50
CASE FILES: BIOCHEMISTRY
The long terminal repeat (LTR) contains the enhancer and the pro-
moter regions of HIV. The
gag
encodes the structural proteins, which help in
packaging the RNA of the virus to generate new virus particles. The
pol
gene
encodes both the critical enzymes reverse transcriptase and integrase. The
env
codes for envelope proteins of the virus that along with the host plasma
membrane help the complete virus particle to bud off from the cell. Apart from
these proteins, the three regulatory proteins, namely, the negative factor Nef,
trans-activator of transcription Tat, and the regulator of viral gene expression,
Rev, can affect viral transcription output. Tat specifically promotes transcrip-
tional activity, while Rev is responsible for switching from early to late HIV
gene expression and is located in the 3' end of the
env
gene. With the latest
research identifying new proteins in addition to the preexisting knowledge,
one wonders what would be the most effective antiretroviral therapy. The avail-
able drugs in the market include nucleoside reverse transcription inhibitors
and protease inhibitors.
Nucleoside reverse transcriptase inhibitors act as substrates for the
reverse transcriptase enzyme and require a phosphorylation event in order to
be activated. The nucleoside drugs lack the 3'-hydroxyl group; therefore,
their incorporation into viral DNA will effectively terminate the elongation
process. This class includes zidovudine, didanosine, stavudine, lamivudine,
and the latest, abacavir. As these agents affect very early events in pathogene-
sis of HIV they prevent acute infection of susceptible cells but have little effect
on already infected cells. The common side effects of these drugs are lactic
acidosis, hepatomegaly, anemia, anorexia, fatigue, nausea, and insomnia.
A subcategory to this class of drugs is the nonnucleoside inhibitors, which act
by binding close to the active site, inducing a conformation change and thereby
inhibiting enzyme function. Some of the members of the class are delavirdine,
nevirapine, and efavirenz. A major drawback with these nonnucleoside drugs
is that they are effectively metabolized by the cytochrome P450 system and are
prone to drug interaction. The most common adverse effects are rash, elevated
liver function, and impaired concentration.
Protease inhibitors are targeted towards the HIV proteases, which are
essential to activate precursors of
gag-pol.
HIV protease is essential for
infectivity and cleaves the viral polyprotein
(gag-pol)
into active viral enzymes
and structural proteins. The mechanism of action of these drugs is by binding
reversibly to the active site of HIV protease and blocking subsequent viral mat-
uration. This major class includes saquinavir, ritonavir, indinavir, and nelfi-
navir. Toxicities of protease inhibitors include nausea, vomiting, and diarrhea.
HIV inhibitor treatment eventually leads to the selection of resistant muta-
tions, one key reason being that the reverse transcriptase is error prone since
it lacks the 3' exonuclease activity. Currently, combinatorial inhibitors with dif-
ferent protein targets, for example, two reverse transcriptase (RT) nucleoside
inhibitors and one protease inhibitor (PI), are used in highly active antiretroviral
previous page 64 Case Files   Biochemistry read online next page 66 Case Files   Biochemistry read online Home Toggle text on/off