HIV Flashcards
HIV-1 genome is made up of structural and non structural genes. What do non structural genes control?
replication
where is the envelope around the virus derived from?
own cell membranes
large protein nuclear capsid structure inside the vireon is produced from what gene?
gag gene
what are the 2 main cellular targets for hiv?
cd4 lymphocytes and macrophages
where are cd4 lymphocytes localised ?
lymph nodes, GIT, other tissues
where are macrophages distributed?
all tissues and lymphatic system
what is the role of cd4 lymphocytes?
global immune helper cell
what is the role of macrophages?
phagocytosis and presenting foreign antigens within lymph nodes
What forms the trimer of receptors when viruses reach the surface of CD4 cells?
CCR5
CXCR4
CD4
some ppl have deletion in CCR5 so this means…
theyre naturally resistant to HIV
name 2 co receptors in close proximity to cd4 receptors that allow for hiv binding and virus entry?
CCR5 and CXCR4
as the gp41 and gp20 from the virus binds with cd4 receptors what happens, to allow for binding ?
conformational change to gp20 that allows interaction with CCR5, fusion takes place
post fusion, virus enters and nucelocapsid is within cell. Virus moves towards nuclus via microtubules in the cytoplasm. During this process, what enzyme starts to become active in the nucleo capsid?
reverse transcriptase
when the reverse transcriptase and RNAse H enzymes come into contact with the nucleus what process is commenced?
proviral dna synthesis and viral RNA digestion
..
so single RNA strand becomes RNA w a DNA template, RNA then degraded down -> another strand of DNA formed
when the nucelocapsid breaks down which dna is available at the nuclear pore?
proviral dsDNA
segments of proviral dsDNA is bounded to integrase enzyme. What is the role of this enzyme?
cuts proviral dsDNA, finds cellular dna and inserts proviral dna into our double stranded dna
post integration proviral dna is inserted into our dna. proviral dna may remain dormant and later be reactivated via cellular transcription pathways.
If reactivated, what is generated from cellular dna?
viral mRNA
true or false: viral rna is looped and spliced to different lengths?
true
what is the role of the cell protein TAT?
directs viral mrna to leave nucleus via nuclear pores
what different things can happen to viral mrna when it leaves the nucleus?
some goes to ribosomes and used as templates for hiv protein synthesis like gag and some form stable dimer of 2 copies as new viral genome
what causes infected cell surfaces to start to bulge?
new viral proteins and gag pack together with viral genome
once the surface of an infected cell membrane starts to bulge, proteins are recruited and pull together the virion and protease enzymes. What process do these catalyze?
viral protein cleavage into functional units
what is closure facilitated by to allow the virus to bud off from the cd4 cell?
specific contractile proteins that draw the neck together
p655 summary of hiv1 life cycle
what are NRTIS?
nucleoside reverse transcriptase inhibitors
How do nucleoside reverse transcriptase inhibitors work?
Prevents viral replication.
NRTIS are incorporated into dna chains and act as X to prevent replication?
chain terminators
How do non-nucleoside reverse transcriptase inhibitors work? NNRTIs
bind to and block HIV reverse transcriptase
How do integrase inhibitors work?
Prevents viral DNA being integrated with the host cellular DNA
fast reductions in HIV viral load
How do protease inhibitors work?
Prevents processing and packaging of viruses before release from the lymphocyte.
what does success of HIV relate to?
enormous viral replicative capacity (new gen per 1-4 hrs)
each gen archived in memory cells
Why do viruses not produce identical replicas?
Reverse transcriptase is very error prone and lacks a proof-reading function.
slight mutations causes new viral cells.
what allows real-time evolution of viral cells to changing environmental pressures in the host?
mutated viral replicas are archived in memory cells.
what are the 3 types of mutations?
neutral
deleterious
advantageous
whats a codon?
3 bases = 1 aa
the evoluation of an advantageous virus is a process of selection under what pressure?
environmental
eg BP
we take plasma virions to test for hiv, what is the half life?
6hrs
true or false primary infection (PHI) involves 1 or 2 genetic types?
true
majority of virions are produced via which pool?
productively infected
activated CD4 lymphocytes
t1/2 2.2 days
follicular DC t1/2?
14 days (longer)
virus gets incorporated into cells DNA but dont become activated + can become dormant and cause extremely long lived popns with extrememly long…
t1/2
what is meant by viral quasispecies?
multiple rounds of replication, viral genetic errors, (due to absence of proof reading)
VQ = daughter viruses genetically distinct, archived in memory cells, portfolio of thousands of genetically related viruses
in acute infection is the viral population homogenous or heterogenous?
homogeneous
in established infection is the viral population homogenous or heterogenous?
heterogeneous
every single mutation that can cause drug resistance alr pre-exists in a chronically infected px
T/F?
