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Author Topic: 'Runaway' Theory Doesn't Explain Slow CD4 Loss  (Read 4082 times)

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Offline bimazek

  • Member
  • Posts: 781
'Runaway' Theory Doesn't Explain Slow CD4 Loss
« on: May 22, 2007, 07:20:37 PM »
'Runaway' Theory Doesn't Explain Slow CD4 Loss
http://www.aidsmeds.com/articles/1667_11909.shtml

front page of aidsmeds today

basically some scientists feel that no one knows why the CD4 cells slowly disappear in hiv disease in first place, the models they have dont work right

sometimes i feel that science is so compartimentalized now and they are so much about just publishing and not really solving or finding the solution

but of course slow cd4 loss  is not because of cd4s not being replenished

if you search on my posts in research here

u see that

only one in one million cd4 cells are infected and only one in a hundred trillion if someone is undetectable

what causes them to die off is a fas tcell homing signal, and the exhaustion of the CD8 cell by some yet unknown protein that hiv produces that goes into the receptor on the cd8 cell called pd-1

this disease is one of the Tcell homing signal or the disfunction of the cd8 cell due to some errant signal into the receptor of pd-1 on cd8

yes the cd4s are being slowly distroyed but that is in the course of the natual fight and put the soldiers the fighters away into the nodes

that goes on on daily basis in this disease


Offline hahaha

  • Member
  • Posts: 123
Re: 'Runaway' Theory Doesn't Explain Slow CD4 Loss
« Reply #1 on: May 23, 2007, 01:08:18 AM »
I agree.  The same theory will apply on the News several days ago:

"No Drop in Non-AIDS Cancer Rates",

why? I think it is simple because while Pd-1 is high, cancer rate is high,
The current medicince do nothing to reduce the Pd-1 receptor in CD-8,
Therefore PD-1 is high,
Whereas Pd-1 is high, the cancer rate can not be reduce.

It is just simple, why the scientist don't get it??
Aug 9, 2006 Get infected in Japan #$%^*
Oct 2006 CD4 239
Nov 2006 CD4 299 VL 60,000
Dec 1, Sustiva, Ziagan and 3TC
Jan 07, CD4 400

Offline ronaldinho

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  • Posts: 79
Re: 'Runaway' Theory Doesn't Explain Slow CD4 Loss
« Reply #2 on: May 23, 2007, 09:38:53 AM »
This kind of news is scary, cause it shows that scientists still have a very imperfect idea of how HIV works in the body. Considering everything that scientists do not  know about HIV, it is amazing that they have come up with efficient drugs to fight it. I think medical science advances much thanks to  experimental trial and error method. People do not fully  understand what is going on inside ther body, but as long as they can come up with some useful stuff thanks to the trial and error method, then it is OK. In the end, we are just smart monkeys, even the brightest of mankind are nothing more than that.

Offline bimazek

  • Member
  • Posts: 781
Re: 'Runaway' Theory Doesn't Explain Slow CD4 Loss
« Reply #3 on: May 23, 2007, 04:59:40 PM »
 

true
all meds so far, nukes, non nukes, protease inhib

they all work by stopping or slowing a genetic process that the body has that HIV uses to reproduce, it does not directly do things against the virus, but actually do things against body biochem processes that hiv needs

the new gene therapies cut up the virus directly using the bodies natural properties to cut up genes and dispose of them -- this happens all time with old cells and such -- body knows how to cut things up inside cell

the cd8 has not yet been harnessed... it took 20 years to even find the pd-1 and

just 6 months to find all

LTNP have special pd-1 resceptors

this was found by the chinese at univ of beijing in 2007

medarex in NJ has a pd-1 blocker but it is not doing enough in my humble opinion

can someone go to NJ and talk with them


Offline hahaha

  • Member
  • Posts: 123
Re: 'Runaway' Theory Doesn't Explain Slow CD4 Loss
« Reply #4 on: May 23, 2007, 11:21:50 PM »
Just check the pubmed for update, and found out that PD-1 research is now in simian stage:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17376899&query_hl=3&itool=pubmed_docsum

Conclusion: (a) SIV-specific CD8 T cells express PD-1 after exposure to antigen but downregulate expression under conditions of antigen clearance and enhance expression under conditions of antigen persistence.
                (b) The level of PD-1 expression per cell rather than the presence or absence of expression plays an important role in regulating CD8 T-cell dysfunction in pathogenic SIV infection.
                (c) similar to HIV infection, the PD-1:PD-1 ligand inhibitory pathway is operational in pathogenic SIV infection,
                (d) macaque/SIV model would be ideal to test the safety and therapeutic benefit of blocking this pathway in vivo.

