Case 5 Flashcards
What are the different antiretrovirals? what are the keys steps in viral replication that they target?
- Fusion/entry inhibitors
- Co-receptor blockers e.g. Maraviroc – blocks entry at the CC05
- Reverse transcriptase inhibitors (nucleoside and non-nucleoside)
- Integrase inhibitors
- Protease inhibitors
What is Pneumocystis jiveroci (formely P.carinii)? what does it most commonly cause? who do you normally see it in? at what stage is it seen? what does it do? what is pneumonia? what are the symptoms? what is the clinical examination? what is the diagnosis? and what is the treatment?
- Yeast-like fungus
- This organism most commonly causes pneumonia (Pneumocystis pneumonia (PCP))
- It is seen among immunocompromised hosts
- Seen when CD4 count falls below 200
- The organism damages alveolar epithelium, which impedes gas exchange and reduce lung compliance
- Pneumonia: inflammation of the lungs caused by infection, in which the alveoli fill with puss and may become solid
- Symptoms: shortness of breath, non-productive cough, fever and discomfort
- Clinical examination: reveals tachypnea (increased respiratory rate), tachycardia (increased heart rate), cyanosis (blue/purple appearance of skin due to lack of oxygen), signs of hypoxia (decreased oxygen levels) and crackling sounds on inhalation
- Chest X-ray: bilateral diffuse interstitial shadowing (alveolar shadowing)
- Diagnosis: PCR amplification of the fungal DNA from blood sample. Silver staining (gram staining). CD4 cell count.
- Treatment: co-trimoxazole (antibiotic)
What is Candida? what does it cause?
- Candida is yeast
- Causes fungal infections
- HIV: mucosal infections as a result of candida – oral candida is one of the most common conditions (creamy plaques in the mouth and pharynx)
What are lower respiratory tract infections? what are the most common ones?
- Lower respiratory tract infections – affect the airways and lungs
- Common lower RTIs include:
- flu
- bronchitis
- pneumonia
- bronchiolitis
- tuberculosis – persistent bacterial infection of the lungs
What are the main symtoms of lower RTI?
- The main symptoms of lower RTI is a cough – usually quite severe and you may bring up phlegm and mucus
- Other possible symptoms are a tight feeling in your chest, an increased rate of breating, breathlessness and wheezing
Describe how the infection of the pulmonary system affected the person in the case.
Bilateral (affecting both sides) diffuse (spread over a large area) interstitial (affecting the interstitium – the tissue and space around the air sac of the lungs) shadowing (a term used to describe the image on an X-ray – it usually means inflammation – the inflammation could occur due to infections or some inhaled irritant)
What is fever? what is triggered by? and what does it do?
- High temperature triggered by resetting hypothalamic thermostat
- Trigger by toxins from microbes/cytokines from immune system (e.g. IL-1beta)
- Inhibits bacterial growth
- Speeds up some reactions aiding repair
What are the 4 classic symptoms of inflammation?
- Redness
- Swelling
- Pain
- Heat
When do these 4 symptoms become fever?
These are local symptoms but when the inflammation becomes systemic, the symptoms are then called fever
What controls temperature? how does inflammation cause a change in temperature? and why does it do this?
- Temperature normally controlled by hypothalamus
- What happens in inflammation, is that the microbes causing that inflammation can release toxins or the immune system, seeking to clear up the infection, produces cytokines (particularly LPS and IL-1) – there are receptors on the hypothalamus for these molecules, so when they reach the brain and bind, they reset that thermostat several degrees higher and then you have fever – the idea is that the infection wants to grow at 37 degrees and so by increasing the temperature you are making the environment less habitable – increase in temperature also speeds up a number of immune functions, e.g. phagocytosis, antibody production, production of complements and other proteins – also with fever you tend to rest and that helps you to heel
What is HIV?
A lentivirus (subgroup of retrovirus) that damages CD4 (T) cells of the immune system: reduces the ability to fight off infections and cancers
What are the different types of HIV?
- HIV 1 and HIV 2 – within which different subtypes
- HIV-1: origin – chimpanzee found to be positive for HIV-1 antibodies against SIV retrovirus – hunters ate chimpanzee meat affected by SIV – the SIV mutated to affect humans – HIV
- HIV-2: origin – sooty mangabey monkeys – this is rarely found outside of Africa
What is AIDS?
A later stage of HIV infection where someone develops potentially fatal infections and cancers
What are the different stages of HIV infection?
Acute (acute retroviral syndrome, ARS) Latent (or ‘asymptomatic’ or ‘chronic’) AIDS - Infectious throughout all stages - Use CD4 cell counts or/and WHO clinical staging protocols
Describe the HIV virus.
