 -=> Quoting Billi Goldberg to All <=-

 BG> Newsgroups: sci.med.aids
 BG> Subject: Is The AIDS Research Focus Wrong?
 BG> Message-ID: <1993Jan6.150425.3745@cs.ucla.edu>
 BG> From: Billi Goldberg <bigoldberg@igc.apc.org>
 BG> Date: Tue, 5 Jan 93 23:06:27 PST
 BG> Sender: usenet@cs.ucla.edu (Mr Usenet)
 BG> Organization: unspecified
 BG> Approved: phil@wubios.wustl.edu (J. Philip Miller)
 BG> Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction
 BG> allowed. Nntp-Posting-Host: sole.cs.ucla.edu
 BG> Archive-Number: 6719
 BG> Lines: 137

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

 BG> This article is very interesting for a number of reasons. It undercuts
 BG> the theories that HIV is not involved in AIDS. Also, it is showing
 BG> that  a larger percentage of cells are infected that previously
 BG> thought. Dr. Haas present an interesting concept that HIV should be
 BG> inhibited  when it leaves the CD4 cell after translation and
 BG> transcription rather  than prior to integration into the cellular
 BG> genome. 
 BG> =======================================================================
 BG> "Tests Show Infection by AIDS Virus Affects Greater Share of  Cells" 
 BG> New York Times (01/05/93), P. C3  (Kolata, Gina)

 BG> Researchers have found that more human cells are actually 
 BG> latently  infected with HIV, which helps explain how the entire  immune
 BG> system is  eventually destroyed.  In 1986, it was believed  that only 1
 BG> in 1,000  white blood cells were infected with the  virus.  But now,
 BG> researchers  are finding that 10, 20, even 30  percent of white blood
 BG> cells may carry  HIV, in addition to other  cells.  As a result,
 BG> researchers conclude  that direct infection  with HIV should be
 BG> sufficient to explain the  destruction of the  immune system in AIDS
 BG> patients.  The polymerase  chain reaction  (PCR) can be used to examine
 BG> HIV by using enzymes to  copy  fragments of genes 100,000 to a million
 BG> times, making it easier   for researchers to study.  PCR is usually
 BG> performed in the test  tube,  with enzymes added to raw DNA.  But
 BG> recently it became  possible to use  cells themselves as miniature test
 BG> tubes, making  holes in the cells,  diffusing reagents for PCR, and
 BG> letting the  biochemical reaction  multiply copies of HIV that are
 BG> hidden in  the cell's DNA.  In a paper  in the current issue of the 
 BG> Proceedings of the National Academy of  Science, Dr. Ashley Haas  and
 BG> colleagues from the University of  Minnesota reported using a  variant
 BG> of PCR to examine tissue from a lung  tumor taken from an  HIV-positive
 BG> patient.  They discovered that as many  as 15 to 20  percent of the
 BG> white blood cells surrounding the tumor were   latently infected with
 BG> HIV.  Regarding drugs to treat HIV  infection,  Dr. Haas said, "I'm not
 BG> sure we can ever prevent  activation."  It makes  more sense, he said,
 BG> to attempt to inhibit HIV when it tries to emerge  from a cell, perhaps
 BG> by blocking a  crucial viral enzyme. 
 BG> =======================================================================
 BG> 
 BG> The past and present concepts in the pathogenesis of AIDS is that HIV 
 BG> destroys CD4 cells rendering the immune system incapable of fighting
 BG> off  opportunistic infections. This leads to the end points of death
 BG> due to  disease progression.

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

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

 BG> Activating the immune response was considered to be "feeding the
 BG> virus"  since immune activation was shown to increase HIV replication
 BG> in CD4  cells resulting in destruction of these cells and increased
 BG> viremia. 
 BG> In the final analysis, the driving force behind HIV/AIDS research in
 BG> the  last ten years was to increase CD4 counts. That is why in clinical
 BG> trials, the primary surrogate marker used to ascertain efficacy 
 BG> of the drugs being tested was CD4 counts. If CD8 counts were done, why
 BG> were they not reported. My guess is that the CD8 counts during the 
 BG> trials decreased due to immunosuppression and were not reported for
 BG> that  reason. It is interesting that nobody has demanded information on
 BG> CD8  counts from the hundreds and hundreds of completed and ongoing
 BG> clinical  trials 

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

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

 BG> When the research focus is turned on its head, we must stop worrying 
 BG> about CD4 counts. We must also be thankful that the immune system is 
 BG> destroying the infected CD4 cells and the intracellular pathogens that
 BG> infect self-cells. Luckily, destruction of these infected self-cells
 BG> is  not controlled by the CD4 cells. These cells when activated can
 BG> cause  proliferation of B cells resulting in antibody production. But
 BG> this arm  of the immune system has little effect in eliminating
 BG> intracellular  pathogens. CD4 cells activate macrophages causing
 BG> proteolysis of  exogenous antigens resulting in macrophage presentation
 BG> on the Class II  MHC. CD4 cells also activate killer macrophages which
 BG> destroy pathogens  by phagocytosis or chemolysis. This type of
 BG> macrophage activation is  local and not systemic nor is it specific.
 BG> But it might be helpful in  forcing antigen presentation of
 BG> intracellular pathogens on Class I MHC  in monocytes and macrophages.
 BG> But, no matter what the CD4 counts are,  there are still billions and
 BG> billions of virgin and memory CD4 cells  that can be activated by
 BG> macrophages, Langerhans, and dendritic cells.  Therefore, CD4s are
 BG> still able to play an important role in acquired  immunity if the
 BG> immune response is not suppressed by drugs. 
 BG> The fly in the ointment is that intracellular infection results in 
 BG> antigen presentation on the Class I MHC which exists on all
 BG> self-cells. The only lymphocytes that are activated by Class I MHC
 BG> presentation are  cytotoxic T8 lymphocytes. These cells do not require
 BG> CD4 helper cells  but are activated by cell-to-cell contact with
 BG> infected or tumor cells.  Along with this specific activation is the
 BG> non-specific activation of  killer cells. These lymphocytes primarily
 BG> destroy infected or abnormal  self-cells; they are most toxic for tumor
 BG> and virus-infected cells. When  CD8 cells are activated, they secrete
 BG> interferon-gamma and IL-2. High  doses of IL-2 are known to be involved
 BG> in the activation of lymphokine  activated killer (LAK) cells which are
 BG> derived from NK cells and T  
 BG> cells. The primary CD8 cytotoxic subsets are HLA-DR and CD56 which
 BG> need  to be increased. CD38 (immature lymphocytes) should be maintained
 BG> at  baseline levels or decreased. Increased CD38s are a sign of disease
 BG> progression. Natural killer (NK) cell activity does not result from an
 BG> immune response but acts continuously and nonspecifically on non-self 
 BG> and tumor antigens located on the surface of self cells.

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

 BG> I say that the focus should be on increasing the number of CD8 cells
 BG> and  disregarding the CD4 counts. Since it is the evolutionary
 BG> responsibility  of the CD8 cells to destroy infected and abnormal
 BG> self-cells, CD8 counts  should be increased. This, then, results in a
 BG> treatment focus  concentrating on boosting the HIV/AIDS weakene


