From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: AZT and the Immune System: Revisited
Note: non-commercial reproduction.
Archive-Number: 5777
Organization: UCLA, Computer Science Department
Date: Fri, 24 Jul 92 06:35:04 PDT

          AZT AND THE IMMUNE SYSTEM: ANOTHER SILLY THEORY
                         Billi Goldberg

Another one of my *silly* theories.  So I thought I might as well post 
it to provide some *humor* to the seriousness of AIDS and the 
Conference.

I've always been intrigued about AZT and its effects both positive and 
negative.  There is little doubt about its negative effects: it 
terminates DNA formation by interfering with the chains formed by DNA 
polymerase in fast-replicating cells.

The methodology of AZT, so the theory goes (and shown in vitro), is that 
AZT has a somewhat greater affinity for the DNA polymerase component of 
reverse transcriptase (the other component is ribonuclease H which 
cleans up the mess after DNA polymerase gets done).  AZT (and its 
analogs) are phosphorylated intracellularly and can be incorporated into 
the elongating DNA chain.  The 3' hydroxyl group of the analog is either 
nonexistent or is blocked, preventing subsequent elongation of the 
nascent DNA chain.  Once incorporated, the viral enzymes lack the 
capacity to excise such chain-terminating nucleosides.  The cellular DNA 
polymerases (alpha, beta, gamma), supposedly, have more fidelity and are 
less likely to incorporate the phosphyorylized AZT.  But that fidelity 
isn't that great or else there wouldn't be so much toxicity from the use 
of AZT (and the rest of the nukes).

It has been established that AZT users have benefits from AZT such as 
transient increases in CD4 T cells and decreased numbers of 
opportunistic infections resulting in a delayed AIDS diagnosis but very 
little or no increase in survival time.

The accepted explanation for this is that CD4 T cells are not getting 
infected because of the action of AZT in preventing viral DNA formation 
because of interference with the action of reverse transcriptase.  
Therefore, the CD4 T cells are not getting destroyed by infection 
resulting in increased numbers and more T helper cells to mediate the 
effector cells that control opportunistic infections.  But it has been 
established that the T helper cells are not destroyed just because they 
become infected.  In fact, they can still function quite normally when 
the provirus is integrated into its cellular genome.  

During the chronic or latent phase of AIDS, there is only a small amount 
of virus being released but the increase in CD4 T4 counts of AZT users 
can be 10 to 50% of the baseline counts in peripheral blood as 
determined by FACS or other methods.  Since these counts are only a 
reflection of the total number of T4s in the body, that would mean that 
AZT is preventing the infection and destruction of millions and millions 
of T4 cells by HIV.  But, it has been established, that HIV production 
is small at this time and that T4 cells are not necessarily destroyed 
when infected.  Also T4 cells are being replaced daily in huge numbers 
and only a small number are actually infected.

For the sake of my *silly* new theory, I will *pretend* that this 
explanation for the results shown in AZT users is not very realistic or 
even logical.

What, then, could explain these positive benefits shown in most AZT 
users when AZT is first used?.

AZT is not only absorbed/adsorbed by T4 cells but by most other cells.  
Studies have shown that monocytes/macrophages can also intracellularly 
accumulate AZT.  They are the scavengers of the immune system and *eat* 
all sorts of antigens: they are not very particular with what they 
ingest.  They also have the ability to catabolize (breakdown) what they 
*eat* and present these non-self antigens on their Class II MHC 
molecules (HLA-DR,DP, DQ in humans).  Monocytes/macrophages circulate 
through the system including the lymph nodes, bone marrow, brain, CNS, 
thymus, spleen, etc.  Probably presenting antigens wherever they go and 
since they are continually being destroyed and replaced, they might just 
be dropping off AZT in all parts of the body along with HIV (they are 
known to be infected by HIV--they have CD4 markers on their surfaces).

If this catabolized AZT was presented to T4 cells as a non-self antigen, 
the T4 cells would respond and initiate first a primary response and 
then a secondary response. The primary response would form memory T4 
cells which would result in circulating AZT memory cells.  Whenever AZT 
was presented by monocytes/macrophages, secondary responses would incur.  
This secondary response is greater than the primary response and would 
result in activation and proliferation of more T4 cells. The result of 
this would be an increased number of T4 cells in the immune system.  
Since AZT is taken continuously during treatment, the immune response 
would be in a constant state of activation similar to what happens to 
allergy suffers when they are constantly exposed to pollen during the 
bad times of the year.

Activated T4 cells initiate effector responses causing activation of 
macrophages and killer cells.  These activated (by AZT memory T cells) 
effector cells would then attack all sorts of microbial agents in the 
body since they are not specific cells but attack indiscriminately and 
randomly.  As the macrophages attack and ingest microbial parasites, 
they would then present these new antigens, activate memory T4 cells 
which would activate more effector cells, ad infinitum, resulting in 
control of the microbial agents that cause opportunistic infections.

The result of all this would be increased T4 cells and control of OIs, 
which is exactly what happens when individuals first use the nuke drugs.

What causes these beneficial effects of AZT to cease after a period of 
time?  The immune system is quite interesting.  If it is in a constant 
state of activation, it wears down and becomes tolerant to the antigen 
that has been continuously stimulating it; this is known as tolerance.
AZT is no longer an immunogen but a tolerogen which is ignored by the immune
system.  It could be caused by clonal anergy, clonal deletion, clonal
exhaustion, clonal abortion, or whatever of the AZT T4 memory cells.  This
effect is well documented in allergy sufferers.  By constantly exposing
ragweed sufferers to continually increasing amounts of ragweed extract, the
immune system becomes tolerant of the ragweed antigen and no longer reacts to
this antigen.  Perhaps, this is what happens in AZT users and results in
cessation of beneficial effects from AZT.  AZT is a non-varying antigen due to
the perfection of the Burroughs Wellcome manufacturing process, unlike HIV
which is a constantly changing antigen.

Some individuals do not become *tolerant* to AZT, therefore their 
beneficial effects last longer.  Other individuals become tolerant in a 
very short time and have limited or no benefits from AZT.  This effect 
could explain the so-called benefits of other nucleoside analogs.  The 
*experts* now are suggesting using nuke drugs in combo.  Perhaps these 
benefits are only from a greater number of immunogens in the body that 
are initiating immune responses resulting in transient benefits until 
the immune system becomes *tolerant* to these antigens.  

Maybe the so-called mutations of HIV have absolutely nothing to do with 
the loss of the positive effects of the nuke drugs.  This theory has 
been questioned many times, because HIV is a continually mutating and 
variable virus.  The only place nukes were ever tested for effectiveness 
was in vitro.  Macrophage AZT antigen presenting capability has not been 
tested.  It has been postulated that infected monoctyes/macrophages 
spread HIV infection while circulating throughout the body.  Perhaps 
they also spread AZT, present AZT, and deposit AZT which results in the 
known toxicity of AZT.

Like I said in the beginning, just another one of my *silly* theories, 
but it was very interesting writing it and, who knows, might provide a 
few chuckles for the *experts*.  But wonder, just wonder, if that might 
be what is happening to users of the nucleoside analogs.
Newsgroups: sci.med.aids