True
we give drugs not fully suppressive to select out those mutations alr present
over time as genetic diversity increases, how does VL viral load change?
decreases
high diversity, low VL
What are the 3 main pathways to persistent viral replication then -> drug failure in HIV?
drug resistance
sub-inhibitory drug levels
host immune failure
On what two bases can drug resistance occur in patients?
pre-exists
selected by drug
give 2 ways that drug resistant varients can pre exist in patients?
transmitted or drug independent evolution
how does persistant viral replication lead to drug failure?
evolution of drug resistance
name 2 factors that lead to sub inhibitory drug levels?
pharmacological issues
or poor adherence
2 types of selected drug resistance, regarding virus
selected or transmitted drug resistance
what is meant by wt virus?
no drug resistant mutations
outline how selected drug resistance works and can be lead to an emergence of wt virus after discontinuing therapy?
initial wt virus -> resistant variants selected during therapy -> rapid reemergence of wt virus upon discontinuing therapy
in selected drug resistance - with continued presence of drugs, the resistant variant (WT) become what?
dominant quasispecies
->reemergence of WT virus
How can transmitted drug resistant cells be treated by drug?
upon reversion back to wild type virus.
outline how transmitted drug resistance works and can lead to the reversion of wt virus?
initial drug resistant virus, slow reversion to wt virus due to error prone replicative mutations
what information can you gather from a patient that is M184V in reverse transcriptase gene?
m exchanged for v, becomes mutant virus, resistant to 3tc drug so not effective
Methionine = WT = 3TC sensitive :)
Valine = mutant = 3TC resistant :(
T/F
wt virus is the one that is best adapted to living in the host?
true
dominant and fittest virus
why is resistance an important factor to consider ?
treatment starts earlier and lieflong,
resistance = limited treatment options,
difficult to treat,
greater cost of care,
premature virological failure
what is the cause of AIDS?
HIV
Antiviral drugs + tretament…
What is the goal of HIV treatment? 2
suppress viral replication
allow CD4 counts to recover
What is 1st line treatment of HIV?
2 nucleoside analogues + NNRTI/Boosted protease inhibitor
how long can clinical latency last?
6 months to 10 years
what is seen in HIV rna copies and cd4 t lymphocyte count during primary infection?
immediate fall in cd4 t lymph
rapid increase in hiv rna
natural history of HIV IS w/out treatment, after a while what opportunistic infections are seen?
thrush (direct link to low CD4)
oral hairy leukoplakia
TB
..
…
damage and destruction of cd4 cells can allow for opportunistic infections, if this is not controlled what does the body do?
immune response to allow cd count to recover
why is HIV testing important?
saves lives!!
where are NRTIs active? nuceloside reverse transcriptase inhibitors
reverse transcriptase enzyme
what is maraviroc an example of (drug class)?
CCR5 blocker
AZT, ABC, 3TC are examples of…
NRTIs
ATV, LPV, DRV are examples of…
PIs
goal of HIV treatment?
drive HIV VL (RNA) to undetectable levels
and maintain lifelong viral suppression
we aim for undetectable limits by x months since diagnosis?
6
true or false: if patients are not undetectable by 6 months it is considered treatment failure?
true
what is the limit of detection below in c/ml to be classed undetectable?
40
if viral levels rebound greater than 1000 what assay can be performed to look for development of resistance?
genotypic assay
the goal of treatment is to allow the x counts to recover, rebuild the x system and protect the individual?
CD4, immune
what are the first line treatment options that are comprised of potent combination anti retroviral therapy?
2 NRTIs + integrase inhibitor/ nnrti/ boosted protease inhibitor
list some reasons why intregrase inhibitors have come to the forefront of treatment?
potency, lack of ddis, robust towards resistance, lack of long term side effects
give one benefit of single tablet regimes?
increased adherence
give 2 ways by which the development of virological failure and resistance can be avoided?
maximising drug adherence and full persistant viral suppression
can resistance develop if there is no viral replication, yes or no?
no
(cant select out viral resistant variants)
can resistance develop is there is no selective pressure such as drug?
no
(to select out those resistant viruses)
what is meant by ic50 in the context of hiv treatment?
conc of drug required to suppress in vitro viral replication by 50%
What happens to the IC50 of a drug with resistant viruses?
Increases
causes 10 fold increase in drug conc needed to suppress hence increased resistance
what measure is used as a measure for resistance?
IC50
how does IC50 curve change for resistant virus w mutation X=100ng/ml.
as compared to original curve for WT virus? ie no mutations = 10ng/ml?
shift to right
resistant IC50 = higher i.e. need more drug to overcome resistance
true or false: viral resistance is a relative phenomenon?
true
not all or nothing
if someone is failing on an HIV drug and have on going viral replication, why will you continue to get resistance?
yes and virus will accquire more mutations whichll make virus more resistant
with single -> double -> triple mutant, does resistance increase/ decrease?
increase
T/F
v large intra px variability in metabolism of HIV drugs
true
what is the term given to the flexibility to miss a dose without virological failure?
forgiveness
What is forgiveness in HIV?
The flexibility to miss doses without virological failure.
Examples of factors affecting pharmacological forgiveness?
How long drugs remain above the MEC.
