD4+ T cells = conformational changes in envelop
    – HIV genome has access to interior of cell
  3. Dissemination to lymph nodes (days-weeks)
    – infection of many CD4+ T cells
  4. Local proliferation (1-2 weeks)
    – peak plasma virus levels
    – CD4+ memory cell loss in MALT
  5. Partial Immune Control (weeks-months-years)
    – Neutralising Abs
    – Activation of CTLs
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18
Q

How does HIV evade the immune system?

A
  • Sequence variation
  • Altered antigen presentation
  • Loss of effector cells
  • Latency
  • Privileged sites of replication
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19
Q

Explain the sequence variation in HIV evasion

A
  • lack of recognition
    • both CTL & antibody
  • antagonism
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20
Q

Explain the loss of effector cells in HIV evasion

A
  • clonal exhastion
  • Loss of CD4+ T cell help
  • Replicative senescence
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21
Q

List what cells latency impact in HIV evasion

A
  • in resting T-cells, Macrophages & Astrocytes
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22
Q

What is the clinical hallmark of HIV infection?

A

CD4+ T cell depletion

23
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
24
Q

What are the causes to CD4+ T-cell decline?

A

Increased Destruction

  • Direct Infection
    – GIT > Blood
    – incomplete reverse transcription in naive T-cells
  • Indirect effects
    ‘SAIL’
    – Syncitium formation
    – Apoptosis
    – Immune activation
    – Lymph node fibrosis

Impaired Production

  • Thymus
  • CD34+ progenitor cells
25
Q

Why is CD4+ T cell depletion variable?

A

Viral factors

  • CXCR4 virus = accelerated T cell loss
  • Nef deleted virus = limits T-cell loss

Host factors

  • Genetic: CCR5 del32 heterozygote
    – Slower disease progression
  • Age: thymic function dependent on age
  • Immune response: HLA type
  • Sex: Women = greater CD4 decline
26
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

27
Q

What happens to CD8+ T cells in HIV infections?

A
  • ↑ Abnormally high during acute phase
  • ↓ Decline at later stages = exhausted
28
Q

What happens to NK cells in HIV infections?

NK = Natural Killer

A
  • Decrease numbers
  • impaired function
29
Q

What happens to Monocytes & Macrophages in HIV infection?

A
  • defects in chemotaxis
  • inability to produce T-cell proliferation
  • defects in Fc receptor function
30
Q

What happens to B-cells in HIV infection?

A

Production of IgG and IgA but ↓ antibody responses

31
Q

How does HIV cause chronic immune activation

A
  • immune system is constanly ‘on’
    1. Mucosal depletion of CD4+ T-cells
    2. Activation of innate immune response
    3. Cytomegalovirus (CMV)-specific response
    4. Loss of T regulatory cells
32
Q

What does mucosal depletion of CD4 T-cells cause in HIV?

A
  • Increases Microbial Translocation
    – damaged mucosal barriers = allows bacteria & product to leak into bloodstream more easily
  • Activation of TLR4 by bacterial products (LPS)

TLR = toll like receptors

33
Q

What are potential targets for anti-viral drugs for HIV?

A
  • Fusion/Entry inhibitors
  • Reverse Transcriptase Inhibitors
  • Integrase Inhibitors
  • Protease Inhibitors
34
Q

What are the current limitations to ART?

ART: AntiRetroviral Therapy

A
  • Life expectancy almost normal
    – still reduced if treatment start late
  • Life long Adherance
  • Toxicities of medications
  • Drug resistance - very rare
  • Immune Activation
    – multiple drivers and consequences
35
Q

What are the combination HIV prevention?

A
  • Blood Supply screening
  • condoms
  • education/behaviour modification
  • clean syringes
  • treatment/prevention of drug/alcohol abuse
  • STI treatment
36
Q

What is Pre-Exposure Prophylaxis (PREP)?

A
  • medication used to prevent HIV infection is people who are at high risk of exposure (relationships)
  • highly efficacious in MSM
  • reduces aquisition by 95%

MSM =malexmale

37
Q

What are the main concerns of PREP?

PREP: Pre-Exposure Prophylaxis

A
  • Adherance
  • effects on condom use
  • STIs
  • cost
38
Q

What procedure reduces the risk of HIV acquisition by 70%?

WHY?

A

Circumcision

  • many DCs in epithelium under foreskin that captures virus = infection
  • remove = decrease infection
39
Q

What are the vaccine approaches for HIV?

A

Recombinant proteins

  • good antibody BUT poor T-cell responses
  • no protection

Live vectors

  • good T-cell responses BUT poor antibody

Nucleid acid vaccines

  • DNA: good T-cell responses BUT poor antibody responses
  • mRNA: broad T-cell responses

Live attenuated virus

  • potentially unsafe = not pursued
40
Q

What are the prime-boost vaccination approaches?

A

DNA + Protein

  • Reduced risk of HIV acquisition by 30%

DNA + Live Vector

  • Non-replicating poxviruses expressing HIV-1 genes → good T-cell responses Ad5 virus
  • possibly increased risk of infection

Live Vector + Protein

  • showed no benefit
41
Q

What are the most promising HIV vaccine approaches?

A

Broadly Neutralising Antibodies

CMV Vectors

  • persistent antigen presentation

mRNA Vaccines

  • immunogen can be changed easily
42
Q

What are the potential role of Broadly Neutralising Antibodies (bNABs) in HIV treatment?

A

HIV-infected individual = Clone HIV specific B cells = Broadly neutralising anti-HIV = Passive transfer of Abs

  • HIV prevention
  • Direct anti-HIV therapy
  • Prolonged suppression of viral rebound following interuption of ART
43
Q

What are the future direction and goals for bNABs?

bNABs: Broadly Neutralising Antibodies

A

Monovalent antibodies in combination, bi- or tri-specific bNABs = enhance efficacy & reduce resistance

Modification of Fc tail of bNAB = increase half life OR activate Fc receptors

Challenge = generate bNABs in vivo

44
Q

What are integration sites?

(Position matters: HIV integration site)

A

Determine likelihood of virus being active or silent

45
Q

What is the key differences between cure & remission?

A

Cure
* eradication of all HIV-infected cells
* difficult in HIV

Remission
* long term health in absence of ART
* HIV present at low levels
* Reduce & control

46
Q

What is HIV latency reversal?

A
  • shock & kill
  • using LRA in HIV cells = induced to express HIV RNA & proteins = immune or viral-mediated killing
  • increases transcription= BUT no decline in no. of infected cells
  • pro-apoptotic drugs used
  • Dual activity in TLR agonists or anti-PD1

LRA = Latency Reversing Agent

47
Q

What is the role of the immune checkpoint molecules PD-1 & CTLA-4?

A
  • dampen immune response
  • expressed on exhausted T cells = in treated & untreated HIV
48
Q

What is the role of Anti-PD1?

A

Reverses HIV latency in vivo in PLWH on ART

49
Q

What are the targets and strategies of gene therapy?

A

Attack
* enhance anti-HIV immune responses

Protect
* Engineer uninfected cells to be resistant to HIV

Purge
* directly eliminate virus itself

50
Q

What are the current cure/vaccine for HIV?

A

None BUT multiple strategies are being testing to allow people to safely stop ART and achieve remission

51
Q

What is newly acquired infection?

A

infection diagnosed in patient who has had a negative HIV test in the past 6 months

52
Q

What is newly diagnosed infection?

A

Time of acquiring virus is not clear = not recent negative tests

53
Q
A

BIOM30002: Molecule to Maladay (3 decks)

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