MIC Test 1 Lecture 3 Flashcards

ANSWER: B (be permanently infected with HIV)

before 1987 could only target opportunistic infections

could NOT target HIV at this point

human cells try to fight back (restriction factors)

• human cells have processes that fight viruses (like HIV) -> factors in cells. Evolved ways to fight intracellular infection
• if have this, then why does HIV succeed???
  • HIV has ways to counteract/inhibit cellular mechanisms that fight HIV
  • HIV evolves these like all viruses do

unfortunately, HIV tries to prevent the restriction factors from working (viral antagonists)

figure:

• HIV binding to CD4 receptor + coreceptor
• fusion w/ host cell membrane
• uncoating viral capsid
• release up HIV RNA and proteins into cytoplasm
• reverse transcription RNA -> DNA now
• formation of pre-integration complex (PIC) + translocation into the nucleus
• in nucleus, viral DNA integrated into host DNA and subsequently transcribed + translated to form new viral RNA and viral proteins that translocate into the cell surface to assemble into new immature virus forms
• new viruses bud off + released
• maturation: protease enzymes cleave structural polyproteins to form mature Gag proteins = new infectious virions
• key HIV restriction factors and corresponding viral antagonists exhist

we want drugs to inhibit individual steps

1st drug against HIV: blocks reverse trasncriptase (unique characteristic of the virus compared to our body)

published in nature june 27th 1970

• viral RNA-dependent DNA polymerase: RNA-dependent DNA polymerase in virions of rous sarcoma virus 1211
• temin + baltimore were awarded nobel prize in 1975 for upending the "central dogma"
• not sure abt what this slide is saying (slide 8)

• 1970s, gertrude elion developed AZT drug as nucleoside analog specific for viral reverse transcriptases
  • mimics thymine, becomes incorporated and reverse transcriptase cannot extend chain of nucleotides
  • AZT = chain terminator (name of drug class)
• in 1970s, there was effort to get anti-retroviral drugs to fight HIV

• AZT was forgotten about until 1983 when realized retrovirus caused disease to try to prevent HIV replication
  • paper made to show that AZT may work for HIV
    • in vitro - inhibited HIV replication in dish/culture
    • figure:
      • cultured cells infected w/ HIV, no drug or increasing amounts of AZT
      • amount cells HIV+ being measured
      • cells not treated: day 8, 15%, day 9, almost 40%, day 10 about 75%
      • cells treated: much reduced replication of HIV
• AZT has anti-HIV activity in vitro

6x per week 250 mg AZT or placebo

24 week period

results:

• 19 placebo and 1 AZT died during study
• opportunistic infection in 45 subjects w/ placebo and 24 w/ AZT
• statistically significantly increase in # CD4 cells noted in AZT subjects
• data showed that AZT administration can decrease mortality and frequency of opportunistic infections in selected group of subjects w/ AIDS or its related complex
• probability of developing oppotunistic infection was 0.23 vs 0.43
• this was the 1st time a drug had some efficacy to slow down the virus

good:

• AZT slowed down viral replication reducing viral load
• prolonged life for about 1 year

bad:

• initially used in doses (about 1500 mg) that had toxic side effects
• rapid appearance of AZT-resistant HIV
  
  • AZT resistant strains emerged
  • made new reverse transcriptase, mutated to have ability to remove AZT from chain

only in mid 90s was there a decrease in death rate

• used drug cocktails
• KNOW: 1996 considered the MIRACLE YEAR
  
  • figured out how to keep HIV from killing people
  • new class of drugs discovered
    • started to also be used in combination (drug cocktails)
    • 1 of most powerful developed = protease inhibitors
      • AZT was for reverse transcriptase, while protease inhibitors act on late phase
      • protease - scissors to free proteins = functional proteins
      • if protease prevented -> proteins cannot be freed to function and resulting virion is NOT infectious
      • THIS drug BINDS to protease + prevents it
  • protease inhibitors in combination w/ other drugs = sufficient to suppress HIV virus (keep viral level low/suppressed) = prevents onset of AIDS
  • drugs today keep HIV so low that cannot detect it bc of using prinicple of drug mixture

the MIRACLE YEAR

...

1) 1981-1983

2) 1983-1987

3) 1987 – could slow down replication

4) 1996 - miracle year

5) Current ( still no cure or vaccine )

in last 28 years, progress has been made, but no cure or vaccines

we HAVE figured out how to prevent transmission