Micro Test 4: Anti-viral Therapy

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BrookeNH10
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197671
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Micro Test 4: Anti-viral Therapy
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2013-02-03 16:49:54
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Micro Test Anti viral therapy
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Micro Test 4 Anti-viral therapy
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  1. Binds to gp41 gene, inhibits cell fusion
    Fuzeon
  2. Binds to CCR5 and prevents cell fusion
    Selzentry
  3. Anti-viral drugs:  1st line drugs
    • Nucleoside and Nucleotide RT Inhibitors (NRTIs)
    • Non-nucleoside RT Inhibitors (NNRTIs)
    • Protease Inhibitors (PIs)
  4. Anti-HIV drugs:  Back-ups
    • Fusion inhibitor:  blocks gp41-mediate fusion
    • CCR5 antagonist
    • Integrase inhibitor
  5. If you become resistant to one drug in an HIV class, you may become resistant to all of that class because they all work in the same manner
  6. Combination of anti-HIV drugs simplify dosing:  Combivir
    Lamivudine (NA) + Zidovudine (NA)
  7. Combinatons of anti-HIV drugs simplify dosing:  Atripla
    Atripla= Emtriva (NA) + Viread (NA) + Sustiva (NN)
  8. Structure of Nucleoside and Non-nucleoside analogues
    R1-CO-NH-R2 peptide bond is present
  9. Act as DNA chain terminators
    Cannot eliminate a latent HIV-1 infxn, but can control an ongoing infxn
    Toxic!!!  Adversely affect phosphorylation of normal nucleoside and inhibit mitochondrial DNA polymerase gamma
    Nucleoside RT Inhibitors
  10. NRTI: Can accidentally inhibit
    Mitochondrial DNA Polymerase gamma
  11. Which has a higher affinity for RT, NRTI or host DNA Pol?
    NRTI

    NRTIs are active only on the triphosphate
  12. Non-competitive inhibitors of RT that bind elsewhere than at the active site and block RT activity
    Non-nucleoside RT Inhibitors

    (Work synergistically with NRTIs)
  13. Bind the active site of the viral protease and inhibit its activity.
    Must be used along with NRTIs and/or NNRTIs
    Protease Inhibitors

    (Can't be used by themselves)
  14. Approved for HIV+ pts who have tried other HIV-1 drugs but who can't control their viral RNA loads.  Used in combination with other drugs
    Fusion Inhibitors (Fuzeon)
  15. Must be injected 2x daily
    Fuzeon
  16. Initiate HAART when pt. has
    • AIDs-defining illness
    • CD4 count <350 cells/mm
  17. HAART
    Highly Active Anti-Retrovirus Therapy

    • 2 NRTIs + 1 protease inhibitor OR
    • 2 NRTIs + 1 NNRTI
  18. Ppl who get HAART therapy
    • Pregnant, HIV+ women
    • Persons with HIV-associated nephropathy
    • Persons co-infected with hepatitis B virus (HBV) when HBV tx is indicated
  19. Tx goals:
    Pts. should show a 1 log decrease in HIV RNA in 8 wks and no detectable virus at 4-6 months.
  20. 4 Challenges to HIV Drug Tx
    • NK cells act as reservoir
    • Macrophages and microglial cells within CNS are protected by BBB
    • Virus-infected macrophages and virus-coated FDCs are longer-lived than HIV-infected lymphocytes
    • There is a pool of latently infected CD4+ cells within HIV+ pts.
  21. Approaches to root out latent HIV-1
    • Use IL-2 to reactive latently-infected cells
    • Structured tx interruptions (STI) to ractivate latently-infected cells  (whack-a-mole)
    • Development of drugs that better pass the BBB
  22. Inhibitor of histone deacetylase (HDAC)
    Vorinostat
  23. Vorinostat inhibits
    histone deacetylase
  24. HIV and Pregnancy:
    HAART in USA
    3rd world?
    • Single dose of NNRTI during delivery
    • C-sections for women with RNA levels >1000 copies
  25. Prophylactic Options for HIV
    • Vaginal cream containing tenofovir
    • Daily, pre-exposure use of truvada
  26. HAART-Associated Adverse Clinical Events
    • Fat Maldistribution (Buffalo hump)
    • Drug interactions (PIs and statins)
    • Hyperglycemia
  27. NO vaccine for HIV.  Why?
    Can make Abs against virus, but virus mutates.
  28. Problem with HIV Live attenuated vaccine
    Deletion of nef gene caused disease in young monkeys and some of the viruses were able to repair themselves.
  29. Problem with HIV Inactivated Vaccine
    Produces some protection, but does not protect from infxn.  Decreases severity.
  30. Problem with HIV Merck's T-cell vaccine
    • Trivalen rAd5 vectors expressing clade B Gag, Pol, and Nef
    • Vaccine failed to protect against infxn and those with Ad5 Abs showed an enhanced rate of HIV-1 infxn
  31. Problems with HIV vaccines: Monomeric Env gp120 vaccine
    No detectable protection in man even though it elicited type-specific binding Abs; failed to reduce broadly reactive neutralizing Abs
  32. Problems with HIV Vaccines:  DOD's RV144
    Vaccination did not affect the degree of viremia or the CD4+ cell count in subjects who became HIV+
  33. Blood in the US is screen by
    • ELISA:  anti-HIV-1; anti-HIV-2, HTLV-I and II
    • PCR:  HCV-RNA; HIV-1 RNA; WNV RNA
  34. Long Term Non-Progressors
    HIV+ individuals who have been disease free for > 15 years.
  35. Elite Neutralizers
    Generate neutralizing anti-HIV antibodies
  36. How have LTNPs and ENs remained disease free?
    • Infxn with Nef- or Vif-minus virus
    • Defective in CCR5 or overproduce its ligand
    • Generate a neutralizing primary antibody response
    • Certain HLA haplotypes are linked to good control of the virus and a better prognosis
  37. Where is HIV-2 mostly seen
    West Africa
  38. Differences between HIV-1 and HIV-2
    HIV-2 has a slower progression to AIDS, HIV-2 is more difficult to transmit because the viral burden is lower
  39. 1st human retrovirus to be isolated
    Human T Cell Leukemia Virus (HTLV-1)
  40. Infection with HTLV-1 leads to
    • Leukemia/lymphoma
    • Tropical Spastic Paraparesis (TSP) or HTLV-1 Associated Myelopathy (HAM)
  41. HTLV-1:  Transmitted by free virus or virus-infected cells?
    Virus infected cells

    (Transmitted via the same routes as HIV-1)
  42. HTLV-1 is endemic to
    • Southern Japan
    • Caribbean basin
  43. HTLV-1 infxn does not invariably progress to illness.
    1.2 million Japs are infected but only 700 new cases of ATL/ year
  44. Slowly progressing degenerative disease that primarily affects the corticospinal tracts of the thoracic cord
    TSP/HAM
  45. No effective therapy for HTLV-1
  46. HTLV-II infects humans but has not been linked to a specific illness.  Endemic in?  Prevalent among?
    • North/South American-Indian tribes
    • IVDAs
  47. HTLV-3 and -4

    Seen in?
    • Linked to no known disease
    • Seen among native Africans, specifically bush meat hunters and those with close contact with primates
  48. Animal Lentiviruses:  Visna virus
    Neurological defects in sheep

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