Half-life dependent
Examples of factors affecting virological forgiveness?
genetic barrier to resistance.
what term describes how long drugs remain above the MEC?
pharmacological forgiveness
what pk parameter is pharmacological forgiveness dependant on?
half life
virological forgiveness is related to the genetic barrier of resistance, what does this mean?
how many mutations does a virus need to acquire until drugs no longer effective
both pharmacological and virological forgiveness depend on presence of what?
viral replication in presence of drug
why is stopping antiviral drugs not recommended?
increases risk of opportunistic HIV events eg MI -> most likely due to release of inflamm. mediators on stopping therapy
do boosted protease inhibitors and some integrase inhibitors have higher or lower genetic barriers to resistance than some NRTIS?
higher
what is meant by higher genetic barrier to resistance in terms of mutations?
multiple mutations have to be acquired before virus is resistant to treatment
list some of the factors that genetic barrier to resistance is dependant on?
The effect of mutation on drug resistance.
Number of mutations required to cause resistance
impact of mutation of viral fitness
low genetic barrier drugs often require how many mutations to cause high level resistance?
1
What will happen if you continue to use a drug in the presence of a HIV virus-carrying mutations?
more mutations occur which makes the virus fitter and more resistant
in the case of low genetic barrier drugs does resistance develop rapidly or slowly in the prescence of viral replication?
rapidly
would it be appropriate to use a low genetic barrier drug as monotherapy in patients where replication is not fully suppressed? yes or no
NO
do high genetic barrier drugs develop resistance mutations slowly or quickly, even when used as monotherapy?
slowly
What type of drug would you not want to use as monotherapy?
drug with a low genetic barrier to resistance
true or false, single mutations in high genetic barrier drugs may only cause low level resistance?
true
are high or low genetic barrier drugs more likely to require an accumulation of mutations before high level resistance occurs and are generally more forgiving in the case of non adherence?
high genetic barrier drugs
how can low genetic barrier drugs be protected by virological failure?
used in combination with high genetic barrier drugs
eg atripla
What can cause sub-therapeutic levels of HIV drugs?
enzyme induction
what enzyme is induced the most by HIV drugs?
cyp3a4
“boosting”
what hiv drug is a common enzyme inducer/inhibitor?
RTV
Effects of Efavirenz EFV on CYP3A4 enzymes when used with ATV?
EFV induces cyp3a4, which increases ATV metabolism thu decreases ATV conc
what enzyme is induced and inhibited by RTV?
CYP3A4
What is the principle of pharmaco-enhancement - boosting?
To administer low, therapeutic doses of a drug to inhibit metabolising enzymes and transport molecules and thereby reduce first pass loss and or clearance.
what effect does boosting have on the following parameters,
peak conc,
AUC,
Cl,
half life,
Cmin
increase,
increase,
decrease,
increase or decrease,
usually increase
name 2 boosters that are commonly used in HIV, to boost the plasma levels of anti retrovirals?
Cobicistat
Ritonavir
higher Cmin of atazanavir + ritanovir allowing for moroe what?
forgiveness for late/ missed dose
the predominant MoA of Cobi and RTV is to inhibit which 2 enzymes?
CYP3A4
CYP2D6
What METABOLIC mechanisms cause DDIs with HIV drugs?
inhibition/induction of hepatic enzymes or transporters.
What ABSORPTION mechanisms cause DDIs with HIV drugs?
inhibition/induction of intestinal enzymes or transporters
gastric pH
mineral supplements
What EXCRETION-related mechanisms cause DDIs with HIV drugs?
inhibition of renal drug transporters
for each drug involved what things should you think about when identifying DDIs?
metabolism renal/hepatic,
is it an inducer/inhibitor,
is it a substrate for metabolising enzymes or for specific drug transporters,
does it inhibit or enhance transporter function,
degree of protein binding
total Cl of drug = what 2 types of Cl combined?
hepatic + renal Cl
usually if a person has impaired liver functions, are hiv art drug levels higher or lower?
higher as will spend more time there
are the majority of hiv drugs cleared by the liver or the kidneys?
liver
hepatic
DDIs can -> over or under exposure of the antiviral or co admin medicine.
What is the consequence of this to the patient? 2
reduced clinical effectiveness of either medication
or
increased chance of AEs
perpetrator-victim model of DDIs, what are the 4 possible consequences?
AEs or loss of efficacy of either HIV drug or co-med
What drugs have high DDI potential?
Boosted PIs
EVG/cobi
efavirenz/nevirapine/etravirine
What drugs have moderate DDI potential?
Rilpivirine
Maraviroc
Doravirine
(all victims of enzyme inhib and induction)
What drugs have low DDI potential?
Raltegravir
Most NRTIs
Dolutegravir/bictegravir
What co-morbidities in HIV commonly emerge?
Renal dysfunction
Cardiovascular disease
Osteoporosis
cancer
What is the risk of sexual transmission from +ve partner on successful ART treatment to a -ve partner having regular unprotected sex over a 5 year period?
0!
whats U=U?
when ART now so effective, px treated amd have undetectable VL (<200 copies) have lvls of virus that are untransmittable even in USI
