HIV Treatment

Question 1

HIV life cycle:

Answer 1

1) attachment (via CD4)
2) co-receptor binding (usually CCR5)
3) fusion
4) reverse transcription (via reverse transcriptase)
5) integration (via integrase)
6) transcription
7) translation
8) cleavage of precursor proteins (via protease)
9) maturation
10) budding

Question 2

HAART therapy:

Answer 2

At least three drugs from at least two classes. This is usually two nRTIs with one protease inhibitor or one nnRTI. HAART is capable of restoring NEAR-NORMAL IMMUNITY, even in patients who have suffered devastating damage to the immune system.

Question 3

Major reasons for the limited worldwide success of HAART:

Answer 3

1) poor access to drugs
2) drug resistance
3) drug toxicity
“Due to drug toxicity and cost, clinicians and patients should delay starting therapy until the danger HIV poses to the immune system merits these risks.”

Question 4

APOBEC3G

Answer 4

A host enzyme that is capable of disrupting HIV mRNA. It is inhibited by the viral protein Vif.

Question 5

Six FDA-approved classes of antiretroviral medications:

Answer 5

1) nucleoside reverse transcriptase inhibitors
2) non-nucleoside reverse transcriptase inhibitors
3) protease inhibitors
4) fusion inhibitors
5) CCR5 antagonists
6) integrase inhibitors

Question 6

nRTIs:

Answer 6

nRTIs resemble nucleosides, but lead to chain termination when they are added to the growing DNA chain.
Resistance involves interference with nucleoside analog incorporation into the elongating viral DNA chain or ATP-mediated excision of the nucleoside analog.
Side effects: nausea, headache, diarrhea, LACTIC ACIDOSIS, FAT WASTING (stavudine and didanosine), potentially lethal HYPERSENSITIVITY (abacavir, which is associated with HLA-B57).

Question 7

Hypersusceptibility mutations

Answer 7

Mutations in HIV proteins that diminish the impact of other resistance mutations, thereby making other retroviral drugs more efficacious.

Question 8

nnRTIs:

Answer 8

Inhibit reverse transcriptase, but don’t look like nucleosides (bind at a different site).
Resistance arises from mutations in the hydrophobic pocket that normally holds the nnRTI.
Side effects: rash (may include Stevens-Johnson syndrome), hepatitis (severe with nevirapine), and CNS SIDE EFFECTS (from efavirenz) including agitation, irritability, and nightmares.

Question 9

Protease inhibitors:

Answer 9

Resemble peptides that are cleaved by protease, thereby inhibiting the enzyme.
BOOSTED PIs refer to giving a large dose of a PI that does not inhibit CYP450 with a low dose of another PI that does inhibit CYP450 to “boost” the levels of the first PI.
Resistance involves mutation in the PI binding site.
Side effects: diarrhea, rash, HYPERGLYCEMIA, HYPERLIPIDEMIA, multiple drug interactions (due to CYP450 interactions).

Question 10

CCR5 antagonists:

Answer 10

Maraviroc
Prevents attachment via co-receptor CCR5.
Side effects: hepatotoxicity, cancer, and X4 EMERGENCE.

Question 11

Integrase inhibitors:

Answer 11

Inhibits incorporation of HIV DNA into the genome. No known toxicity.

Question 12

Fusion inhibitors:

Answer 12

Clogs up HIV fusion complex, essentially trapping the virus on the surface of the cell.
Resistance occurs by mutation in the gp41 protein.
Side effects: injection site reactions, increased risk of pneumonia.

Question 13

Goals of antiretroviral therapy:

Answer 13

Decrease HIV RNA (to undetectable levels)

Increase CD4 count (by 100 cells/ul in the first year)