CHAPTER 3 TUBERCULOSIS AND HIV/AIDS Flashcards
Describe the life cycle of HIV describing the key proteins implicated (important for pharmacological understanding)
Fusion:
Virus entry occurs when the HIV gp120/gp41 complex binds CD4 receptor and co-receptor, CCR5. Then gp41 undergoes several conformational changes resulting in fusion.
Reverse transcriptase and Integrase:
Reverse transcriptase transcribes viral RNA into viral DNA (circular complementary DNA) which is then integrated into the nuclear genome by integrase.
Protease:
Proteases are involved in gag and gag-pol polyproteins during virion maturation. The activity of this enzyme is essential for virus infectivity, rendering the protein a major therapeutic target for AIDS treatment.
What is HIV, what cells does it effect.
Human immunodeficiency virus is a retrovirus that contains two copies of s(+) RNA genome. HIV destroys CD4+ T cells which is responsible cytokine release to activate B cells.
What is the difference between HIV and AIDs.
Acquired immune deficiency syndrome (AIDs) is a medical condition where the immune system is too weak to fight infection whereas HIV is a virus which attacks the immune system in humans.
How is HIV transmitted.
Horizontal transmission: Blood, semen, mucosal site: vaginal+colorectal area.
Vertical transmission: Mother to child.
What is the % of SA population live with
19% of the adult population (15-49 years).
What type of HIV is concentrated in West Africa.
HIV-2- less infectious and progresses slower than HIV-1.
In the acute phase of HIV infection what are the symptoms, viral load, CD4+.
The patient may present with fever-like symptoms, viral load is high (viremic) and the CD4+ T cell count is low.
What is the CD4+ T cell number like in the acute phase HIV infection and what is the clinical implications (give example).
CD4+ T cells number <350 cells μl, so the risk for several infectious complications arises. E,g, tuberculosis.
What are the characteristic of chronic stage of HIV infection (clinical latency): viral load, symptoms?
Patient tend to be asymptomatic.
HIV continues to multiply in the body but at very low levels. People with chronic HIV infection may not have any HIV-related symptoms.
What are the characteristic of AIDs: viral load, cd4+ T cell count, infection likelihood.
Patient has high viral load with CD4+ count of less than 200 cells/mm3 and can contract opportunistic infections readily.
Without Antiretroviral therapy (ART) what is the prognosis of patient who is in chronic stage of HIV infection compared with patient on ART.
HIV infection usually advances to AIDs in 10 years or longer. Whereas ART may delay progression for years and prevent transmission by reducing the viral load.
By understanding the …(a)… of HIV-1 proteins such as …(c)…. Membrane and …(d).. binding proteins can be elucidated and targeted.
(a) genomic map
(b) transmembrane proteins
(c) nucleic acid binding proteins.
Looking at the genomic map of HIV-1 what are the two key extracellular and transmembrane protein that evade the innate immune evasion. (120- x=n 80-1).
a. How does this protein the evade the innate immune system.
b. How could you target this.
a. Extracellular protein gp 120 and transmembrane protein gp 41 are non-covalently complex that form a trimer on the virus surface. As gp41engages with HIV’s receptor, CD4, and co-receptor, e.g. CCR5, gp41 undergoes several conformational changes resulting in fusion between the viral and cellular membranes.
gp-41 activates the compliment pathway system and enhances the viral entry and spread through compliment receptor CR3. While gp120 induces production of inflammatory cytokines and inhibits cytolytic activity of NK cells.
b. Targeting gp41 via fusion inhibitors it can lead to reduced infiltration of HIV virus but also bystander apoptosis. e.g. Enfuvirtide.
What is thought to be the major cause of HIV progressing to AIDS.
By-stander apoptosis which causes major loss in CD4+ T cells leading to immunodeficiency (AIDs).
Mechanism of Enfuvirtide.
Binds to the first heptad-repeat (HR1) in gp41 subunit of viral envelope glycoprotein preventing conformational changes required for the fusion of viral and cellular membrane.
What is the treatment strategy for treating HIV and why.
Antiretroviral therapy (ART): suppress HIV viral load to undetectable levels in the blood, stop transmission, improve patient morbidity and mortality and improve immune function.
Why is combination therapy used in HIV.
To prevent HIV viral resistance reducing the number of drugs available to the patient and reducing patient prognosis. It also allows for comprehensive viral suppression.
Describe nucleoside reverse transcriptase inhibitors MOA and give an example of first-in-class.
Nucleoside reverse transcriptase inhibitors (NRTIs) act by blocking reverse transcriptase. These drugs are analogues of natural nucleosides and nucleotides, and are preferentially incorporated into HIV DNA, leading to termination of DNA synthesis.
Example: Zidovudine which is thymidine analogue.
MAO of Lamivudine.
Nucleoside reverse transcriptase inhibitor, which blocks reverse transcriptase directly by binding to enzyme polymerase site and interfering with its function.
MAO of dolutegravir.
Inhibits HIV integrase responsible for integration of of viral DNA into the DNA of the infected cell.
