HIV Flashcards
1
Q
What is the number of people living with HIV globally?
A
38.4 Million
* 25.6 Million - Africa
2
Q
What are the Risk Factors for HIV infections globally?
A
- Remaining Population
- Clients of Sex Workers & Sex Partners of Key Population
- Gay men & men-men sex
- Sex Workers
- People who Inject Drugs
- Transgender Women
3
Q
Which groups are more commonly represented with new HIV infections?
A
Men who have sex with men (MSM)
Heterosexual Contact
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
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
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
7
Q
Describe the life cycle of HIV
A
- CD4 - gp120 binding
- CoR binding
- Fusion
- Reverse transcription of viral genome into DNA
- Integration of proviral DNA into host genome
- Transcription of DNA into viral RNA
- Translation
- Assembly
- Budding
- Maturation into new HIV virion
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
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
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
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
12
Q
What is APOBEC3G? What HIV protein inhibits it?
A
- Host protein that edits RNA
- vif Inhibits it
13
Q
What is TRIM 5a?
A
- Host protein that blocks uncoating of retroviruses
- capsid = Human TRIM 5a = inactive against HIV
14
Q
What is Tetherin? What HIV protein inhibits it?
A
- Host protein that blocks release of virus
- vpu = inhibits tetherin to allow exit
15
Q
What is LEDGF?
A
- Host protein that tethers HIV to host chromatin
- Integrase HIV protein = facilitate integration
tethers= ties
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
17
Q
Describe the early events in HIV transmission
A
-
Virion introduced in vaginal epithelium (hours)
– microtears = allows virion to cross epithelium -
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 -
Dissemination to lymph nodes (days-weeks)
– infection of many CD4+ T cells -
Local proliferation (1-2 weeks)
– peak plasma virus levels
– CD4+ memory cell loss in MALT -
Partial Immune Control (weeks-months-years)
– Neutralising Abs
– Activation of CTLs
18
Q
How does HIV evade the immune system?
A
- Sequence variation
- Altered antigen presentation
- Loss of effector cells
- Latency
- Privileged sites of replication
19
Q
Explain the sequence variation in HIV evasion
A
- lack of recognition
- both CTL & antibody
- antagonism
20
Q
Explain the loss of effector cells in HIV evasion
A
- clonal exhastion
- Loss of CD4+ T cell help
- Replicative senescence
21
Q
List what cells latency impact in HIV evasion
A
- in resting T-cells, Macrophages & Astrocytes
22
Q
What is the clinical hallmark of HIV infection?
A
CD4+ T cell depletion
23
Q
Describe CD4+ T cell homeostasis
A
- Production in bone marrow
- Development in thymus
- Proliferation of naïve cells
- 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
Why is CD4+ T cell depletion variable?
**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
Describe the effect of HLA on HIV infection
Certain HLA alleles are associated with **good** progression, whilst others are associated with **poor** progression
27
What happens to CD8+ T cells in HIV infections?
* ↑ Abnormally **high** during **acute phase**
* ↓ **Decline** at **later** stages = **exhausted**
28
What happens to NK cells in HIV infections?
| NK = Natural Killer
* **Decrease** numbers
* **impaired** function
29
What happens to Monocytes & Macrophages in HIV infection?
* **defects** in chemotaxis
* **inability** to produce T-cell proliferation
* **defects** in Fc receptor function
30
What happens to B-cells in HIV infection?
Production of **IgG** and **IgA** but **↓ antibody responses**
31
How does HIV cause chronic immune activation
* 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
What does mucosal depletion of CD4 T-cells cause in HIV?
* **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
What are potential targets for anti-viral drugs for HIV?
* **Fusion/Entry** inhibitors
* **Reverse Transcriptase** Inhibitors
* **Integrase** Inhibitors
* **Protease** Inhibitors
34
What are the current limitations to ART?
| ART: AntiRetroviral Therapy
* **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
What are the combination HIV prevention?
* Blood Supply screening
* condoms
* education/behaviour modification
* clean syringes
* treatment/prevention of drug/alcohol abuse
* STI treatment
36
What is Pre-Exposure Prophylaxis (PREP)?
* 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
What are the main concerns of PREP?
| PREP: Pre-Exposure Prophylaxis
* Adherance
* effects on condom use
* STIs
* cost
38
What procedure reduces the risk of HIV acquisition by 70%?
| WHY?
**Circumcision**
* many DCs in epithelium under foreskin that captures virus = infection
* remove = decrease infection
39
What are the **vaccine approaches** for HIV?
**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
What are the **prime-boost** vaccination approaches?
**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
What are the **most promising** HIV vaccine approaches?
**Broadly Neutralising Antibodies**
**CMV Vectors**
* persistent antigen presentation
**mRNA Vaccines**
* immunogen can be changed easily
42
What are the potential role of **Broadly Neutralising Antibodies** (bNABs) in HIV treatment?
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
What are the future direction and goals for bNABs?
| bNABs: Broadly Neutralising Antibodies
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
What are integration sites?
| (Position matters: HIV integration site)
Determine likelihood of virus being active or silent
45
What is the key differences between **cure & remission**?
**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
What is HIV latency reversal?
* **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
What is the role of the immune checkpoint molecules PD-1 & CTLA-4?
* dampen immune response
* expressed on exhausted T cells = in treated & untreated HIV
48
What is the role of Anti-PD1?
**Reverses HIV latency** in vivo in PLWH on ART
49
What are the targets and strategies of gene therapy?
**Attack**
* enhance **anti-HIV immune responses**
**Protect**
* Engineer uninfected cells to be **resistant to HIV**
**Purge**
* directly **eliminate** virus itself
50
What are the current cure/vaccine for HIV?
None BUT multiple strategies are being testing to allow people to safely stop ART and achieve remission
51
What is newly **acquired** infection?
infection diagnosed in patient who has had a negative HIV test in the past 6 months
52
What is newly **diagnosed** infection?
Time of acquiring virus is not clear = not recent negative tests
53