- RNA virus
- GP120 envelope protein on virus
- P24 capsule proteins – tested for in 4th generation HIV tests
What are the key steps in HIV replication?
- Viral entry – binds to CD4 receptor (two types CCR5, CXCR4) – Th cells, monocytes, macrophages, microglial cells
- Reverse transcription – RT transcribes RNA into DNA
- Integration – viral DNA integrates into host DNA
- Viral assembly – genome ‘packaged’ by proteases
- ‘budding’ of mature virus – able to infect other cells
What is the pathology of HIV - what does in mainly target?
- Innate immune response – non-specific – macrophages, neutrophils, NK cells
- Adaptive immunity – antigen specific – mainly targeted
- cellular – cell mediated
- humoral – antibody mediated
- coordinated by T cells
- dependant on B cells and Th cells
What is the natural history of HIV infection? (viral load and CD4 count)
- Primary infection – CD4 count dips down quite dramatically
- Then it increases back to near normal levels
- Then it reduces gradually, if not treated
- Within 10 years can do very low levels
- Under 200 cells/mm3 = AIDS
- Primary infection – viral load increases dramatically
- Then dips significantly – may be undetectable
- Then over many years slowly increases
What does the risk of opportunistic infection depend on?
CD4 count
- Once CD4 count falls below 200 that’s when you become at risk of a number of different opportunistic infections – e.g. pneumocystic pneumonia
What is the normal range of CD4 count in someone with HIV?
Normal range for CD4 count in someone with HIV = 500 to >1000 cells/mm3
At what stage in the history of HIV and TB occur?
TB can occur at any stage of the history of HIV, even about 200 CD4 count
What are the methods of HIV transmission?
- Sexual: increased by STI’s, esp. genital ulcers – immune barrier (the mucosa) is broken down so increases chance of virus crossing the mucosa
- Parenteral: (by some route other than through the alimentary canal, such as subcutaneous, intramuscular, intrasternal or intravenous injection) e.g. PWID (people who inject drugs), blood transfusion (although screen in the UK)
- Mother to baby, breast feeding (to reduce risk of transmission can give mother antiretroviral therapy, can give baby post-exposure prophylaxis with antiretroviral therapy for the first 28 days of life, bottle-feeding only – all of these have greatly reduced transmission and now in the UK only 1% of babies born to HIV-positive women are positive themselves)
Describe in detail the replication cycle of HIV.
- HIV infects CD4 cells (mainly), monocytes and dendritic cells
- All of these cells express the CD4 receptor
- The gp120 protein binds to CD4 receptor
- M-tropic strains of HIV: the gp41 protein binds to co-receptor (CCR-5) on the cell
- T-tropic stains (only affect CD4 T cells) : The gp41 protein binds to co-receptor (CXCR-4) on the CD4 cell
- Neuclocapsid enters cell and is removed
- Reverse transcriptase copies viral RNA into double-stranded DNA
- Viral DNA integrates into hot DNA, where it lies dormant as a provirus – this is the virus in its latent stage
- Upon activation of the affected cell, viral DNA is transcribed into viral RNA (MRNA)
- Viral RNA is translated into viral proteins
- The viral proteins and viral RNA assemble to form new viral particles (using the host cell’s membrane as its lipid membrane)
- These particles can now infect other cells
What are the three stages in the life cycle of HIV?
- Infection
- Latent stage
- Development of AIDS
Describe what happens during the infection stage.
- Virus infects cells, resulting in high levels of virus in the blood (viraemia)
- Asymptomatic but some people may experience acute retroviral syndrome (ARS) – ‘the worst flu ever’ – this is also called primary infection
- Following infection, the body responds with an immune response:
1. Infected cells, via the endogenous pathway, present viral proteins with MHC-I on their surface – CD8 cells kill these infected cells
2. Antibodies for gp120 (envelope glycoprotein) envelope and p24 (HIV antigen) are produced (complement or opsonisation) – seroconversion
3. Immune response eliminates 99% of the virus - CD4 cell count begins to decrease
- The detection of antibodies to HIV is used to test for infection
- Following the immune response, the virus enters the latent stage
- The immune system does not clear the virus completely because HIV has a number of features that enable it to survive:
1. It has a very high replication rate
2. It can hide as a provirus where it is not detectable by the immune system
3. It has a very high mutation rate
Describe the latency stage of HIV,
- Generally asymptomatic (few patients have swollen lymph nodes)
- Viral DNA lies dormant as provirus
- CD4 cell count decreases slowly
- Individuals with a lower level of viraemia in latency develop slower to AIDS
- The average time from infection to the development of AIDS is about 10 years – the latent stage counts for most of this
Describe the development of AIDS stage.
