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Author Topic: 2007 FasL anti-body would block this process - sounds like breakthrough to me  (Read 3649 times)

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Offline bimazek

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  • Posts: 781
scientific papers online about hiv and i did a search on 2007 hiv papers, there are 87 so far.  This one really stands out!
 
*2007
 
*new cd4 cells die in the lymph nodes not in the blood but specifically in the lymph nodes of the gut
 
*but the loss in the gut lymph nodes is not mirrored in the blood or other lymph nodes
 
*which explains why blood cd4 counts do not give a whole picture of the person and what he is facing
 
*also strangely uninfected nearby bystander cd4 cells die --- not the hiv infected ones
 
*FasL anti-body would block this process - sounds like breakthrough to me
 
*only one cd4 cell in 1,000,000 is producing virus, very few of them is infected
 
*hiv is a disease of the homing of the cd4s back to the nodes to be distroyed, the body thinks it has cleared the infecton
after the 2 week initial burst or the chronic fight and then cytokines that home the cds back to the nodes are relesased this tricks the cd4s to go back to nodes and some other molecule switch tells the cd4s to aposisis the un-infected cd4s in the nodes
 
A HOMING RECEPTOR ON OUTSIDE OF UNINFECTED CD4 CELLS GETS TURNED ON BY BEING CLOSE TO OR TOUCHING AN HIV PARTICLE (BUT NOT INFECTED BY IT) THIS CAUSES THE CD4 TO HOME BACK TO THE LYMPH NODE TO KILL ITSELF CALLED APOSISOS...
 
so the disease is actually a disease of the uninfected cells dying
the cd4s that are dying ARE NOT INFECTED
we loose cd4s that are not even infected!!!
this is a huge breakthru if you ask me...
 
sure
 
when you get a flu there is that awful giant wave of immune response and all those terrible chemicals cytokines and bugs being killed off
then the immune system pulls back and says, did i get it all, and then it hits with another wave, then pulls back, and then
says ok i finished and i have to put away all the tanks and big guns and rifles...  thats when the cells get called back to the nodes
that means...
 
that is the period called homing back to the lymph nodes
 
so something wierd is happening in hiv disease because the body thinks the infection has been dealt with then
it calls back the cd4s into the nodes and because they have touched or recieved a signal -=BUT ARE NOT INFECTED OR NOR WILL THEY BE INFECTED-
THEY do aposisos and they die and that is why cd4s deplete
 
it is not the infected ones that die off!!!!
 
also this explains why all those weird alternative therapies though they dont stop it can have some minor effects
 
anything that disrupts the homing of the uninfected cd4s back to the node to aposisos or self die.
 
it all has to do with the FasL --- some chemical in immune system
CD62L is also involved
 
the cool thing is with a anti-FasL monoclonal antibody... which is big time expeimental stuff real complicated to create
they can stop the FasL induced death of the cd4s
 
listen they just figured out which and how the cd4s where dying off a few weeks ago.. before they thought the infected ones were dying
 
now they find out more
 
only the CD62L receptor tells the poor uninfected cd4 cell to go home
but it may be that CD62L and a few other receptor switches get turned on once in the node and the poor cell is told to die off
your job is done
 
 
http://www.jleukbio.org/cgi/rapidpdf/jlb.0506338v1.pdf
 
The hallmark of HIV-1 disease is the
gradual disappearance of CD4 T cells from the
blood. The mechanism of this depletion, however,
is still unclear.
 
Evidence suggests that lymphocytes
die in lymph nodes, not in blood, and that uninfected
bystander cells are the predominant cells
dying. Our and others’ previous studies showed
that the lymph node homing receptor, CD62 ligand
(CD62L), and Fas are up-regulated on resting
CD4 T cells after HIV-1 binding and that these
cells home to lymph nodes at an enhanced rate.
During the homing process, signals are induced
through various homing receptors, which in turn,
induced many of the cells to undergo apoptosis
after they entered the lymph nodes. The purpose of
this study was to determine how the homing process
induces apoptosis in HIV-1-exposed, resting
CD4 T cells. We found that signaling through
CD62L up-regulated FasL. This resulted in apoptosis
of only HIV-1-presignaled, resting CD4 T
cells, not normal CD4 T cells. This homing receptor-
induced apoptosis could be blocked by anti-
FasL antibodies or soluble Fas, demonstrating that
the Fas-FasL interaction caused the apoptotic
event. J. Leukoc. Biol. 81: 000–000; 2007.
 
