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THE
FULL MONTY
CHAPTER ONE: DECONSTRUCTING THE
THEORY
Throughout
The THEORY, certain mechanisms -- such as Apoptosis, Syncytia formation
and Margination -- have been introduced as models of known biological processes
that might fill in some of the details as to how The THEORY accomplishes
its goal. None of these processes are critical to the heart and soul
of The THEORY. They are a means to an end. Although ALL
of these processes are known to occur in HIV infection, in truth, they
might not be the most significant factors involved. Cell death might
occur through other processes in addition to apoptosis. Long-lived
HIV infected cells might exist for reasons that are not syncytial.
Infected cells might migrate out of circulation and become sequestered
in tissues through means other than margination.
These three
processes, however, provided the simplest and most direct means of explaining
The THEORY through known biological models. They may or may
not be critical to the process The THEORY attempts to describe. The
THEORY is married to none of them.
What IS critical
to The THEORY is its basic framework. The critical postulates of
The THEORY are these:
-
T-cell depletion
is caused by the failure to replace some infected cells, not by the wholesale
death of cells.
-
This failure to
replace cells is the result of a failure to receive a "replacement signal"
from dying cells.
To my knowledge,
neither of these postulates has been proven or disproven (that's why its
called "The THEORY" and not "The CERTAINTY").
These two postulates
are important, because they help explain most of the anomalies that we
see in HIV disease that currently accepted theories do not explain - at
least not without great difficulty.
The Currently
Accepted Theory (which, hereinafter, we will refer to as "the CAT") is
that there is this "raging war" going on between HIV and the human body's
ability to replace T-cells. In the CAT, HIV releases millions - perhaps
billions - of viral particles into the bloodstream constantly; and a percentage
of these particles infect and kill T-cells in a wholesale slaughter of
the body's immune system. The body responds by pumping out new T-cells
as fast as it can. But the body is apparently supposed to be always
just one step behind the virus, and slowly loses the war.
I don't buy
it.
This currently
accepted explanation seems to me to fall short in accounting for some major
anomalies seen in HIV disease. We will now pit elements of The THEORY
against the Currently Accepted Theory (CAT) by exploring some of these
anomalies. In the process, we will likely see The THEORY reconstruct
itself.
SKINNING
THE "CAT" -- EXPLORING ANOMALIES
ANOMALY
#1: HIV viral load (the amount of free-floating virus in the
bloodstream) can increase to VERY high levels during outbreaks of other
viral illnesses such as herpes or the flu. Even vaccination can cause
an increase in viral load. But increases under these circumstances
are almost always temporary. Once the illness has passed, HIV viral
load tends to decline back to the level it was at prior to the occurrence
of the illness. Why?
If the HIV
virus is overwhelming the immune system gradually by some very fine margin
of cell-death vs. cell replacement, then these increases in viral load
should nearly always be disastrous for the patient. More virus
would mean a greater number of T-cells would be infected, which would mean
more infected cells producing more virus and then dying off. If the
immune system is just barely able to keep up with HIV infection in the
first place, then this set of circumstances would logically be expected
to result in the HIV gaining a decisive edge in this contest. Viral
load would spiral upward, and T-cell counts would crash. In
fact, this usually doesn't happen. Viral load jumps - and then falls back
down. Patients usually survive this temporary increase in viral burden
relatively unscathed. How can this be?
I can think
of four possible explanations for why this would happen:
-
The immune system
somehow responds more strongly to the increase in viral load, and wipes
out the extra burden.
-
The additional
viral particles (virions) formed by this process are non-infectious mutations.
-
The increase in
viral load in the bloodstream does not represent the stimulation of viral
replication at all, but is caused by the return to circulation of virally
infected cells that are usually sequestered outside the bloodstream.
-
The increase in
viral load represents an increase in free-floating virus that was never
all that critical to reducing T-cell counts in the first place (The THEORY).
Now, of the above
explanations, # 1 seems to me to be the least likely. If the immune
system can control additional viral load and effectively eradicate it,
then why wouldn't it go on to wipe out the rest of the viral particles
as well?
