Term
| Problems/Challenges with Treatment |
|
Definition
1. HIV is a provirus so the body can never be rid of it
2. HIV infects a variety of cells (difficult to pinpoint drug target) ie. macrophages, dendritic cells, T-cells, memory B-cells, brain cells
3. brain cells are separated from the blood stream
-infected cells are difficult to target with drugs because they must penetrate the blood-brain barrier membrane
-brain cells do not regenerate so damage is permanent
4. drugs cause severe side effects decreasing the quality of life
5. HIV is more aggressive in children
-there are less drugs being developed for children
-drugs are harder for children to take
6. opportunistic infections - taking multiple drugs causes drug interactions and side effects and takes a toll on the body with stress
7. mutation - 1 mutation occurs every time HIV multiples
-T-cells are producing 3,000 to 4,000 HIV at any given time
-a permanent change in the genome could change the structure of the drug's target leading to resistance
8. pharmaceutical companies lack experience in producing anti-viral drugs. it's a relatively new field |
|
|
Term
| Purpose of Anti-HIV Drugs |
|
Definition
1. prevent HIV from multiplying in the body
2. keep the viral load low
-undetectable = <50 copies HIV RNA /ml plasna
3. maintain a high CD4 count
-makes people less susceptible to opportunistic infections |
|
|
Term
|
Definition
-each drug targets only 1 aspect of the replication cycle
1. prevent binding to CD4 receptor
2. inhibit reverse transcriptase
3. inhibit release of RNA from capsid
4. inhibit synthesis of viral RNA
5. inhibit synthesis of capsid
6. inhibit budding |
|
|
Term
|
Definition
as of 2010, there are 25 FDA-approved HIV drugs
1. nucleosides (7) and nucleotide analogs (1)
2. non-nucleosides (5)
3. protease inhibitors (3)
4. HIV entry inhibitors (2)
5. integrase inhibitors (1)
6. antisense (1)
7. maturation inhibitors (1) |
|
|
Term
| 1. Reverse Transcriptase Inhibitors |
|
Definition
reverse transcriptase converts ssRNA to dsDNA
a. nuclesoside analogs (nucleoside reverse transcriptase inhibitors or NRTIs)
-first anti-HIV drug developed was AZT
RT make a phosphoester bond by removing OH at the 3' end and attaching phosphate of the next nucleoside
-nucleoside analogs have N3 instead of OH at the 3' so the phosphodiester bond cannot be formed and the chain terminates
AZT originally an anti-cancer drug
-first used against HIV in 1985
-FDA approved in 1987
other examples are ddC, ddI, 3TC, abacavir, tenofovir |
|
|
Term
| Nucleoside Analog Advantages |
|
Definition
-slows infection of new T-cells
-restores immune function
-decreases HIV viral load
-patients gain weight, no fever
-taken orally
-penetrates blood-brain barrier |
|
|
Term
| Nucleoside Analog Disadvantages |
|
Definition
-not 100% effective
-inactivated by liver within 1 hour
-toxic side-effects (anemia, blood clots)
-rebound effect - once you stop taking it, viral load spikes
-possible resistance |
|
|
Term
|
Definition
protease enzyme - assemble new viruses, trims capsid proteins. discovered in 1989: 3D enzyme structure (specified location of atoms)
-computer generated protein analogs
-bind to active sites and block capsid proteins
-viruses are produced but they're defective (no capsid)
side effects: lipodystrophy - fat drains from some places and accumulates in others, nausea, vomitting, diarrhea
-developed in early 1990's
-led to HAART - Highly Active Anti-Retroviral Therapy
-drug cocktails: combo of multiple drugs
ie. AZT, 3TC, and Protease Inhibitor
-combo therapy reduces resistance development
-much less likely to be resistant to 2 or all 3
-very personalized. every combo is different depending on patient
-effective but very costly ($19,000-150,000/year)
-involves multiple pills and injections multiple times a day
-important factors: timing, take some on empty stomach, some on full stomach
-1 of 4 results:
1. CD4 ^ and HIV v
2. CD4 ^ and HIV stays same
3. CD4 stays same and HIV v
4. CD4 stays same and HIV stays same (high) :( |
|
|
Term
|
Definition
fusion of HIV requires gp41 on HIV envelope
-inhibitor (T20) binds to gp41 and inhibits fusion |
|
|
Term
|
Definition
1. determine the sequence of CD4 gene
2. CD4 gene is inserted into E.coli chromosome
3. grow E.coli in liquid culture
4. E.coli cells secrete CD4 proteins
5. purify them, then inject CD4 proteins in patient
->CD4 proteins bind to gp120 on HIv and block adhesion |
|
|
Term
|
Definition
HIV has 2 ssRNA molecules
-one of these (sense strand) is converted to DNA
-chemically synthesize an antisense strand (complementary) that will bind so the sense strand can't be converted to DNA
-no side effects and very effective
-"magic bullet" of AIDS treatment
- but it is VERY costly and the dose must be high enough to penetrate all infected cells |
|
|
Term
|
Definition
integrase - incorporates dsDNA into host chromosome
in 2007 the FDA approved the drug raltegravir |
|
|
Term
|
Definition
-disrupts the gag protein which puts together the capsid
-Bevirimat and Vivecon are in clinical trials |
|
|
Term
|
Definition
-9 million people who need drugs yet have no access
-for every 5 people infected, 3 die without access to drugs
-2010: only 21 countries provided anti-HIV drugs
-cost: $18,000 to 150,000 per year, while many people survive on only $2/day |
|
|