 
Steroids, which are known to down-regulate CD62L and retard
lymph node homing, have been shown to stop reduction of CD4
cells in the blood of patients  This may be the consequence
as control of aberrant homing signals for the marked
reduction in apoptosis. Future studies, testing whether inhibition
of lymph node homing or homing receptor induction of
apoptosis would prevent depletion of CD4 cells in patients,
are needed.

One of the
major observations in this study is that apoptosis of HIV-1-
exposed, resting CD4 T cells, in which CD62L was crosslinked,
could be inhibited significantly by blocking anti-FasL
antibodies or sFas (Fig. 4). This indicated that apoptosis of
HIV-1-exposed, resting CD4 T cells, subsequently signaled
through the homing receptor, is Fas-FasL-mediated. It is interesting
that apoptosis was detected in resting CD4 T cells
exposed with X4 virus strain (HIV-1213) or R5 virus (HIV-1BaL)
strain, subsequently signaled by XLCD62L, indicating that this
is a common property of HIV-1 (Fig. 2). Furthermore, such
effect seems to be independent of HIV-1 replication, as UVinactivated,
HIV-1-exposed, resting CD4 T cells, upon
XLCD62L, underwent apoptosis as well (data not shown).
 

Based on
our data, we proposed that in vivo, CD4 T cells are infected
with HIV in Peyer’s patches, where they may get the signals for
homing fast and up-regulated Fas and get the further signals,
such as FasL, through interaction between homing receptors
and their ligand on lamina propria and finally, undergo apoptosis
in lamina propria. We are currently working on the
effects of HIV on gut homing receptor  4
7 and consequence
of cross-linking of  4
7 on the HIV-exposed CD4 T cells
 
 
 
With respect to the in vivo relevance of our findings in the
context of HIV-1 pathogenesis, our data implicate the following
scenario to be operative in vivo and may act as a mechanism for
the death of uninfected CD4 cells. Resting CD4 lymphocytes
in lymphoid tissues (in gut, lymph nodes, etc.), coming
into contact with HIV-1 virions, productively infected cells, or
HIV-1-coated, follicular dendritic cells, result in induction of
a partially activated phenotype, including up-regulation of
homing receptors and Fas. Because of normal lymph node/
blood circulation, in which most lymphocytes in lymphoid
tissues migrate back to the blood within 2 days [56], many of
these cells will end up back in the blood at the time of
maximum-induced expression of homing receptors. These cells
would then home rapidly to peripheral lymph nodes or gutassociated,
lymphatic tissue, dependent on the type of homing
receptors (e.g., CD62L for peripheral lymph nodes;  4
7 for
gut). Following transendothelial migration, these CD4 T cells
receive signals through homing receptors, resulting in induction
of FasL expression on some of the cells and rapid susceptibility
 

Consequently, together
with the increased Fas expression within the same
CD4 T cell population, approximately one-third of them
would be depleted, and they do not produce HIV-1 [18]. In
support of this review, features that are characteristically associated
with HIV-1 infection include the following. As CD4
lymphocytes disappear in the blood, their numbers do not drop,
and the CD4/CD8 ratios do not invert in lymph nodes until late
in disease [57]; there is increased apoptosis of uninfected cells,
mainly localized in lymph nodes or gut-associated lymphatic
tissue [6, 45, 58] but not in the blood [59, 60]; there is
increased FasL-expressing cells with the morphology of macrophages
and lymphocytes, and the degree of FasL in vivo has
been shown to be correlated with the degree of apoptosis [61].
 
