4/28 HIV Drugs Lecture, Ch 17 Flashcards
Put these steps of the HIV life cycle in order.
co-receptor binding, transcription, translation, fusion, reverse transcription, protease-mediated cleavage of precursor protein, integration, budding, attachment, maturation
- attachment
- co-receptor binding
- fusion
- reverse transcription
- integration
- transcription
- translation
- protease-mediated cleavage of precursor protein
- maturation
- budding
(pic doesn’t perfectly correlate with the steps, but pretty close)
what was the first class of antiretrovirals available? what is an example?
(nucleoside reverse transcriptase inhibitors) nRTI
AZT = example
what resulted in a dramatic increase in survival in HIV patients who had access to treatment around 1996-onward?
availability of protease inhibitors
How is HIV now treated (generally)?
highly active antiretroviral therapy (HAART)
consists of at least three drugs from at least 2 classes!
what are the 3 major reasons for limited worldwide success of HAART?
- poor access to drugs
- drug resistance
- drug toxicity
why do clinicians delay starting HAART?
what is the current CD4 cut-off for starting treatment?
delay starting HAART until the danger that the HIV poses to the immune system merits treatment, due to cost and toxicity
current CD4 cut off for treatment is 500 - though some clinicians think we should start treatment regardless of CD4 count.
HIV Life cycle, steps 1 and 2: what is important to know about attachment and co-receptor binding?
On first contact with host T helper cells, HIV attaches to the CD4 molecule.
Alao attaches to a co-receptor (usually CCR5)
HIV life cycle: what happens after attachment to CD4 cell and CCR5 co-receptor?
Forms a fusion complex that enters the cell and releases viral RNA and proteins into cytoplasm.
The HIV enzyme reverse transcriptase converts viral RNA to DNA.
After HIV RNA is converted to DNA, what is next in the life cycle?
Viral DNA transported to nucleus, integrated into host DNA by integrase.
When host cell replicates, viral genes are transcribed and translated into viral precursor proteins (these are like the baguette that still needs to be sliced)
Once viral precursor proteins are in the cytoplasm, what needs to happen for them to reach their final form?
Once they are in their final form, where do they go/what do they do?
Viral precursor proteins need to be cleaved into final form by protease.
Once cleaved, they gather (with HIV RNA) near the cell membrane inside a proteinaceous viral capsid for escape (aka maturation)
while viral proteins and HIV RNA are gathered near the cell membrane preparing to exit the cell, what can disrupt them?
What is the last step in the HIV life cycle?
When waiting to bud off from the cell, the HIV RNA can be disrupted by host enzyme APOBEC3G. But HIV counteracts with a protein called Vif, disabling the host defense. (memory trick: HIV thinks it’s Very Funny that the host can try to stop it -> Vif protein)
Last step: HIV buds off from host cell, taking some of the lipid bilayer with it. Goes to infect its next cell.
what is in the multiple drug “cocktail” used in the mid-90s that led to sustained recovery of CD4 counts?
protease inhibitors + nRTIs
in late 90s, HIV related survival was dramatically improved due to this drug combo.
HIV is now treated with HAART, consisting of at least 3 drugs from at least 2 classes. what are those drugs/classes more specifically?
At least 2 nRTIs + one protease inhibitor
OR
at leaset 2 nRTIs + one nnRTI
In addition to the classes of nRTIs, nnRTIs, and protease inhibitors, what are the 3 additional classes of HIV meds?
when are they used?
- fusion inhibitors
- CCR5 antagonists
- integrase inhibitors
Generally used for patients with resistance to current regimen (=HAART w 3 drugs from 2 categories)
what are the 3 reasons why our early successes in HIV treatment are not the end of the war?
- most HIV infected people in the world do not have access to HAART
- virus can still acquire resistance to all known therapy
- antiretroviral drugs have significant toxicity
if a patient is non-adherent to their antiretroviral therapy, what can result?
(HIV has an error-prone reverse transcriptase -> mutations in genes encoding targets of HIV therapy)
–> resistance
what do all 6 classes of HIV drugs have in common (what can they all do)?
all can incr CD4 count and reduce HIV viral load
(when taken as part of HAART regimen)
what is a major caveat /danger of HAART therapy?