I think we need to know more on the Simian first, but the conclusion shall come soon.  All we need to know from Simian is : (a) whether PD-1 can suppress SHIV; and (2) Is there any side effect after injection of Gag specific antibody for PD-1 and (c) what will be a proper dose for Simian? 

Luckily.  The writer of the paper is also in the same group of Vaccine in Emory Univ.  (which just claim that the vaccine may induce LTNP of Monkey)  I guess they will definitely use antibody PD-1 + MVA vaccine as an combination to try on human being. 

Now, all we need is TIME.  To be honest, I feel time is the most essential and urging here.  I am not an American (I am from Taiwan).  Nevertheless, I do sincerely wish there is some activism here to push the Emory Univ vaccine to put into a clinical trial as early as possible.   Thousands of human are dying everyday just because the progress of HIV and millions of people are in HAART treatment all over the world.   This vaccines will definitely need to be in a super-super-super-super hurry to prevent people from DYING. 

CAN ANYONE HELP TO PUSH IT HAPPEN QUICKLY? PLEEEEEEEAAAAASE.
Aug 9, 2006 Get infected in Japan #$%^*
Oct 2006 CD4 239
Nov 2006 CD4 299 VL 60,000
Dec 1, Sustiva, Ziagan and 3TC
Jan 07, CD4 400

Offline SASA39

  • Member
  • Posts: 690
Re: 'Runaway' Theory Doesn't Explain Slow CD4 Loss
« Reply #5 on: May 24, 2007, 06:37:56 AM »
"Therefore, PD-1 is a major regulator of apoptosis that can impact the frequency of antiviral T cells in chronic infections such as HIV, and could be manipulated to improve HIV-specific CD8+ T cell numbers, but possibly not all functions in vivo"

http://www.jem.org/cgi/content/abstract/203/10/2281

                               Al
Oct.     `06.  CD4=58  ?    %       VL not perform. ?!?
25.Dec.`06.         203       14        VL= 0
29.May.`07.    broken device        VL=1363
20.June`07     broken device        VL=0
25.Dec `07  CD4=582                  VL=70
14.May `08  CD4=448
29.July `08                                  VL=0
26.Nov `08  CD4=674                    VL=179
16.Mar `09  CD4=554                    VL=0
19.Jan`10 CD4=715               
03.Mar`10                                    VL=0
24.Aug`10 CD4=524                     VL=0
04.Dec`10 CD4=626                     VL=0
15.Sep`11                                   VL=93
17.Nov`11                                   VL=0
05/26 .Jul`12 CD4=713                 VL=0
28.Nov`12 CD4=916                     VL=0
09.May`13                                 VL=0

Offline bimazek

  • Member
  • Posts: 781
Re: 'Runaway' Theory Doesn't Explain Slow CD4 Loss
« Reply #6 on: May 24, 2007, 05:29:42 PM »
hahaha... i hear you

i understand

did you read the university of beijing article that said ... do a search on my username bimazek and china or chinese
or LTNP

it seems exciting

pd-1 is marker for all LTNP -- perhaps you can search in your language for articles
is there any research going on in taiwan?


Offline bimazek

  • Member
  • Posts: 781
Re: 'Runaway' Theory Doesn't Explain Slow CD4 Loss
« Reply #7 on: May 24, 2007, 05:50:21 PM »
there are some other interesting findings in this abstract which i will try to translate into human language

first the exciting part..

the level of PD-1 expression per cell rather than the presence or absence of expression plays an important role in regulating CD8 T-cell dysfunction in pathogenic SIV infection. = this tells us why we can do fine even with, well some people can do fine with 180 t cells or 90 or 60 or 5 and not have any horrible aids symptoms while other people can just be a total mess at much higher CD4 numbers... why because the PD-1 receptors PER CELL makes a huge difference on how well the CD8's do thier job and clear up the infection daily as they do for the 7-11 years of the chronic stage of hiv infection... then one day the   PD-1 receptors PER CELL makes a huge difference on how well the CD8's -- sudeenly day by day there are more and more pd-1 expression  PD-1 receptors PER CELL --- that is when the cliff is fallen off -- and then the cd4s get eaten up really fast...

so what this means is to me proof positive that -- the CD8 gets just overwhelmed with exprssion of pd-1 ...
sometimes when at the beginning of infection say the first 3-9 years only say for example one or two a few of the pd-1 receptors on the cd8 cells are turned on... A OK... no problem the CD8 does its job and doesnt collapese and stop working and get exhaused, but one day

there are just tons of more and more pd-1 expression on each CD8 cell-- this is when things get bad and body cant fight off the virus and the CD4s really start dropping...


title...
elevated Expression Levels of Inhibitory Receptor Programmed Death 1 on Simian Immunodeficiency Virus-Specific CD8 T Cells during Chronic Infection but Not after Vaccination.

to me this title is like them trying to say...   we did it we won we succeeded we found a way to turn PD-1 off...
but they say it in a double negative round about scientific way...