Steroids, which are known to down-regulate CD62L and retard
lymph node homing, have been shown to stop reduction of CD4
cells in the blood of patients [62]. This may be the consequence
as control of aberrant homing signals for the marked
reduction in apoptosis. Future studies, testing whether inhibition
of lymph node homing or homing receptor induction of
apoptosis would prevent depletion of CD4 cells in patients,
are needed.
ACKNOWLEDGMENTS
 
Steroids, which are known to down-regulate CD62L and retard
lymph node homing, have been shown to stop reduction of CD4
cells in the blood of patients [
 
Steroids, which are known to down-regulate CD62L and retard
lymph node homing, have been shown to stop reduction of CD4
cells in the blood of patients  This may be the consequence
as control of aberrant homing signals for the marked
reduction in apoptosis. Future studies, testing whether inhibition
of lymph node homing or homing receptor induction of
apoptosis would prevent depletion of CD4 cells in patients,
are needed.

 
Infection with HIV-1 is usually characterized by a gradual and
inexorable depletion of CD4 T lymphocytes. The importance
of the loss of these cells in the development of AIDS is
unquestioned, as it correlates with the loss of immune capabilities
and the consequent occurrence and severity of opportunistic
infections and HIV-1-associated neoplasms. However,
understanding the mechanisms by which HIV-1 causes CD4
T cell loss remains one of the unanswered questions in the
AIDS field. Many mechanisms have been proposed to explain
how HIV-1 causes depletion of CD4 T cells and the earliest
theorized that virus replication in CD4 T cells resulted in
their death or that virus-specific CTLs killed these infected
cells. However, elimination of productively infected cells could
not explain the significant loss of CD4 T cells [1], as few cells
in vivo are producing virus at any given time (approximately
one in 105 cells) [2, 3]. Recent studies suggest that depletion
of CD4 T cells mainly occurs in lymphoid tissues of the
gastrointestinal tract [4, 5], but the loss of these cells in the gut
is not mirrored in the blood and lymph nodes. In fact, CD4 T
cell depletion occurs in the “effecter area” of gut (lamina
propria) not in the “inductive area” (Peyer’s patches), where
most of the cells producing virus reside. It has also been shown
that increased numbers of CD4 cells are dying in peripheral
lymphoid tissues of HIV-infected subjects, but cells replicating
HIV-1 are not the principal cells dying; uninfected, neighboring
cells are dying [6]. Therefore, most theories about how
HIV-1 depletes CD4 T cells now depict ways uninfected
bystander cells can be eliminated. Some early studies indicated
that HIVgp120 binding to CD4 and CXCR4 receptors
induced apoptosis [7, 8]. All of these studies used transformed
cell lines, and studies using normal CD4 lymphocytes did not
find this phenomenon [7–11]. Also, the apoptosis induced in
cell lines was not Fas/Fas ligand (FasL)-mediated, but other
pathways were [7–9]. Recently, collagen deposition-associated
fibrosis and damaged lymphatic tissues that accompany immune
activation have been shown to be correlated inversely
with blood CD4 T cell count [4, 12]. Some studies suggest
that there is a significant dysregulation of cytokine responses,
which likely, influences T cell susceptibility to apoptosis [13].
Many of these factors may play some roles in CD4 T cell
depletion. However, excessive apoptosis of uninfected CD4 T
cells is thought to be the major reason for depletion of CD4
T cells [13, 14].
Our previous studies showed that HIV-1 binding to resting
CD4 T cells up-regulated the expression of CD62L, the
receptor for homing to lymph nodes, on some cells and enhanced
the homing of these cells from the blood into lymph
nodes [15–17]. Subsequent signaling through various homing
receptors during the homing process on these abortively infected
CD4 T cells induced many of them to undergo apoptosis
[16]. These signaling events occur when the cells transendothelial
migrate into lymph nodes, and it was shown that
CD4 T cells in the blood of HIV-infected people
 
 





Steroids, which are known to down-regulate CD62L and retard
lymph node homing, have been shown to stop reduction of CD4
cells in the blood of patients  This may be the consequence
as control of aberrant homing signals for the marked
reduction in apoptosis. Future studies, testing whether inhibition
of lymph node homing or homing receptor induction of
apoptosis would prevent depletion of CD4 cells in patients,
are needed.

