Regal and Skildum- HIV Learning Exercises Flashcards
Describe the natural life cycle of HIV in a T cell.
- Gp120 binds CD4
- Gp41 binds CCR5/CXC4
- Virus enters cell and uncoats
- ssRNA is dumpted into cell w/ RT, integrase and protease
- RT copies genome into dsDNA (
- Integrase inserts genome into host genome (provirus)
- Expression of viral oncogenes and creation of spliced and unspliced RNA.
- Spliced RNA–>Rev, Taf, Nef (TF that promote un-spliced genes)
- Unspliced RNA–> env, gag, pol (new genome and particle proteins)
Does HIV do the same thing in a macrophage? Why?
Yes because Monocytes and macrophages also have a CD4 marker so HIV can bind to it.
What drugs are protease inhibitors? MOA?
Atazanavir
Rionavir
Darunavir
Prevent processing of viral proteins into functional conformations.
What drug is a fusion inhibitor?
Enfuvirtide
Blocks HIV entry into cell by binding to gp41 preventing the viral transformation necessary for fusion of viral and cellular membranes.
What drugs are NTRIs? MOA?
AZT Lamivudine Abacavir Emtricitabine Tenofovir
Competitively inhibit HIV-1 RT
Incorporation into viral DNA chain causes premature chain temrmination d/t binding w/ an incoming nucleotide
What drugs are NNTRIs? MOA?
Etravirine
Efavirenz
Bind directly to HIV-1RT and directly inhibit
What drug is a chemokine receptor antagonist?
Maraviroc
Binds to host protein CCR5
What drug is a integrase inhibitor?
Raltegravir
Binds integrase and inhibits strand transfer and the integration of reverse transcribed HIV DNA into chromosomes of host cells.
Which of the antiretroviral host drugs targets a host protein?
Maraviroc–targets CCR5
Would you expect any of these drugs to be affective against latent virus?
NO
All of the drugs work in virus entry, replication and packaging, which will no longer be necessary when HIV incorporates into the genome
Is the HIV-1 virus genome bigger or smaller than HepB? EBV?
HepB< HIV < EBV
What are the implications of genome size on antiviral therapy?
Large genome has more unique viral drug targets
A small genome relies more on host machinery , so drugs may target host product
What proportion of potential drug targets are encoded by the virus vs the host?
Large- greater proportion of drug targets are viral
Small- greater proportion of drug targets are host
Is it easier to envision development of selectively toxic drugs w/ a bigger or smaller viral genome?
LARGER- produce more viral targets
What is a provirus? Where are the sites of integration?
A viral genome that is integrated into a host genome. LTRs are the sites of integration of the viral genome and they serve as strong promoters and bind TFs.
If ritonavir is given in combination with darunavir, would you expect an increase, decrease, or no change in serum concentration of darunavir compared to monotherapy with darunavir?
Darunavir is extensively metabolized by CYP3A
Ritonavir is an inhibitor of CYP3A.
Using these two drugs together–> decreased metabolism and increased plasma concentration of darunavir.
What is the MOA of trimethoprim/sulfamethoxazole?
Sulfamethoxazole is a structural analogue of PABA. Interferes with the conversion of PABA into folic acid which is essential for bacterial development.
Trimethoprim binds and irreversibly inhibits DHFR–> bacteria can’t synthesize thymidine–> interferes w/ bacterial nucleic acid and protein formation.
Why is it selectively toxic to penumocystis compared to the host?
Humans don’t synthesize folic acid through PAPA ( it is a dietary requirement). Also have different DHFR than bacteria.
Why do you use a drug combination for treatment of HIV?
Minimum of 3 retrovirals necessary to guarantee effective long term suppression of HIV replication w/out resistance.
Includes at least 2 drugs w/ different MOA.
If pt is treated w/ only one drug, a drug resistant virus will inevitably emerge.
What is an indirect ELISA?
Ag on plate>
detect Abs in serum (amt of colored product is proportional to Ab conc in serum)
Detect anti-p24 Abs, anti-env Abs
What is a sandwich ELISA?
Ab on plate>
detect viral proteins in serum>
detect specific HIV ags like p24 or viral RNA
What is the quickest test for HIV infection?
direct ELISA
What is the gold standard for confirmation of a HIV infection?
Western blot
Detects/confirms specificity of Abs to a variety of epitopes.
At least 3 bands directed against the following Ags must be present (p24, gp41, or gp120/160)
What is a tropism test and when is it helpful?
Helpful in deciding whether a CCR5 blocker will be useful in controlling a pt.s HIV. Required before beginning treatment w/ maraviroc.
What is the best indicator of the immediate state of immunologic competence of the pt?
CD4 T cell enumeration
Lets you follow the CD4 count of a pt
What is resistance testing?
can be done through genotypic or phenotypic testing
genotypic- genomes from pt are compared w/ known antiretroviral resistance profiles
phenotypic- viral isolates form the pt are compared to growth of reference strains of virus in the presence or absence of different antiretroviral drugs.
A 35 y/o F who tested for HIV1 has been on efavirenz/tenofovir/emtricitabine for 2 years and maintaining CD4 coutns of 1000. She returns to your office and her CD4 levels are now 400. What are possible explanations for this?
- emergence of antiretroviral drug resistance from virus
- non-compliance
- new medication that alters affect of antiretroviral
- New infection–> T cell proliferation
You are considering including maraviroc in your drug regimen to treat an HIV-1 pt. What would you need to determine prior to initiating therapy w/ a drug?
The trophism of the virus. Maraviroc is approvide for adults w/ CCR5 tropic HIV infections.
A 43 yo M has a 20 yr hx of alcoholism. His alanine aminotransferase and aspartate amino transferase are severely elevated. HOw does this alter your approach to drug tx of his HIV?
Important to avoid or adjust dosage of drugs that are metabolized or activated by the liver.
What HIV drug is most important to avoid with reduced renal function?
Tenofovir
