Unit 13 Week 3 Flashcards
Pathogenesis of HIV
1) recognition, adsorption and penetration
HIV-1 binds to the CD4 receptor and its coreceptor CCR5 on t cells using its envelope glycoprotein. Virus is endocytosed
2) Disruption and release of DNA/RNA
HIV RNA and several HIV encoded enzymes are released into the host cell. Uncoating of the virus via protein action.
3) reverse synthesis of RNA
4) synthesis of viral subunits via reverse transcriptase. DNA is produced from viral RNA. This process is very error prone and leads to mutations. Integration of viral DNA with host dna
5) assembly of viruses- new viruses have been formed and a “self-assembly” process is taking place
6) lysis of cell and release of virions- killing the CD4 cells. More are lost to CD8 NK cells killing CD4 in immune response.
HIV results in what kind of immunodeficiency
cell mediated
what is undetectable HIV
viral load of HIV is measured via:
1) PCR 2) branded DNA 3) NASBA test
viral load is undetectable following antiretroviral treatment- cant be detected by standard blood tests
role of HIV in co-infection with TB
- CD4+ and CD8+ T lymphocytes become activated and release IFN-γ, IL-2 and TNFalpha as well as macrophage colony-stimulating factor in response to the intracellular TB pathogen.
- This activates macrophages which then proceed to inhibit M. tuberculosis replication and ultimately kill it.
- There is strong evidence from both animal and human studies demonstrating that Th1-type CD4+ T lymphocytes are essential for protective immunity against M. tuberculosis because of IFN-gamma production.
- The host’s immune response depends on an intact cellular immune system – which is why HIV is a big risk factor as it impairs cell-mediated immunity.
- TB appears when the immune response can’t limit the growth of mycobacteria to the granuloma that forms as part of the disease process.
- HIV infects and kills CD4+ T lymphocytes and the concentration of CD4+ T cells declines as the HIV infection progresses.
- INF-gamma production also falls dramatically because of HIV
Mtb entry into macrophages
Mycobacterium tuberculosis (Mtb) is phagocytosed into macrophages via several receptors on the surface of the macrophage. The receptors involved in this process may influence the likelihood of Mtb survival:
- Complement receptor 3 (CR3) – thought to inhibit macrophage activation.
- FcϒR – leads to pro-inflammatory response and respiratory burst.
- Mannose-binding lectin – studies suggest low levels confer protection from TB.
Mtb replication in macrophages in primary infection
Mtb inhibits maturation of the phagosome and inhibits formation of the phagolysosome by inhibiting Ca2+ signals and recruitment of proteins that mediate phagosome-lysosome fusion. This allows the bacterium to replicate within the vesicle and avoid degradation by lysosomes.
This proliferation of bacteria within the pulmonary alveolar macrophages and air spaces can then result in bacteraemia (bacteria in the blood) and spread to other sites.
Most people at this stage are asymptomatic or have mild flu-like symptoms
innate immune reponse to MTb
PAMPs of Mtb, such as lipoproteins and glycolipids, are recognised by host PRRs including TLRs, C-type lectin receptors (CLRs) and nod-like receptors (NLRs).
These then initiate the innate and adaptive responses to Mtb which attracts inflammatory cells to the area causing a focal area of infection which produces the characteristic tubercles seen histologically.
Th1 response
3 weeks after infection mycobacterial antigens are presented to T cells within lymph nodes.
APCs that have encountered the Mbt produce IL-12 which promotes differentiation from naive to Th1 cells
stimulation of TLR2 by Mbt ligands also promotes production of IL-12 = more Th1 cells. <strong>IL-12 STIMULATES IFN-gamma release</strong>
Th1 cells then produce IFN-ϒ which activates macrophages and enables them to contain the Mtb infection – via several mechanisms:
- IFN-ϒ stimulates maturation of the phagolysosome in infected macrophages which exposes bacteria to an acidic, oxidising environment.