Which one is a reverse transcriptase inhibitor
(a) Ritonavir
(b) Lamivudine
(c)Dolutegravir
(d) Atazanavir
(e) Abacavir
B) Lamivudine.
Which one is a integrase inhibitor.
(a) Ritonavir
(b) Lamivudine
(c)Dolutegravir
(d) Atazanavir
(e) Abacavir
(c) Dolutegravir used in high genetic barrier regimes.
Give an example of macromolecule/drug in the HIV pipeline (UB40)
UB-421 (CD4 receptor) monoclonal antibody currently in the drug pipeline.
What is the drawback of monoclonal antibody for HIV being distributed to Africa.
Temperature, storage concerns: Antibodies are sensitive to mechanical, temperature and pH changes causing aggregation and inactive antibody. High temperature in Africa.
Parenteral route: how will it be administered in sterile environment?
Give a list of the classes of antiretroviral drugs that are currently using to treat HIV patient. Each one give an example.
Give an example of HIV combination therapy.
DOVATO
What is DOVATO a combination of.
Lamivudine/Dolutegravir.
What is another pharmacological way to combat HIV, excluding ART.
HIV vaccines.
What are the various approaches to the development on a HIV vaccine with examples.
Whole inactivated
Recombinant viral
When looking at the HIV drug pipeline what agents are currently underdevelopment ( in terms of immune response they are trying to activate).
Aim is to find vaccines that elicit immune response that would protect from HIV.
Neutralising antibody response are currently the HV vaccines in development in pre-clinical and phase I and II trials.
What pharmacological preventative measure can be put in place to inhibit HIV
What is the name of the trial where HIV prophylactic vaccine regime is being trialed and what is the trial design and location of trial.
PrEPVacc partnership is in phase 2, adaptive trial design, in Uganda, SA, Tanzania and Mozambique.
What is a non- pharmacological way to combat HIV.
School based education is an effective strategy for reducing HIV-related risk —> reducing risky sexual behaviours.
Raising awareness on sexual health screening and destigmatizing HIV.
Laws to reprimand individuals knowingly transmitting HIV to their sexual partners.
Education on testing when engaging with a new sexual partner.
How is TB transmitted.
Mycobacterium tuberculosis is transmitted by droplets nuclei expelled from respiratory tract of infected individual through coughing, sneezing laughing, singing.
2.25 - B
2.26 - A
Memorise table.
What is the profile we want for new TB drugs
Give the one treatment regime that has been employed to improve the treatment outcome for patient with MDR-TB (Please call Lizo Back)
Pretomanid, Linezolid, Bendaquiline is used as combination treatment for MDR-TB.
How has the distribution of new combination therapy such as (BPaL) been increased (include companies names).
Give a first in class Anti-TB agent in clinical trails: a. MAO and b. Phase in the trials.
a. Telacebec is novel first-in-class agent targets Mycobacterium tuberculosis cellular energy production through inhibition of the mycobacterial cytochrome bc1 complex.
b. Phase 2 trials.
Describe the life cycle of HIV describing the key proteins implicated (important for pharmacological understanding)
Fusion:
Virus entry occurs when the HIV gp120/gp41 complex binds CD4 receptor and co-receptor, CCR5. Then gp41 undergoes several conformational changes resulting in fusion.
Reverse transcriptase and Integrase:
Reverse transcriptase transcribes viral RNA into viral DNA (circular complementary DNA) which is then integrated into the nuclear genome by integrase.
Protease:
Proteases are involved in gag and gag-pol polyproteins during virion maturation. The activity of this enzyme is essential for virus infectivity, rendering the protein a major therapeutic target for AIDS treatment.
Looking at the genomic map of HIV-1 what are the two key extracellular and transmembrane protein that evade the innate immune evasion. (120- x=n 80-1).
a. How does this protein the evade the innate immune system.
b. How could you target this.
a. Extracellular protein gp 120 and transmembrane protein gp 41 are non-covalently complex that form a trimer on the virus surface. As gp120 engages with HIV’s receptor, CD4, and co-receptor, e.g. CCR5, gp41 undergoes several conformational changes resulting in fusion between the viral and cellular membranes.
gp-41 activates the compliment pathway system and enhances the viral entry and spread through compliment receptor CR3. While gp120 induces production of inflammatory cytokines and inhibits cytolytic activity of NK cells.
b. Targeting gp41 via fusion inhibitors it can lead to reduced infiltration of HIV virus but also bystander apoptosis. e.g. Enfuvirtide.
Give an example of macromolecule/drug in the HIV pipeline (UB40) +MAO Give an example of macromolecule/drug in the HIV pipeline (UB40) +MAO
UB-421 (CD4 receptor) monoclonal antibody currently in the drug pipeline. UB-421, an antibody that blocks the virus-binding site on human CD4+ T cells.
Give a list of the classes of antiretroviral drugs that are currently using to treat HIV patient. Each one give an example
What pharmacological preventative measure can be put in place to inhibit HIV