Explanation
# 1 implies that the immune system commonly gains an edge in the war against
HIV. But, if that were the case, then the immune system ought to
be able to wipe out the virus completely, and progression to fatal illness
would not occur. This is obviously not the case, and I am dismissing
explanation # 1 on those grounds.
Explanation
# 2 (that additional virions produced by environmental factors are
almost always noninfectious mutants) seems possible,
but has a slight problem: why would the newly stimulated viral growth be
any more prone to non-infectious mutation than the virus as it is normally
found? Wouldn't virions produced under most conditions have the same
percentage chance of survival as virions formed under normal circumstances?
Explanation
# 3 (that the increased viral load represents a return to circulation
of infected cells that HAD been sequestered somewhere outside the bloodstream)
also seems possible, but you'd still have to explain why the increased
viral load isn't doing more damage. Wouldn't the increased
level of virions also give rise to an increase in cell infection and death?
I suppose one could endeavor to explain this by saying
that the sequestered cells were always causing the same amount of damage
- they just weren't SEEN doing this because they were in sequestration.
The net effect of returning them to circulation would therefore be zero.
But it could also be true that the new virions are largely noninfectious
- just as required in explanation #2 above. For Explanation
# 3 to work, it would have to concede at least one (and perhaps both) of
two major issues in The THEORY: That infected cells are often found
OUTSIDE the bloodstream, and that they produce virions that are unlikely
to infect other cells in the bloodstream.
This leaves explanation # 4:
that HIV virions are USUALLY not responsible for the decline in T-cell
counts. This explanation is not exclusive of any of the other explanations,
and declares the increase in viral load largely irrelevant to the outcome
of the disease process.
To summarize:
of the four explanations, #1 seems impossible, #2 seems improbable, #3
must claim the whole effect is something of an illusion, while conceding
at least one key issue to The THEORY, and #4 claims the issue is mostly
irrelevant.
The CAT relies
on at least one of the first three explanations being true, while the fourth
one MUST be untrue.
The THEORY
suggests that explanation # 4 is true regardless of whether any of the
others are true or not.
ANOMALY
#2: In a certain, small percentage of cases, patients undergoing
successful antiretroviral therapy experience BOTH an increase in viral
load, AND an increase in T-cell counts. The increased T-cell counts
tend to be sustained and correlate well with an increase in immune response
leading to a favorable clinical outcome. Why is that?
Again we are
faced with the issue of increasing viral load, and we return to the four
explanations offered above.
The CAT tells
us that the new virions are non-infectious because the antiretroviral therapy
has resulted in poorly formed viral particles. I can believe that.
So, it now looks like the CAT favors explanation #2. This is the
only consistent hypothesis the CAT offers us to explain viral load anomalies.
This suggests that only virions produced under natural circumstances
are capable of initiating successful infection leading to viral reproduction
and cell death. To me, that seems possible, but a little hard to
swallow.
The THEORY
suggests that explanation #4 (that the death of cells is NOT what gives
rise to T-cell depletion) would hold true in virtually all circumstances.
I have no problem
accepting the idea that any of the first three explanations might turn
out to be true - although, clearly we've seen some problems with making
them "fit". The reason explanation #4 was chosen to be incorporated
into The THEORY is its pure simplicity. The other three explanations
all require acceptance of the idea that there are times when circulating
viral load does not cause a decline in T-cell counts. Explanation
#4 simply says, "Yes: and that is MOST of the time."
As we examine
this issue further, you may begin to see why I think explanation #4, as
offered by The THEORY, simply collapses the complex arguments implied in
explanations #1, 2 and 3 down to a more basic point: virions in the bloodstream
are clearly not always deadly, and CAN be controlled by the body's immune
system.