- IFN-ϒ stimulates expression of inducible nitric oxide synthase leading to the production of nitric oxide (NO) – this combines with other oxidants forming reactive nitrogen intermediates to kill the Mtb.
- IFN-ϒ mobilises defensins (antimicrobial peptides) against the bacteria.
- IFN-ϒ stimulates autophagy – process which sequesters then destroys intracellular bacteria (Mtb)
granuloma formation
Macrophages activated by IFN-ϒ can now differentiate into a form that allows them to aggregate (epithelioid histiocytes) and form multinucleated giant cells and granulomas. In most people this stops the infection before significant tissue damage and illness occur. These granulomas may have caseous and necrotic centres. Granulomas eventually calcify which are known as Ghon lesions.
Tubercle bacilli can survive in this granuloma material for years and the balance between the host’s resistance and microbial virulence determine whether the infection becomes resolved without treatment, remains dormant (latent) or becomes active.
Secodnary/ post-primary infection
This is the disease that arises in a previously infected host. It may follow immediately after primary infection but is commonly years later when host resistance is weakened.
once the TB cavity connects with an airway, the individual becomes infectious as the cough sputum now contains bacteria
TST
if you have a latent tb infection you skin will be sensitive and a hard red bump will develeop at the site of infection
general treatment of HIV
Maximize wellbeing with long-term, effective suppressive therapy with chronic condition model, beginning before patient is symptomatic.
Its about maintaining physical and mental health, improving QoL, increasing survival rates, restore + improve immune function, avoid onward transmission and appropriate clinical care as needed.
Involves MDT, ARV medication, regular assessment, psychological support, dietary assessment, regular monitoring weight etc and general health promotio
antiretroviral drugs
these must not be stopped suddenly, adherence is key, can be compromised by introducing other medications
o Nucleoside. Nucleotide analogies – Nucleoside reverse transcriptase inhibits (NRTIs) = inhibit synthesis of DNA by reverse transcription and also act as DNA chain terminators.
o Non-nucleoside analogues – non-nucleoside reverse transcriptase inhibitors (NNRTIs) = interfere with reverse transcriptase by direct binding to enzyme.
o Protease inhibitors – acts competitively on HIV aspartyl protease enzyme, which is involved in production of functional viral proteins and enzymes so viral maturation impaired and immature dysfunctional viral particles produced.
o Integrase inhibitors – selective inhibitor HIV integrase which blocks viral replication by preventing insertion HIV DNA into human DNA genome.
o Co-receptor blockers – Maraviroc antagonist that blocks cellular CCR5 receptor entry by CCR5 tropic strains of HIV.
o Fusion Inhibitors – Enfuvitide – inhibits gp41-mediated fusion of HIV with target cell.
efavirenz
Class: (oral) Non-nucleoside reverse transcriptase inhibitor (NNRTI)- Anti viral
Chemistry: Small molecule, synthetic purine derivative
Pharmacodynamics: Inhibits activity of viral RNA-directed DNA polymerase (ie, reverse transcriptase).
Physiology: Believed inhibition reverse transcriptase interferes with generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes then eliminate HIV particle that previously had been uncoated and left unprotected, during entry into host cells. So reverse transcriptase inhibitors are virustatic and don’t eliminate HIV from body.
Clinical:
Desired – Used as part of Highly active antiretroviral therapy (HAART) for treatment HIV type 1. (CDC recommends as part of 3 drug regiment with another NRTI, Protease inhibitor).
Undesired – Abdominal pain, anxiety, depression, dizziness, drowsiness, fatigue, headache, skn reaction, vomiting, sleep disorders, dyslipideamia…
Emtricitabine
Anti-retroviral drug- nucleoside reverse transcriptase inhibitor
Inhibition of reverse transcriptase prevents transcription of viral RNA into DNA,
This means the virus is unable to incorporate its DNA into host DNA and replicate using host cell machinery
This reduces viral load
Used in combionation with other antiretrovirals
