HIV Flashcards
Brief timeline of HIV
1981: first cases
1983: discovery of retrovirus
1985: first blood test
1987: first drug
1995: first HAART
2020: estimated 75million have been infected, 36.3million associated deaths
Which cells are targeted by HIV?
- vital cells of the immune system:
- CD4+ T cells
- macrophages
- DCs
Name the mechanisms that lead to low levels of CD4+ T cells
- pyroptosis of abortively infected T cells
- apoptosis of uninfected bystander cells
- direct killing of infected cells by lysis
- killing of infected cells by CD8+ lymphocytes
HIV biology
- retrovirus
- (+)ssRNA, enveloped
- upon entry genome is reverse transcribed and integrated into host DNA -> provirus
HIV glycoprotein envelope
- trimer with glycine shield
- 1990 first broadly neutralising ABs (bnAB) was identified
- 2008 single B cell analysis identified numerous bnABs
What is special about the HIV envelope?
very few spike proteins
reasons:
- to limit transmission?
- prevent bivalves AB binding?
- delay induction of potent neutralising ABs?
Is there a vaccine?
No
There where trials in 1987/92/98 & 2003
Name the possible targets for HIV-drugs
- fusion inhibitor
- CCR5 inhibitors
- integrase inhibitors
- RT inhibitors
- protease inhibitors
What did the introduction of HAART change?
- 1995 introduced
- AIDS-related death decline
- # of HIV infected people still rising
Name the six classes of antiretroviral drugs used in HAART
- nucleoside-analogue reverse transcriptase inhibitors (NRTI)
- NNRTI
- integrase inhibitors
- protease inhibitors
- fusion inhibitors
- coreceptor antagonists
resistances for all classes observed
HIV-1 RT
- ~50 molecules per infectious virion
- cellular t-RNA(lys3) molecule functions as primer
- (+)ssRNA is converted into dsDNA (in vitro capsid is needed; mutation in palindromic initiation signal stops it)
- no proof reading
RT inhibitors (NTRI)
- analogues of natural nucleosides that lack 3‘-OH -> also inhibit cellular polymerase
- used in low dose in combination therapy
resistances:
1. reduced affinity to drug
2. stimulate excision of incorporated analogue
RT inhibitors (NNRTI)
- bind to allosteric hydrophobic pocket -> changes conformation of active site
- allosteric pocket not as conserved
- 6 approved NNRTIs -> important in HAART
How does the HIV integrase work?
- palindromic integration at conserved 3‘-OH AC
-> cleavage adjacent to invariable dinucleotide d(C-A) - 2 distinct activities:
1. 3‘-processing
2. DNA strand transfer
Integrase strand transfer inhibitors
- raltegravir was first (2007)
- elvitegravir allows once-daily usage
- dolutegravir exhibits higher genetic barrier to resistance development
HIV protease
- cleaves gag- and gag-pol-encoded polyproteins (cleavage in extracellular virion)
- important for maturation of virus
- 2 identical peptide chains
- flap movement between open and closed (substrate or inhibitor bound) form
Protease inhibitors
- saquinarvir was first in 1995
- resistances:
1. mutations leading to drug resistance
2. compensatory mutations
What is rionavir used for?
- boosts the bioavailability of other protease inhibitors
- is strong inhibitor of cytochrome P450 (drug metabilization)
- important part of combination therapy
CCR5 anatagonists
- bind to allosteric hydrophobic pocket -> prohibiting co-receptor function
- some carry single aa mutation in CCR5 and are resistant to HIV
- maraviroc can cause severe side effects (life threatening)
Fusion inhibitors
- interfere with the collapse of fusion proteins
- very conserved region (6 alpha-helix bundle)
- enfuvirtide/fusion inhibitor T20:
- binds to heptane repeat region of gp41
- blocks formation of postausganges conformation of gp41
- approved but two s.c. injections per day needed
HIV cure?
a) mark cells with provirus and kill via CTL -> CTL escape mutations
b) CCR5 knockout -> impractical in broad population
c) provirus mutation and excision -> must be cell specific, potential risk of long-term expression of recombinase and nuclease, off-target effects
What about bnABs?
- > 20 ongoing trails
- bnABs should block infection of new cells or/and induce death of infected cells