There are other,
similar circumstances in which increases in HIV viral load do not correlate
well with expected disease progression. However, the situations
we examined above are the clearest and simplest examples. The
arguments and explanations in all cases would be the same. Taken
together, the incidence of HIV viral load NOT correlating well with consequent
impact on the immune system - while it is the exception rather than the
rule - seems to me to be sufficiently high so as to make HIV viral load
appear to be useful as a surrogate marker, but not as an explanation for
T-cell loss. Viral load might give you an indication of how many
cells are already infected, or the rate at which already infected cells
are producing virus, but not of how many cells are likely to BECOME successfully
infected through the bloodstream. If infectivity through the bloodstream
were the cause of the decline in T-cell counts, then I would expect there
to be a more consistent cause-and-effect relationship between viral load
and T-cell counts.
ANOMALY
#3: This is actually more of a puzzle than an anomaly,
because it occurs universally: when HIV viral load is brought under control,
T-cell counts do not return to normal automatically. In fact, recovery
of the immune system literally takes years, even in the presence of viral
load brought so low as to be undetectable. If there really were a
raging battle going in which the body was constantly replacing rapidly
disappearing T-cell populations, then removal of the causative factor ought
to result in an immediate huge jump in T-cell counts to nearly normal levels.
This just simply NEVER EVER happens. I've never seen it occur even
once. I've never heard of a REPORT of it happening. Immediate
and significant T-cell increases do occur, but not in huge numbers.
T-cell counts increase gradually over a period of years - and usually in
spurts. Why?
I've never
seen a really satisfactory explanation of this that adheres to currently
accepted theories. The closest anyone has ever come to an explanation
involves thymic function: T-cells are said to "mature" in the thymus gland.
The condition of the thymus declines with age, and could decline even more
rapidly in the presence of disease. Therefore, CD-4 replacement would be
retarded.
The problem
with this explanation is that it is not really consistent with the description
of slowly declining T-cell numbers being caused by a war between HIV and
the body's ability to replace T-cells. Supposedly, the reason for
the decline in numbers of T-cells occurring slowly over a number of years
is because HIV has a slight edge over the body's replacement capabilities.
The CAT describes the body as being unable to replace CD-4 cells quite
as quickly as HIV destroys them, and so the body gradually loses the war.
But, if this is true, then where did all those replacement CD-4 cells that
DID appear during this "war" come from? Didn't THEY require
a healthy thymus in which to mature? What happened? Did
the thymus suddenly "poop out" just at the moment when effective treatment
was applied against the virus? In EVERY patient? ALL THE TIME?!?
Baloney.
It seems far
more likely to me that the cells are being replaced as they die off.
Remember that current treatments do not kill off infected cells - they
only curtail viral reproduction. (Think of it as being more like a chastity
belt than a gunshot to the head.) If certain cells are exceptionally
long-lived, then they will be replaced only after a long time passes.
And a cluster of cells dying out all at once would create a "spurt" of
replacement. Syncytia are sometimes described as "cell clusters".
Hmmmm...
But wouldn't
the replacement of dying cells require some sort of signal from the cell
to the body that death was occurring? Hmmm...
(But let's
not get ahead of ourselves.)
There are other,
more scientific, reasons for doubting the thymus hypothesis. Some
studies have been published comparing the rate of T-cell replacement in
persons with a relatively normal thymus gland to that of persons whose
thymus has been completely removed. I am aware of at least one study
that concluded there was no difference.
I have heard
it rather peripherally argued that the NUMBER of T-cells that re-appear
in the bloodstream is not what is significant: what counts is whether they
are mature and functional. It is argued that patients need a healthy
thymus in which these cells can mature to a more functional state.
I have two replies to that: First, the NUMBER of T-cells is precisely
what we are talking about, since that is the most commonly used way to
monitor recovery in AIDS patients. Secondly, in my involvement with
lending support to AIDS patients, I spent a lot of time in hospitals and
hospices. When effective drug treatment finally became widely available
about three years ago, the "AIDS wards" of hospitals and hospices emptied
out literally in a matter of weeks. Patient recovery was so startlingly
rapid that it placed a financial strain on some hospitals and doctors whose
practices consisted largely of HIV-positive patients. If those new
T-cells weren't working, I'd like to hear a really good alternative explanation
for why that happened.
Don't get me
wrong: I think it is better to have a healthy thymus than NOT to have one.
I just don't think it figures critically into this issue.
