Lecture 8: HIV

Question 1

HIV overview
genome
family
mechanism
what does it attack ?

Answer 1

→ + ss RNA
→ two subtypes (HIV1/HIV2)
→ Lentivirus
→ integrated into host cell genome (provirus)
→ different processing → splicing
→ replication in nucleus
→ attacks mainly CD4+ cells → AIDS

Question 2

HIV viral glycoprotein

Answer 2

→ CD4 binding site
→ low spike density
→ plenty of different antigenic regions
→ targeted by broadly neutralising antibodies

Question 3

HIV vaccines

Answer 3

no vaccine on market

RV144 phase 3 trial
→ prime boost

reaserch topics
→ vector based, bnABs, RV144 trial

Question 4

HAART (cART) therapy

→ 6 different targets
→ mechanism

Answer 4

→ Fusion inhibitors

→ Integrase Inhibitors

→ Coreceptor antagonists like CCR5

→ Nucleoside analog RT Inhibitor

→ non nucleoside RT Inhibitor

→ Protease inhibitors

mechanism
→ highly active antiretroviral therapy
→ triple drug combination to reduce resistances
→ different combination of these classes

Question 5

Reverse Transcriptase Inhibitors
→ RT mechanism
→ 2 drug classes and mechanism
→ example
→ resistence mutations

Answer 5

RT mechanism
→ RNA dependent DNA polymerase
→ t-RNA (Lys) as primer
→ no proof reading → mutations

NRTI
→ analog of natural nucleoside that lacks 3´OH group for termination of nelongation
→ but also incorparated during cellular DNA synthesis
→ Zidovudin
→ Resistence: reduce affinity or stimulate excision of incorporated analog

NNRTI
→ allosteric binding that change conformation of catalytic site
→ bidning pocket is less conseved
→ e.g. Nevirapine

Question 6

Integrase inhibitor
→ mechanism
→ 3 drugs

Answer 6

→ 3´processing from dsDNA
→ only C-A dinucleotide
→ strand transfer
→ inhibitor tagets catalytic site

→ Raltegravir, Elvitegravir (low dose)
→ Dolutegravir → better against resistance

Question 7

Protease Inhibitors
→ mechanism
→ drug

Answer 7

→ cleaves polyproteins
→ aspartic proteases: Renin/Pepsin
→ Homodimer
→ cleavage in virion

drug
→ Saquinavir, Lopinavir, Darunavir
→ peptidodominetic scaffold
→ primary resistence mutations and secondary mutating leading to restored viral fitness

Question 8

Which drug boosts other Protease Inhibitors

Answer 8

Ritonavir, Gilead
→ inhibitor of cytP450 responsible for metabolizing drugs
→ coadministration with Lopinavir, Darunavir, Saquinavir

Question 9

HIV entry inhibitors

Answer 9

CCR5 antagonist
→ mutation in CCR5 leads to resistance
→ allosteric blocking
→ e.g. Maraviroc

Fusion inhibitors
→ T20 (Enfuvirtide)
→ binding to gp41 to block gp41 conformation essential for fusion

Question 10

Cure of HIV possible ?

Answer 10

→ so far not

strategies
→ Shock and kill (reactivation of expression and kill these cells)
→ CCR Knockout
→ provirus mutation
→ Provirus excision (adverse effects)

Question 11

Passive immunization against HIV ?

Answer 11

bnAbs trials ongoing
→ reduction of viral reservoir would be possible due to killing of infected cells