HIV Pathogenesis and Drug Resistance
By Jason Socrates
Bardi
By the middle of the last decade, several pharmaceutical
companies had developed HIV drugs (commonly called antiretrovirals)
and had successfully brought these drugs to market.
The first antiretroviral was AZT, a type of chemical known
as a nucleoside analogue, which targets the HIV enzyme called
reverse transcriptase. AZT was approved by the U.S. Food and
Drug Administration (FDA) in 1987. Later, the FDA approved
several other drugs in the same class.
In the1990s, another major class of HIV drugs began appearing
on the market—protease inhibitors. According to AIDSinfo,
a service of the U.S. Department of Health and Human Services,
seven protease inhibitors have been approved to treat HIV—amprenavir,
atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and
saquinavir.
These protease inhibitors function by preventing the maturation
of an HIV virion. HIV codes for a handful of structural genes,
which encapsulate the RNA and are produced by a gene called
gag. The protease and a few other necessary enzymes
are encoded by a viral pol gene. Both gag and
pol code for several proteins, and in an infected cell,
the virus produces a large Gag polyprotein and a Gag-Pol polyprotein.
The Gag-Pol polyproteins are chopped up inside a budding virion
into their constituent pieces by the all-important HIV protease.
Once folded and active, the protease has a binding pocket
that targets particular sequences along these polyproteins.
Whenever there is a tyrosine amino acid followed by a proline
(Tyr–Pro), or when there is a phenylalanine followed
by a proline (Phe–Pro), the protease acts like a pair
of molecular scissors.
When the protease active site comes into contact with one
of these sequences, it draws a flexible flap down on the peptide
chain, transfers a few electrons around, and cuts the peptide
in a precise location.
Protease inhibitors block this interaction by occupying
the active sites of the protease enzymes and preventing them
from processing the polyproteins. This prevents the virions
from maturing completely and effectively prevents that virion
from infecting a human cell.
But the effectiveness of protease inhibitors is undermined
by drug resistance.
Drug Resistance
In HIV, the problem of drug resistance is a consequence
of the virus' propensity to mutate.
HIV has an RNA genome of around 10,000 bases that is packaged
in a protein and lipid capsid and coat. The infectious particle,
called a virion, binds to receptors on the surface of particular
types of human cells and gains entry. Once inside a human
cell, the virus does something known as reverse transcription—where
it uses its own enzyme called reverse transcriptase to convert
its viral RNA into corresponding DNA (it's called "reverse"
transcription because transcription, in biology, is where
pieces of RNA are made out of DNA genes).
Mutations arise because HIV's replication machinery lacks
what is known as a proofreading mechanism.
Such proofreading mechanisms exist in humans, along with
other mechanisms, to ensure that whenever human DNA is replicated,
it is copied with such high fidelity that a mistake or mutation
is made on an average of only once every million bases copied.
Since HIV has no proofreading mechanism, it copies itself
with such notoriously low fidelity that it makes a mistake
about once every 10,000 bases—in general, the virus may
make one mistake every time it replicates.
As a patient starts to take an HIV protease inhibitor, the
viral "load" or amount of HIV that is in the bloodstream may
fall dramatically, helping the patient fight infections.
However, because of the propensity of the virus to mutate,
new strains arise all the time. Some of these mutations change
the amino acid sequence of the protease enzyme, which can
disrupt the binding of the enzyme and the inhibitor.
Protease inhibitors, in general, look like the natural protein
"substrate" that the protease targets. These inhibitors mimic
the peptides in their affinity for the active site of the
protease, and if they are powerful inhibitors they sit tightly
in the active site.
But if the protease enzyme is mutated, the interaction between
the drug and the protease is no longer strong enough for the
drug to be able to stop the virus from replicating.
The Ice Man Cometh
The problem of designing a drug that will block the HIV
protease is that the HIV protease is not a stationary target
but a moving one.
Several years of treating HIV with highly active antiretroviral
therapies like AZT in combination with protease inhibitors
has shown that resistance to drugs can rapidly emerge in an
infected person. There are countless mutant strains, and over
a hundred that have been isolated with resistance to some
type of antiretroviral.
If a patient takes a drug that prevents one strain of HIV
from replicating, there will likely be other strains in the
patient's body already that have randomly acquired mutations
that confer resistance. The drug then acts as a selective
tool that holds back the sensitive virus more than the mutant
virus. Perhaps these mutant strains don't flourish in the
patient's body, but they may be replicating nevertheless.
And when they do they may acquire more mutations and more
resistance to the drugs.
The mutant strains may then cause the patient's viral load
to rebound, resulting in further loss of immune cells, placing
the patient at greater risk of developing life-threatening
infections and AIDS. And treatment with the same drugs may
no longer be effective
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