WEEK 8 - Microbiology, Pathogenesis and Immunology of HIV infection Flashcards
HIV INFO
Inc. what it affects, how it was spread
- Its a retrovirus (produces DNA from RNA)
- works backwards = KEY virulence factor
- 2 types: HIV-1 (more virulent) and HIV-2
- Virus has a high mutation rate
- virus adapts rapidly + becomes mroe virulent
- Primarily infects CD4+ T cells, macrophages and dendritic cells
- HIV spread from primates (animals) to humans
- HIV has been around since ealry 1900s but didnt know much about it till 1980s when there was an ↑ in human cases
- especially amongst young, healthy males who were dying from opportunistic infections
- prompted research where it was discovered - HIV is a global infection, but is predominant in Sub-Saharan Africa
What are the 2 Types of immunodeficiency?
- Primary immunodeficiency
- acquried from birth - Secondary immunodeficiency
- acquired from secondary factors
Both types lead to immune response being affected negatively e.g.
- Lack of B-cell maturation = ↓ antibody function
- Altered T cell and phagocyte function
-
Primary Immunodeficiencies
Are acquried from birth
- Are caused by mutations affecting genes that control the expression + activity of immune responses
- e.g. antibody expression, T-cells and phagocyte function
- includes innate + adaptive immunity
Secondary Immunodeficiencies
Are acquired as a consequence from secondary factors
Secondary factors include:
- Environmental
- Diseases e.g. viral infections (e.g. AIDS)
- Starvation or malnutrition (e.g. Fe deficiency)
- Medical intervention (e.g. x-rays, corticosteroids)
Acquired Immuno-Deficiency Syndrome (AIDS) INFO
Example of a Secondary Immunodeficiency
Virus is airbone + resides in blood
Transmission:
- Sexual contact
- Vertical (from mother to baby)
- Direct contact with HIV infected blood (must have open cuts / wounds)
Typical course of HIV infection
i.e. process of HIV infection in body (timeframes)
- Have contact with HIV-infected individual
- Develop flu-like symptoms in first 2-6 weeks post-exposure AND a rapid ↓ in CD4 T cells (< 500)
- e.g. fever, tired, malaise, joint pain
- drop in CD4 levels as body has no immunity against the infection
- patient will have HIGH VIRAL LOAD
- in this period patient WILL get a POSITVE HIV test RESULT
- After 6 weeks have inital ↑ in CD4 T cells
- T cells last several years = infection is latent in body
- asymptomatic phase (have no symptoms) can last 10-20 years
- gradual ↓ in CD4 (over years)
- have STABLE VIRAL LOAD
- After asymptomatic phase have BIG ↓ in CD4 T cells as viral load ↑
- ↓ 500 = symptomatic phase
- ↓ 200 = AIDS acquired
- CRITICAL VALUE - ↓ 100 = terminal decline
HIV Virus Structure
Key proteins + their function
- Glycoproteins (GPs) - on virus syrface
- GP120 - allows HIV to attach to host cell (adhesion)
- GP41 - facilitates fusion between virus + host (fusion)
- Capsid is composed of p24 protein
- Encapsualted in centre is the single viral RNA strand
- Has NO DNA - Envelope is composed of p17 protein
- p10 protease - facilitates maturation of virus
- p64 (reverse transcriptase) - enzyme
- mediates the reversal translation of RNA to DNA
- expresses viral proteins
- KEY virulent factor (as many human cells do NOT have this enzyme)
- uses this to produce viral DNA - Integrase (enzyme)
- allows viral cDNA to integrate into host cell
Mechanism of HIV infection
i.e. pathogenesis / life cycle
- Virus comes into contact with host CD4 receptors (on T cell surface) and Co-receptor (CXCR4 or CCR5)
- GP120 binds to CD4+ receptor forming a complex causing release of GP41
- co-receptors bind to cytokines
- Release of GP41 causes fusion of host cell + virus
- viral genome (RNA) released into host cell cytoplasm as the viral envelope dissociates
- Virus starts prodcuing RT
- single strand RNA is reversed into viral cDNA (by reverse transcriptase / RT)
