Anti-Retrovila Agents for HIV - 1st half of lecture

  1. Define a lentivirus.
    Give an example of one.
    • A retrovirus (RNA virus) that produces a chronic infection
    • with slowly progressive symptoms. It
    • does not show true latency in the body but can be non-replicating in some
    • cells. Example: Human Immunodeficiency.
  2. Name the two major families of HIV. Which family shows selectivity of
    nonnucleoside RT inhibitors?
    HIV-1 & HIV-2; HIV-1
  3. Of the HIV-1 subtypes, which group is the most common?
    Group M (Others discussed are Group N, Group O and Group P)
  4. In the HIV structure, each viral particle has _____ copies
    of the genome surrounded by a ________ which is surrounded by a lipid envelope.
    2; nucleocapsid
  5. How is the outer lipid bilayer of the HIV structure
    Obtained from the host cell when budding
  6. The lipid envelope is studded with viral envelope protein or
    _____ that is required for cell binding and uptake into a new host cell.
  7. Name the two proteins gp160 is made of.
    Gp120 & gp41
  8. When HIV gets into the cell it already has _________
    ___________ (2) attached to its RNA.
    Reverse transcriptase
  9. The small RNA genome encodes for a minimal number of
    proteins through several open reading frames.
    Name them and what they do.
    • Gag: encodes a polyprotein that
    • is processed to several viral structural proteins

    • Pol: overlaps w/ the gag ORF and
    • encodes 3 enzyme activities

    • Env: encodes the gp160 protein
    • complex

    Small regulatory proteins
  10. Name the Pol
    derived proteins.
    RNA-dependent DNA polymerase (reverse transcriptase): also possesses RNase activity

    • Protease: required for
    • processing the larger protein into the functional proteins

    • Integrase: required for
    • integration of viral-derived DNA into host cell genome
  11. Name the two actions of regulatory
    proteins in HIV.
    • 1. Enhance
    • virion production 2. Inhibit host cell anti-viral mechanism
  12. List the small genes coding for
    regulatory proteins in the HIV genome.
    • Tat,
    • Rev, Nef(activates T cells, enhances ability of the virus to replicate), Vpr
  13. Viral entry into a cell is mediated
    by _____ binding to a _______ receptor and the co-receptor __________ present
    on lymphocytes or macrophages.
    Gp160; CD; CCR5 chemokine receptor
  14. With advancing disease, there is a
    shift in co-receptor to the ___________ which allows for CD4+ T-cell uptake.
  15. Once the virus binds to a CD4+
    cell, the ______ _______ (2) controls cell membrane fusion.
    Gp41 domain
  16. True/False. Following fusion, the full-length RNA genome
    enters the nucleus and is replicated into a RNA-DNA duplex.
    False; enters the cytosol
  17. What is the duplexed RNA degraded
    by and what happens once it is degraded?
    • RNaseH; the 2nd DNA
    • strand is copied
  18. About how many transcription errors
    are made per RNA genome and what is this resulting from?
    • 3; the error-prone nature of the
    • HIV RT (this allows for evolution of the organism; too many mutations leads to
    • viral death)
  19. After the DNA enters the nucleus,
    what is it randomly integrated into the host DNA by?
  20. Which of the following proteins is
    not encoded by the HIV pol gene? Regulator of virion, integrase, protease,
    reverse transcriptase
    Regulator of virion
  21. True/False The integrated DNA is
    always immediately used to start virion production.
    False; it can remain quiescent
  22. Upon activation, viral proteins
    & RNA are synthesized by the host ________/___________ apparatus and new
    RNA genomes enclosed in ________________ are produced.
    • Transcriptional/translational;
    • nucleocapsid
  23. Which proteins concentrate in the
    host cell membrane lipid rafts where nucleocapsids are sent and are engulfed?
  24. The initially infected CD4+ cells
    generate a strong burst of new HIV particles within ___________ .
    2-4 weeks
  25. About how many cells are initially
    infected upon sexual transfer of a few viral particles and what happens to CD4+
    • About 109 cell infected;
    • levels of CD4+ T-cells transiently fall
  26. During the initial infection, the
    viral load (plasma HIV RNA level) falls to a quasi-steady state which reflects
    what? (2 things)
    • Immune control & HIV
    • replication and infection
  27. How often do the infected T-cells
    turn over during the initial infection?
    Every 2.2 days
  28. With time, the CD4+ T-cell
    population becomes exhausted and blood levels start to _________ while viral load
    Fall; increases
  29. At what level (cells/mm3)
    will significant opportunistic infections will occur?
    200 cells/mm3
  30. What is the time frame between
    initial infection to late stage?
    8 to 10 years
  31. What are “long-term
    • A subpopulation that can be
    • infected for 10-20 years without having clinically significant
    • immunosuppression (1 in 500 infected people, have mutations in co-receptors)
  32. Name some HIV Drug Targets.
    • Initial entry phase, replication of
    • viral genome, processing of proteins, release of mature particles.
  33. Name the 1st successful
    anti-HIV medication.
    Zidovudine (AZT)
  34. Name the classes of antiretroviral
    agents for HIV.
    • Nucleoside reverse transcriptase
    • inhibitors, Nonnucleoside RT inhibitors, HIV protease inhibitors and fusion inhibitors
  35. _________________ ___________
    _________ _________ (4) rely on the host cell to phosphorylate the analog to
    generally the triphosphate state.
    • Nucleoside/tide Reverse
    • Transcriptase Inhibitors
  36. Nucleoside/tide RT Inhibitors block
    viral RNAàDNA
    synthesis by: (2 ways)
    • 1. Competitive
    • inhibition of nucleotides into growing DNA chain. 2. If incorporated stop chain
    • elongation due to lack of 3’-OH group.
  37. All nucleoside/tide RT inhibitors
    require triphosphorylation, except for _______ which is a ___________.
    Tenofovir; nucleotide
  38. True/False. All nucleoside/tide RT inhibitors work
    against both HIV-1 and HIV-2 viruses.
  39. Nucleoside/tide RT inhibitors have
    _________ __________ (2) for viral DNA polymerase versus eukaryotic DNA
    Preferential selectivity
  40. Why is there some mitochondrial
    toxicity with nucleoside/tide RT inhibitors?
    • They have some activity against
    • human DNA polymerase γ
  41. Name the major nucleoside/tide
    analog drugs according to their purine/pyrimidine.
    Thymidine: Zidovudine (ZDV (AZT)), Stavudine (d4T)

    Guanosine: Abacavir (ABC)

    Adenosine: Didanosine (ddI), Tanofovir
  42. Name the three kinases that
    typically do the phosphorylation events.
    • Thymidylate kinase, CMP kinase and
    • AMP kinase
  43. For a high level of resistance to
    occur with nucleoside/tide RT inhibitors, at least _____ __ ____ _______ ______
    are needed.
    3 to 4 codon variations.
  44. As monotherapy agents,
    nucleoside/tide RT inhibitors will only reduce the viral load by ____ __ __
    percent; however, _______ can lower viral load by 99%.
    30 to 90; abacavir
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Anti-Retrovila Agents for HIV - 1st half of lecture
Anti-Retroviral Agents for HIV