From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Is The AIDS Research Focus Wrong?
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6719
Organization: unspecified
Date: Tue, 5 Jan 93 23:06:27 PST

     PRESENT FOCUS OF AIDS RESEARCH IS IN THE WRONG DIRECTION
                        by Billi Goldberg

This article is very interesting for a number of reasons. It undercuts 
the theories that HIV is not involved in AIDS. Also, it is showing that 
a larger percentage of cells are infected that previously thought.
Dr. Haas present an interesting concept that HIV should be inhibited 
when it leaves the CD4 cell after translation and transcription rather 
than prior to integration into the cellular genome.

======================================================================= 
 "Tests Show Infection by AIDS Virus Affects Greater Share of  Cells" 
New York Times (01/05/93), P. C3  (Kolata, Gina)

     Researchers have found that more human cells are actually  latently 
infected with HIV, which helps explain how the entire  immune system is 
eventually destroyed.  In 1986, it was believed  that only 1 in 1,000 
white blood cells were infected with the  virus.  But now, researchers 
are finding that 10, 20, even 30  percent of white blood cells may carry 
HIV, in addition to other  cells.  As a result, researchers conclude 
that direct infection  with HIV should be sufficient to explain the 
destruction of the  immune system in AIDS patients.  The polymerase 
chain reaction  (PCR) can be used to examine HIV by using enzymes to 
copy  fragments of genes 100,000 to a million times, making it easier  
for researchers to study.  PCR is usually performed in the test  tube, 
with enzymes added to raw DNA.  But recently it became  possible to use 
cells themselves as miniature test tubes, making  holes in the cells, 
diffusing reagents for PCR, and letting the  biochemical reaction 
multiply copies of HIV that are hidden in  the cell's DNA.  In a paper 
in the current issue of the  Proceedings of the National Academy of 
Science, Dr. Ashley Haas  and colleagues from the University of 
Minnesota reported using a  variant of PCR to examine tissue from a lung 
tumor taken from an  HIV-positive patient.  They discovered that as many 
as 15 to 20  percent of the white blood cells surrounding the tumor were  
latently infected with HIV.  Regarding drugs to treat HIV  infection, 
Dr. Haas said, "I'm not sure we can ever prevent  activation."  It makes 
more sense, he said, to attempt to inhibit HIV when it tries to emerge 
from a cell, perhaps by blocking a  crucial viral enzyme. 
======================================================================= 

The past and present concepts in the pathogenesis of AIDS is that HIV 
destroys CD4 cells rendering the immune system incapable of fighting off 
opportunistic infections. This leads to the end points of death due to 
disease progression.

The past and present attempts at treatment for HIV+ individuals have 
been to destroy the virus and attempt to save the CD4 cells while 
increasing their number for, supposedly, without them you die. 
Nucleoside analogues showed efficacy in increasing CD4 cell counts 
therefore they were approved as treatments.

There are concepts like autoimmune and programmed cell death that, 
theoretically, decreased the number of CD4 cells. To counteract these 
effects, individuals were treated with steroids and other 
immunosuppressive drugs in the hope that CD4 counts would increase.

Activating the immune response was considered to be "feeding the virus" 
since immune activation was shown to increase HIV replication in CD4 
cells resulting in destruction of these cells and increased viremia.

In the final analysis, the driving force behind HIV/AIDS research in the 
last ten years was to increase CD4 counts. That is why in clinical 
trials, the primary surrogate marker used to ascertain efficacy 
of the drugs being tested was CD4 counts. If CD8 counts were done, why 
were they not reported. My guess is that the CD8 counts during the 
trials decreased due to immunosuppression and were not reported for that 
reason. It is interesting that nobody has demanded information on CD8 
counts from the hundreds and hundreds of completed and ongoing clinical 
trials 

Just for the sake of debate, let's turn the past and present research 
focus on its head. The hypothesis then becomes that CD4 cells are 
immaterial in the pathogenesis of AIDS, and their destruction is a 
perfectly normal natural and acquired immune response. Any infected 
self cells must be destroyed by the immune system; that is what the 
immune system is supposed to do to keep people alive.

Therefore, the treatments, past and present, did nothing more than 
suppress the immune system's ability to destroy infected CD4 cells 
resulting in transient increases in CD4 cells. This approach is 
obviously artifactual when one considers that there are many people 
still alive with no CD4 cells (I know some) and many people who have 
died with CD4 counts in the hundreds. The past and present research 
focus has not worked; this is obvious by the 160,000 deaths from AIDS in 
this nation.

When the research focus is turned on its head, we must stop worrying 
about CD4 counts. We must also be thankful that the immune system is 
destroying the infected CD4 cells and the intracellular pathogens that 
infect self-cells. Luckily, destruction of these infected self-cells is 
not controlled by the CD4 cells. These cells when activated can cause 
proliferation of B cells resulting in antibody production. But this arm 
of the immune system has little effect in eliminating intracellular 
pathogens. CD4 cells activate macrophages causing proteolysis of 
exogenous antigens resulting in macrophage presentation on the Class II 
MHC. CD4 cells also activate killer macrophages which destroy pathogens 
by phagocytosis or chemolysis. This type of macrophage activation is 
local and not systemic nor is it specific. But it might be helpful in 
forcing antigen presentation of intracellular pathogens on Class I MHC 
in monocytes and macrophages. But, no matter what the CD4 counts are, 
there are still billions and billions of virgin and memory CD4 cells 
that can be activated by macrophages, Langerhans, and dendritic cells. 
Therefore, CD4s are still able to play an important role in acquired 
immunity if the immune response is not suppressed by drugs.

The fly in the ointment is that intracellular infection results in 
antigen presentation on the Class I MHC which exists on all self-cells.
The only lymphocytes that are activated by Class I MHC presentation are 
cytotoxic T8 lymphocytes. These cells do not require CD4 helper cells 
but are activated by cell-to-cell contact with infected or tumor cells. 
Along with this specific activation is the non-specific activation of 
killer cells. These lymphocytes primarily destroy infected or abnormal 
self-cells; they are most toxic for tumor and virus-infected cells. When 
CD8 cells are activated, they secrete interferon-gamma and IL-2. High 
doses of IL-2 are known to be involved in the activation of lymphokine 
activated killer (LAK) cells which are derived from NK cells and T 
cells. The primary CD8 cytotoxic subsets are HLA-DR and CD56 which need 
to be increased. CD38 (immature lymphocytes) should be maintained at 
baseline levels or decreased. Increased CD38s are a sign of disease 
progression. Natural killer (NK) cell activity does not result from an 
immune response but acts continuously and nonspecifically on non-self 
and tumor antigens located on the surface of self cells.

The question now becomes: Has all the HIV/AIDS treatment research for 
the past ten years been 180 degrees from what it should have been? Since 
there is little doubt that 10 to 30% of CD4 cells are infected, 
increasing their number would just result in increasing the number of 
infected CD4 cells and suppressing the immune response. It is natural 
for the immune system to destroy infected self-cells.

I say that the focus should be on increasing the number of CD8 cells and 
disregarding the CD4 counts. Since it is the evolutionary responsibility 
of the CD8 cells to destroy infected and abnormal self-cells, CD8 counts 
should be increased. This, then, results in a treatment focus 
concentrating on boosting the HIV/AIDS weakened immune system with 
biological response modifiers (BRM) that act specifically on cytotoxic 
CD8 cells and other lymphocyte killer cells.
Newsgroups: sci.med.aids