Defending the castle: How
HIV attacks, and how medicines fight back
by Stephen J. Fallon, Ph.D.
Most of us have heard
that HIV creates complex chemical reactions to fool our white
blood cells into producing new baby HIVs (that is, virions).
Our white blood cells make up our immune system, which is
the invisible armor that protects us from colds and other
diseases. Following are some illustrations that describe how
HIV takes over. (I’ll put the technical description in
italics, like this, after each section).
Since our immune system’s
white blood cells shield us from the full effects of most
pathogens, imagine that our bloodstream is filled with white
fortresses, or castles, which protect us from enemies. Castles
are designed to be sturdy, and our castles are just that:
they can stand up against almost any disease we might come
up against. But our deadliest enemy, HIV, has figured out
how to beat our castles. How? Through four basic steps.
Step 1
If any enemy wanted to attack
a castle, what would be his very first objective? Well, he’d
have to make it across the moat (the deep water that surrounds
a castle, keeping enemies from running up to the door). HIV
knows how to get on a raft to get across our moats (in
other words, it fuses and attaches to our cells, using the
T-cell co-receptors, such as CKR-5 and CXR-4). Now, if
an enemy makes it across the moat, has it won the war? Of
course not. You’ve seen movies that show how armies secure
their castle doors. Picture faithful soldiers pouring boiling
oil onto an enemy who is trying to break down the door to
a castle. Your body can also kill off HIV that is still crossing
the moat. But it’s a race to see whether HIV will sneak
in before the troops can catch it.
Step 2
What if an enemy that makes
it across the moat also has a key to the castle’s door?
HIV does, and it can turn the key to get in the door (it
turns its RNA into DNA in the cell, through a process called
reverse transcriptase. RNA is just a piece of information;
DNA is the operating code for cells). If an enemy makes
it through your castle’s door, has he won? No, you still
have a sturdy castle, but your castle is more vulnerable now,
as the enemy can start causing havoc inside.
Step 3
Once inside the castle, a
smart enemy would know that he’s outnumbered, so he’d
want to mess up the castle’s defense system. So an enemy
might sneak down to the castle’s map room, and pin a
phony map up on top of the one that is supposed to correctly
direct the troops in the event of attack. Then he would sound
the alarm, and watch all the soldiers running the wrong way.
In effect, the enemy would turn the soldiers against the castle
they’re supposed to defend! (At this point, HIV integrates
its new DNA into the cell’s nucleus, using an enzyme
called integrase. This step overtakes the cell’s primary
function, and directs the cell to start producing strips of
new material to make future virions). In other words,
the enemy fools the castle into actually sending new soldiers
out to battle other castles, rather than the castle’s
enemies.
Step 4
But the enemy’s
work still isn’t done. Not only does the enemy want to
take over this castle; it wants to take over all of the castles
in the “kingdom” of your body. So it sneaks down
to the weapons room, to arm itself for battle in this and
other castles. It does this by cutting up pieces of “metal”
to make new weapons. (Or, more exactly, HIV cuts up virion
strands, using its protease enzyme. Until these strips are
separated, like pieces of a model car, they can’t be
made into new HIV particles). The enemy would then put
on the special war gloves needed to carry these new, sharp
weapons out to battle. Then he breaks out of the castle to
go attack other castles fully armed (that is, HIV packages
new virions using zinc fingers, and then buds from the cell.
The new weapons are in reality new HIV pieces, which break
out to infect new cells).
Medicine first worked at
trying to stop HIV at the castle door, Step 2, in its overall
attack plan. Medicines like AZT basically try to fake out
HIV, by putting a phony keyhole on the door, so that it won’t
turn its key in the lock. (they set a decoy so that HIV
can’t turn its RNA into DNA through reverse transcriptase;
this class of drugs is called nucleoside analogues).
These drugs work fairly well,
especially if two are combined. A newer strategy to holding
HIV outside the door tries to gum up the lock, in order to
stall HIV even if it does luck out and place its key in the
right hole (these drugs are called NNRTIs, or non-nucleoside
reverse transcriptase inhibitors). The newest defense
of all at this step tries to bend HIV’s key itself, making
it harder for HIV to turn the RNA into DNA. (These drugs
are called nucleotide analogues—not nucleoside. Though
quite potent, they are proving difficult to make in a way
that is safe.)
These days, most people
are talking about “the cocktail,” which is a daily
drug combination made up of three or more different medicines
taken during the course of a day (but, unlike a real cocktail,
you don’t actually mix them in a glass). There are actually
many cocktails, because there are many combinations that you
could take. Cocktails are also called HAART (highly active
anti-retrovial therapy). The earliest cocktails typically
featured two nucleoside analogue RTIs and one protease inhibitor
(PI). Today, some include two PIs, while others use potent
NNRTIs instead of PIs. Another uses the newest nucleoside
analogue, Ziagen, for a total of three RTIs.
Powerful protease inhibitors
have helped many patients lower their virus below detection
(though we know virus is still there, hiding out). Unfortunately,
these meds can also bring the worst side effects some patients
have ever experienced: kidney stones, anemia, neuropathy,
nausea and vomiting, and even lipid redistribution (“protease
paunch” and “buffalo hump”). In addition, PIs
have a weakness of cross-resistance. The tricks that HIV pulls
to outsmart one of the drugs seem to give it an advantage
against other similar drugs later (HIV develops cross-resistance).
Non-peptide PIs (like the coming tipranavir) may help thwart
cross-resistance.
For a while, some scientists
thought that cocktails might push HIV out of a person’s
body. We now see that this probably won’t work. These
days, doctors are talking about “remission,” rather
than “eradication.” We’ve learned that it may
not be necessary to hold the virus completely below the limits
of detection. Our bodies have some ability to recover their
immune systems, if the virus is brought down to fairly low
(but still detectable) levels.
Scientists also continue
to work on a new drug from another new class, integrase inhibitors.
Unfortunately, so far, tests suggest that these drugs are
difficult to make, and don’t work as well as hoped.
Early in the years of our
war on HIV, scientists tried to stop HIV at Step 1, before
it crossed the moat. Some of the medicines looked good in
test tube studies, but then failed when we tried them in live
patients (the anti-oxidants in our blood absorbed the medicines).
Science moved to working on protecting the door, because it
was easier to develop medicines at this step.
Then three years ago, researchers
were startled to discover a few individuals who were virtually
immune to traditional modes of HIV transmission, despite numerous
exposures to the virus. These people don’t have a
boat in their moat! They were born with pieces missing
in their immune system. Normally, this would be a bad thing,
but scientists learned that the missing part was just what
HIV uses to get across the moat to the castle’s door.
Less than 1% of persons tested lacked a boat (or a CC-CKR-5
co-receptor).
The discovery that
people could live without the boat turned scientists on to
new ideas, and new ways to try to slow HIV down at its first
step. Scientists want to learn how to create this “defect”
in other people, so that HIV will be stopped at the moat.
It will take many years to figure out how to program our bodies
to lose its boats. We’re working on gene therapy, which
would pull the boats out of every moat surrounding every new
castle your body produces (forcing the body to produce
CD4 white blood cells that are “born” without the
CKR-5 co-receptor). In the meantime, medicines such as
T-20 (pentafuside) and T-1249 try to block HIV’s fusion
and attachment in slightly different ways.
Taking whatever combination
of medicines works well for you can buy time. By taking your
medicines correctly now, you make it more likely that your
castle will still be intact when medicine finally develops
new reinforcements to bring to the battle.
Stephen J. Fallon is director
of education for CenterOne in Fort Lauderdale.
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