"elevated Expression Levels of Inhibitory Receptor Programmed Death 1 on Simian Immunodeficiency Virus-Specific CD8 T Cells during Chronic Infection" = the CD8 cell becomes disfunctional and stops fighting the hiv infection and the patient looses all thier t cells and eventually dies...

 "but Not after Vaccination" =  but Not after OUR NEW Vaccination  = but Not after OUR NEW super duper Vaccination which we all hope to become famous for but because we are scientists we have to be completely cool and calm and act like it isnt a breakthru or we will upset the scientists who didnt get their first

in this study we study the time based changes in the expression of the inhibitory receptor programmed death 1 (PD-1) on simian immunodeficiency virus (SIV) Gag-specific T cells following pathogenic SIV infection or following vaccination with a DNA/modified vaccinia virus Ankara (DNA/MVA) vaccine and simian/human immunodeficiency virus (SHIV) challenge in macaques. =  we watch moment to moment how the vaccine causes the pd-1 receptor to get turned back on again and how this causes the CD8 cells to work super well again...


Following infection, the majority (>95%) of Gag-specific CD8 T cells expressed PD-1, and the level of PD-1 expression per cell increased over time.   = yes this is why how the cd4s get distroyed cause cd8s dont eat them up anymore


The level of PD-1 expression in lymph nodes and rectal mucosal tissue, the major sites of virus replication, was higher compared to blood. ok

In vitro blockade of PD-1 resulted in enhanced proliferation of SIV-specific CD8 as well as CD4 T cells. = if we block pd-1 in test tube... wow we get tons more cd8 cells and even cd4 cells things seem to get better not worse... this is cool stuff..

These results demonstrate that SIV-specific CD8 T cells express PD-1 after exposure to antigen but downregulate expression under conditions of antigen clearance = when the infection is fought off the antigen
clears itself up too just like its suppose too and we are not seeing some terrible thing happening so that is good thing


 and enhance expression under conditions of antigen persistence.

the level of PD-1 expression per cell rather than the presence or absence of expression plays an important role in regulating CD8 T-cell dysfunction in pathogenic SIV infection. = this tells us why we can do fine even with, well some people can do fine with 180 t cells or 90 or 60 or 5 and not have any horrible aids symptoms while other people can just be a total mess at much higher CD4 numbers... why because the PD-1 receptors PER CELL makes a huge difference on how well the CD8's do thier job and clear up the infection daily as they do for the 7-11 years of the chronic stage of hiv infection... then one day the   PD-1 receptors PER CELL makes a huge difference on how well the CD8's -- sudeenly day by day there are more and more pd-1 expression  PD-1 receptors PER CELL --- that is when the cliff is fallen off -- and then the cd4s get eaten up really fast...

so what this means is to me proof positive that -- the CD8 gets just overwhelmed with exprssion of pd-1 ...
sometimes when at the beginning of infection say the first 3-9 years only say for example one or two a few of the pd-1 receptors on the cd8 cells are turned on... A OK... no problem the CD8 does its job and doesnt collapese and stop working and get exhaused, but one day

there are just tons of more and more pd-1 expression on each CD8 cell-- this is when things get bad and body cant fight off the virus and the CD4s really start dropping...


Offline bimazek

  • Member
  • Posts: 781
Re: 'Runaway' Theory Doesn't Explain Slow CD4 Loss
« Reply #8 on: May 24, 2007, 05:59:19 PM »
http://www.google.com/search?hl=en&q=Elevated+Expression+Levels+of+Inhibitory+Receptor+Programmed+Death+1+on+Simian+Immunodeficiency+Virus-Specific+CD8+T+Cells+during+Chronic+Infection+but+Not+after+Vaccination.&btnG=Google+Search

i am trying to read thru all of these papers...

looks like new stuff on PD-1 that i havent had time to catch up on....  here are some small snippets of hundreds of pages...

At least two interventions have now proven successful in vitro in restoring the proliferation of HIV-specific CD8+ T cells: the addition of IL-2 (or CD4+ T cells producing IL-2) and the manipulation of costimulatory pathways such as PD-1. This raises the question of whether these two different manipulations affect proliferation through overlapping intracellular mechanisms. In addition, whether they can act in a synergistic mode remains to be elucidated. Since IL-2 cannot overcome the proliferative defect in CD57+CD8+ T cells (45), it is of particular interest to examine whether manipulation of PD-1–induced pathways could specifically restore their proliferative capacity.