- Emergence of symptoms that indicate progression to AIDS without treatment
- Symptoms: weight loss, night sweats, fever, diarrhoea and swollen lymph nodes
- Symptoms arise as a result of rapid decrease in CD4 cell count and opportunistic infections that attack a damaged immune system
What is AIDS defined clinically by?
- The appearance of major opportunistic infections
2. Or by a drop in the CD4 T cell count to below 200
What is death mainly caused by in AIDS?
Death is mainly caused by Pneumonia (caused by Pneumocystic jivoreci)
How has the treatment of HIV changed? what is still an issue?
- New drugs better tolerated and extremely effective – less awful side effects than previous
- ‘one pill once a day’ – even though may be a combination of drugs in there
- Look at individual and their lifestyle and come up with a regime that suits them and won’t interact with medication that they’re already on
- Some drug interactions (CYP 450) – can be quite serious (if someone on a protease inhibitor)
- Management of HIV now largely out-patient based
How is prevention used to treat HIV?
- Virally suppressed PHIV less likely to transmit to others: wider public health significance
- Pre-exposure prophylaxis (PrEP) – currently going through stages to become part of standard care
- Post-exposure prophylaxis (PEP) – e.g. if you get a needle-stick injury
How is HIV monitored?
- Immunological monitoring: CD4 T cell count
- Virological monitoring: viral load (HIV RNA levels and viraemia)
- Genotype determination: viral genotype analysis is used to identify strain of HIV
What are the different treatments for HIV? and how do they work?
HAART
1. Reverse transcriptase inhibitors: NRTI and NNRTI
2. Protease inhibitors
3. Integrase inhibitors
Reverse transcriptase inhibitors
1. Nucleoside reverse transcriptase inhibitors (NRTIs): need intracellular phosphorylation to be activated
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) : do not need intracellular activation - instead they interfere with reverse transcriptase by direct binding to the enzyme – they are ineffective against HIV-2
Protease inhibitors (PIs)
- Protease: involved in the production of functional viral proteins and enzymes
- Protease inhibitors cause viral maturation to be impaired and immature dysfunctional viral particles are produced
Integrase inhibitors
- Act as competitive inhibitors to integrase by binding to the enzyme, preventing the substrate form binding to it
What are the three ways antibodies protect from infection?
- Block binding of pathogens and toxins (immune complexes form – ingestion of these by phagocytes)
- Facilitate phagocytosis by e.g. macrophages/neutrophils
- Kill bacteria by activating complement (through the classical complement pathway)
Describe how they block binding of pathogens and toxins. Give examples of which antibodies do this and where.
- Most toxins act by binding to a receptor and then getting inside a cell
- Need an antibody that get can into tissues, and has high affinity so can block binding of toxin
- IgG does this in tissues – forms immune complexes with the toxins that can be phagocytosed by macrophages or neutrophils
- In gut and intestine (to block infection by bacteria), IgA is the main antibody used – more important for whole bacteria than individual toxins
Describe how they facilitate phagocytosis.
- Phagocytes not particularly efficient at recognising the bacteria (particularly encapsulated bacteria – can be both gram+ and gram- - they have extra polysaccharide capsule that coats the cell wall)
- Opsonisation – antibody can coat the bacteria and then the macrophages and neutrophils have Fc receptors (receptors for the constant region of the antibody) – so they can coat the opsonised bacteria and ingest it much more efficiency than if the antibody wasn’t opsonised
- Bacteria coated in antibody and engulfed
(opsonisation = the process by which bacteria and other cells are altered in such a manner that they are more readily and more efficiently engulfed by phagocytes)
Describe how they kill bacteria by activating complement.
(particularly importnat for extracellular bacteria)
- Opsonisation of bacteria
- The antibodies activate complement
- Complement produces this membrane attack complex that lysis the bacteria
- Then the whole complex can be ingested by phagocytes
What is the contribution of antibodies to host resistance?
- Neutralisation of toxins
- Extracellular lysis of bacteria (with complement)
- Facilitates internalisation for intracellular killing of phagocytes (neutrophils and macrophages)
- Expulsion of parasites via inflammatory reactions (IgE)
- Passive immunity by transplacental transfer (IgG)
What is the recommendation for HIV testing?
- Recommendation: universal HIV testing in high prevalence areas (= >2:1000)
- Manchester 5.8 per 1000
- Everyone should be offered a HIV test
What are the tissues of the immune system? and what type of lymphoid tissue are they (primary or secondary)?
- Bone marrow – primary lymphoid tissue (immune cells produced & educated)
- Thymus – primary lymphoid tissue (immune cells educated)
- Spleen – secondary lymphoid tissue (highly organised immune tissues)
- Lymph nodes – secondary lymphoid tissue (everywhere where you have vascularised tissue – highly organised immune tissue)
- Lymphatics
- Blood