- viral cDNA is integrated into host DNA (by integrase enzyme)
= provirus formed
- Activation of CD4+ T cell induces transcription factors (e.g. NFkB)
- NFkB activates transcription of viral genome + produces viral proteins
- NFkB produces pro-inflammatory cytokines
- Viral proteins
- Tat - amplifies transcription (copying DNA into a RNA strand) of viral RNA
- Rev - transports viral RNA to cytoplasm
- GP160 - (GP120 + GP41)
- Polymerase - reverse transcriptase (make DNA from RNA)
- Gag - express proteins which from capsid + envelope (that protects viral genome) - Virus makes more copies of itself
- Virus buds from the cell + is released
- Maturation occurs (protease cleaves pre-protein)
- Mature virus infects other host CD4+ cells
Tropism and Reverse Transcriptase
Tropism relates to what receptor the virus has more affintiy for
- Virus can bind to co-receptor CXCR4 or CCR5 on the T cell
- Some HIV are more virulent depending on what they bind to
Explain HIV immune evasion process
- HIV has a rapid mutation rate (in reverse transcriptase) = helps evade host immune repsonse
- HIV downregulates MHC-1 molecules = ↓ T-cell function
- HIV resides in CD4+ T cells (host) = difficult for immune system to detect + eliminate virus
The immune system of a HIV-infected (immunocompromised) patient
i.e. how HIV affects the immune system
- ↓ CD4+ T cell count over time
- Virus binds to CD4+ receptor and CXCR4 co-receptor = function of T cells is stopped
- virus binding degrades T cells = apoptosis / death = ↓ in no.
- T cells produce cytokines which bring aveolar macrophages to respiratory tract = virus spreads in lung - Functional deficiency in CD4+ and CD8+ T cells and Natural killer (NK) cells
- immune system impaired = susceptible to opportunistic infections - Impaired macrophage and neutrophil function
- macrophages + T cells produce cytokines whcih bring neutrophils to area of infection - May develop cancers due to random insertion of viral genome within cells of host = increases potential of mutation
Opportunisitic Infections and Co-infections
In HIV patients will see infections that wouldn’t cause serious issues in healthy individuals
Opportunisitc Infections Examples:
- TB
- Skin cancer (kaposi’s sarcoma)
- Pneumocystis pneumonia
NOTE:
- These infections are used as diagnsotic factors for HIV / AIDS
- as the infections are only common in people with low CD4 count
Co-Infections
- HIV may occur alongside TB, hepatitis B or C, STIs
- If have HIV and Hepatitis = more likely to die from infection
- these 2 conditions have strong association
Current and emerging Anti-retroviral therapies (ARTs) and the AIM of treatment
4 ARTs
- Fusion Inhibitors / CCR5 inhbitors
- Reverse Transcriptase Inhibitors (RTIs)
- Integrase Inhibitors
- Protease Inhibitors
OTHER:
- Sexual protection e.g. condoms
- Physical protection e.g. gloves, goggles etc. when handling blood borne viruses
- Prevent vertical transmission
AIM:
- Keep CD4+ T cell count as high as possible (>350)
- Once CD4 levels decline can’t get them back
- ↓ viral load to undetectable levels
- Early detection, treatment, and prevention
NOTE:
- Patients are given a combo of drugs to target diff. virulence factors / steps in HIV life cycle
- NOT CURATIVE treatment
Fusion Inhibitors / CCR5 inhbitors
ARTs
- Prevent attachment of virus to host cell
- Prevent interaction between GP and CD4+ receptors and CXCR4 co-receptors on T cells
- Use of small molecules / antibodies to bind to receptor preventing virus from being able to bind
Reverse Transcriptase Inhibitors (RTIs)
ARTs
- Prevent formation of viral cDNA
- prevents conversion of viral RNA into viral cDNA - Inhbit RT = NO viral DNA produced = no viral genome integrated into host cell
- e.g. Nucleosides (chain terminators) / NRTIs: AZT, DDT, etc.
- e.g. Non nucleoside inhibitors / NNRTIs (Nevirapine)