A clear conclusion from our results is that the absolute level of PD-1 expression is a major determinant of spontaneous apoptosis and sensitivity to PD-1 ligation. We conclude this despite our observation that PD-1– HIV-specific CD8+ T cells are often more susceptible to apoptosis than PD-1+ CMV-specific CD8+ T cells (Fig. 5 B). Although it is known that sensitivity to apoptosis is also affected by other factors—specifically the level of T cell activation (defined by CD38 expression; unpublished data) and maturational state, which we have shown is independent of PD-1 expression (Fig. 2, A and B and Fig. 5 C)—our data indicate that PD-1 is a primary determinant of apoptosis sensitivity over and above these other factor



Moreover, in 6 out of 10 subjects there was no
detectable proliferation to HIV p24 protein in the absence of anti-
PD-L1 antibody, but vigorous proliferation in the presence of anti-
PD-L1 antibody in 5 out of these 6 subjects (P ¼ 0.0039; Fig. 4d),
indicating that these HIV-specific CD4 T cells are present but
functionally impaired, and that function can be restored following
blockade of the PD-1 pathway.
These data demonstrate that the PD-1 inhibitory pathway, in
addition to regulating T-cell responses to self antigens and to viral
antigens in mice, also regulates both CD4 and CD8 T-cell responses
to a chronic human viral pathogen characterized by persistent
viraemia and ultimately profound immune suppression. PD-1
expression was upregulated on total CD8 and CD4 T cells in people
with chronic HIV infection naive for anti-retroviral therapy, and
tetramer staining showed that this upregulation was markedly higher



A critical finding of the present study is that therapeutic vaccination is more effective when the viral load is low. These data fit well with our current understanding of T-cell dysfunction during chronic infections (41). First, CD8 T-cell exhaustion during chronic infections occurs in a hierarchical manner, with CD8 T cells gradually losing different effector functions as the viral load increases (interleukin-2 [IL-2] is lost first, followed by ex vivo killing and the loss of tumor necrosis factor alpha and finally the loss of IFN-γ), and eventually virus-specific CD8 T cells may be physically deleted (12, 43). On the one hand, when the viral load is high and exhaustion and/or deletion is severe, therapeutic vaccination alone is unlikely to be highly beneficial. Indeed, the therapeutic vaccination of mice infected with LCMV in utero (LCMV carrier mice), which experienced life-long infection and possessed few, if any, LCMV-specific T cells, did not result in viral clearance or generate substantial LCMV-specific responses (40). Similarly poor results have been reported for the therapeutic vaccination of human hepatitis B virus (HBV) carriers, who are also often characterized by weak to undetectable antiviral responses (9). In these settings, central or peripheral tolerance and the deletion of virus-specific T cells may result in very few, if any, T cells that can be targeted or boosted by a therapeutic vaccine, and these observations suggest that it will be difficult to generate a de novo antiviral response in some cases. On the other hand, our data also suggest that at lower viral loads, when T-cell exhaustion/deletion is less extreme, therapeutic vaccination will be more effective. The clinical implications of this correlation between the viral load and the response to therapeutic vaccination are obvious. If the viral load can be lowered (e.g., by the use of antiviral drugs) and T-cell function thus improves, then the effectiveness of therapeutic vaccination may be enhanced. Indeed, studies with nonhuman primates support this idea since therapeutic vaccination is more effective following HAART-mediated control of SIV replication (15). In future studies, it will be important to more fully determine the impact of changes in the viral load on the effectiveness of therapeutic vaccination.

Offline bimazek

  • Member
  • Posts: 781
Re: 'Runaway' Theory Doesn't Explain Slow CD4 Loss
« Reply #9 on: May 24, 2007, 06:04:19 PM »
 "but Not after Vaccination" =  but Not after OUR NEW Vaccination  = but Not after OUR NEW super duper Vaccination which we all hope to become famous for but because we are scientists we have to be completely cool and calm and act like it isnt a breakthru or we will upset the scientists who didnt get their first


that is a pretty cool statement and they even capitalized Not (for a scientist that is probably like screaming)

BUT NOT after our new vaccination we are using!!!

NOT is a very nice word...

especially when it negates the entire disease process of hiv which is... the cd4s getting killed off

but Not after OUR NEW Vaccination

many bad things happening

but Not after OUR NEW Vaccination

basically i think they are saying... hey take a good long look at this... we are even capitalizing Not...

or at least the first letter,

if they capitalized the entire word NOT they probably wouldnt get invited to the big dinner events

i am very excited about this




 


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