Patients must be adherent!!!!!!!
with poor adherence, HIV replication continues (more slowly, but still) and acquires mutations. the mutated forms will arise when drug pressure is once again applied (when pt starts taking meds again -> drug failure. resistant mutations can also be transmitted to others)
nucleoside reverse transcriptase inhibitors (nRTIs)
MoA?
nRTIs resemble the nucleosides that reverse transcriptase incorporates into the DNA chain during HIV replication. if an nRTI is incorporated, the chain is terminated -> no viral replication.
how does nRTI resistance occur?
- prevention of nRTI incorporation
- ATP-mediated nucleoside analog (nRTI) removal - nRTI is excised from the growing DNA chain
nRTI: MoA?
how many given at once? what else in the regimen?
-MoA: inhibit viral reverse transcriptase via mimicry. an nRTI will become incorporated into the growing viral DNA chain, but cannot be added on to -> elongation halts.
- Note that nRTIs work at the step of reverse transcription: HIV RNA -> DNA.
- At least 2 nRTIs given at once (backbone of most HAART regimens) along with drug from another class.
what side effect is attributed to all nRTIs (but particularly stavudine and didanosine)?
fat wasting.
particularly the buccal mucosa, also arms and legs.
not dangerous but patients don’t like it.
what nRTI can cause a hypersensitivity syndrome?
how does it present?
what % of people will have this reaction?
Abacavir
can look like a mild viral illness on first exposure
then if drug is stopped and re-started -> lethal hypersens rxn.
Sx: rash, eosinophilia, abd pain, GI sx, anaphylaxis, multiorgan failure
8% have a deadly allergy.
nnRTI: MoA?
(non-nucleoside reverse transcriptase inhibitors)
inhibit the reverse transcriptase enzyme by binding in a hydrophobic pocket near its catalytic domain & inhibiting its interaction with viral DNA.
(analogy: duct-tapes the mouth of the enzyme)
nnRTI: how does resistance develop?
mutations to the hydrophobic pocket on the reverse transcriptase enzyme where the nnRTIs bind. mutated binding site.
analogy: the duct tape doesn’t stick anymore
Protease inhibitors: MoA?
Protease inhibitors mimic the long peptides that are made after DNA translation. Nornally these peptides are then cleaved by proteases - but the PIs bind the proteases strongly and prevent them from cleaving the peptide into useable fragments.
what are general goals for HAART therapy?
CD4 count? viral load?
- undetectable viral load by PCR within 6 m
- CD4 count of 100 within 1yr
22 year old George is newly diagnosed with HIV infection. His CD4 count is 87. You are starting antiretroviral treatment. “How long am I gonna live, doc?” How long on average?
A. < 2 years
B. 2-10 years
C. 10-20 years
D. >20 years
22 year old George is newly diagnosed with HIV infection. His CD4 count is 87. You are starting antiretroviral treatment. “How long am I gonna live, doc?” How long on average?
A. < 2 years
B. 2-10 years
C. 10-20 years
D. >20 years
(At this point, with treatment, HIV+ people can live pretty much as long as HIV-)
Review: what are the opportunistic infections to worry about at these CD4 levels:
- below 200 (1 OI)
- below 100 (1 OI)
- below 50 (4 OIs)
- below 200: PCP
- below 100: Toxoplasmosis
- below 50: MAC, CMV, crypto, Kaposi’s sarcoma
Prophylaxis for these opportunistic infections?
- below 200 (PCP)
- below 100 (Toxoplasma)
- below 50 (MAC)
- below 200 (PCP): TMP/SMX, dapsone, pentam, atovaquone
- below 100 (Toxoplasma): TMP/SMX, pyrimethamine/dapsone
- below 50 (MAC): Azithromycin
George did well for a year on zidovudine monotherapy but then his CD4 fell and his viral load rose. “Doc, my friends with HIV are getting started on 3 drugs. Aren’t I supposed to have a bunch of pills?” What combo is right?
A.Two agents from the same class
B.Two agents from different classes
C.Three agents from the same class
D.Three agents from two classes
E.Four agents from two classes
George did well for a year on zidovudine monotherapy but then his CD4 fell and his viral load rose. “Doc, my friends with HIV are getting started on 3 drugs. Aren’t I supposed to have a bunch of pills?” What combo is right?
A.Two agents from the same class
B.Two agents from different classes
C.Three agents from the same class
D.Three agents from two classes (cocktail, which Jen wishes she were drinking right now)
E.Four agents from two classes