To recap a
bit: among the things that the CAT has asked us to accept so far, are the
following two premises:
-
Free-floating
virus in the bloodstream does not ALWAYS result in cell death and the decline
in T-cell counts.
-
Many of the T-cells
that DO die get replaced - and rather rapidly, at that.
There may be more
than one way to skin a cat; but the more you scratch the surface of THIS
CAT, the more it begins to resemble The THEORY.
ANOMALY
#4: HIV-infected patients who are placed on immunosuppressive
therapy, and then have that therapy withdrawn, have been known to exhibit
a rebound in T-cell counts to ABOVE the level they were at before the suppressive
therapy was administered. Why?
If currently
accepted theories are correct, and the immune system is only just barely
losing the war against HIV, then suppressing immune function ought to have
an additive effect on the course of the disease. (That is: clinical decline
in the patient ought to be accelerated.) I am aware of no explanation
that The CAT offers to reveal how lost T-cells would be replaced under
such conditions, let alone result in a net gain in numbers of cells.
But, if inhibiting
the immunological inflammatory responses resulted in the attraction and
absorption of fewer cells into syncytia, then CD-4 counts might actually
rise following the withdrawal of the immunosuppressive therapy. (The therapy
itself might likely lower T-cell counts while it is underway.) This
idea implies that cell ABSORPTION accounts for the critical decline in
T-cell counts.
Hmmm... there's
that "syncytia" thing, again.
The point I'd
like to make here is that, if syncytia figure prominently in the clinical
decline of the patient, then the explanation that declining T-cell counts
are due to the FAILURE of cells to die becomes much more plausible.
This would lead to the "companion" conclusion that dying cells are being
replaced, probably by sending some sort of replacement signal to the body.
It should be
noted that the above postulates are based on my observation of patients,
not on laboratory experiments using test tubes, microscopes, flow cytometry
or the like. It would be nice to have some sort of experimental evidence
to help prove or disprove the premise of The THEORY. But how
could we devise such a test?
COMING NEXT:
THE
FULL MONTY -- CHAPTER TWO:
THE
EXPERIMENT
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A DISCLAIMER
FROM STEVE SCHALCHLIN: Dickie is my friend in Los Angeles who was infected
with HIV in 1981. He's been through more near death experiences than anyone
I know, including a recent two month delirium where his liver was failing
and he was dying. But through a careful balance of some drugs that alternatively
dehydrate and then rehydrate him, he is alive yet again.
Dickie, after he got sick, began
reading books on microbiology. And when we met earlier this year, he used
to sit for hours and just explain for me microbiology and all the sites
on the cells and what proteins do, etc. He kept telling me about his theory
about the immune system. He had it well thought out and, as far as he could
tell, it -- THE THEORY -- can account for all the phenomena that has occurred
so far in the strange tale of HIV.
This does not mean he is right.
His theory is untested. It is ONLY theory. It came to him as he read book
after book on microbiology, so it could be a naive theory or it could be
one of a billion theories. So why have I invited him to be a Bonus Round
site?
Because when he's hot on the
trail of new information and when ideas are popping in his head; when he's
making new discoveries through the books and published studies, I see him
come back to life the same way Jimmy saw my songs bringing me back to life.
There are scientists who read
my page, you know. Even if his theory doesn't pan out, I will learn a lot
about my own body and about the thing that almost killed me. (cue song:
"at least i know what's killing me").
Dickie is not a doctor nor does
he work in the medical field.
He's a Patient. *cue the mannix
theme*
So, the reader should note that
THIS IS ONLY A THEORY we are using as a jumping off point to ask questions
and learn more about HIV and the immune system.
WE ARE NOT SUGGESTING ANY PATIENT
TRY ANY METHOD OF TREATMENT WHICH MIGHT BE SUGGESTED OR INFERRED. WE ARE
NOT RESPONSIBLE FOR YOU IF YOU DO SOMETHING STUPID -- LIKE TRY ANY TREATMENT
WITHOUT THE FULL CONSENT OF A LICENSED MEDICAL DOCTOR.
Tell us what you think. -- The
Bonus Round Management. :-) |