IN THE LATE 80S AND EARLY 90S BEFORE good meds many hiv people seemed to prolong life somewhat
with steroids, perhaps this is the reason it worked

even today many hiv people take steriods for many reason

please comment...

my questions

what kind of steroids are the dr.s talking about?
what is the plan?
how big of a breakthru is this?





 
 
 
also
 
 
2007 hiv vaccines new book
http://books.google.com/books?hl=en&lr=&id=-m6H5kDm1JAC&oi=fnd&pg=PR7&sig=qGajLPO-zwTzLJs4einNA782HWc&dq=hiv#PRA2-PA56,M1

Offline bimazek

  • Member
  • Posts: 781

does anyone else think this is a big breakthrough, is anyone very science educated or a researcher who can comment on this?


Offline milker

  • Member
  • Posts: 4,034
  • Protected phone sex
Bimazek you're obsessed with this "homing" process. It's only a few months old and is just a new discovery that has not been confirmed yet. Calm down. Every new discovery is great, but if the homing process is something that has to be worked on, it won't happen tomorrow.

Please stop declaring new discoveries as possible cures.

Milker.
mid-dec: stupid ass
mid-jan: seroconversion
mid-feb: poz
mar 07: cd4 432 (35%) vl 54000
may 07: cd4 399 (28%) vl 27760
jul 07: cd4 403 (26%) vl 99241
oct 07: cd4 353 (24%) vl 29993
jan 08: cd4 332 (26%) vl 33308
mar 08: cd4 392 (23%) vl 75548
jun 08: cd4 325 (27%) vl 45880
oct 08: cd4 197 (20%) vl 154000 <== aids diagnosis
nov 2 08 start Atripla
nov 30 08: cd4 478 (23%) vl 1880 !!!!!!!!!!!!!!!!!!!!!!!!!!
feb 19 09: cd4 398 (24%) vl 430 getting there!
apr 23 09: cd4 604 (29%) vl 50 woohoo :D :D
jul 30 09: cd4 512 (29%) vl undetectable :D :D
may 27 10: cd4 655 (32%) vl undetectable :D :D

Now accepting applications from blowjob ninjas™

Offline bimazek

  • Member
  • Posts: 781

milker i will not calm down etc, i have read 5000 articles and spent 12 months, 5 hours a day doing it, if i find something that I know is revolutionary and a breakthru i am going to write about it. 

if i find something that I know is important i am going to write about it. 

if i find something that I want others to learn about so they can ask their doctor which can only cause the doctors to ask about it at the next  conference  i am going to write about it. 

you should be thanking me for the hard work

i dont post thousands of  other things that are not as important

homing is important because, it is one of the big big mysteries of hiv... the infected ones are not the ones that die off

90% of what they teach in a basic, you have hiv now this is how the virus and meds work class is such a gross simplification that it could not be really considered true, although the truth is so complicated that it might take 5 months of classes to explain

three big mysteries of hiv for last 25 years...

1.  why do CD8 cells slowly stop fighting the hiv virus infection, even though the day before the person dies of hiv there are tons of cd8 cells, enough to completely surpress the virus!!!! this paradox was found 18 years ago and this mystery paradox was solved only 6 months ago!!!   that is huge discovery and can be seen in my post on CD8 cells on this forum...  everyone on or off haart has enough cd8 killer cells that are hiv specific to completely control the virus with no side effects and no disease progression, the discovery in august 2006 is that the hiv specific cd8 killer cells go to sleep, more and more of them every month... this is caused by a molecule that has yet to be exactly identified, this discovery will win the nobel prize

2.  homing signal... this has been a huge mystery for 25 years, where and when and why do CD4 cells die
now we know exactly how when where and why the uninfected ones self distruct

3.  nef protein ... no nef, no hiv, no aids, no sickness, no disease, hiv produces nef, they are working on this and have made many discoveries

i start my research by looking at all the new scientific articles on a subject then tracing back thru the years to see how important it is...





Thanks

Offline milker

  • Member
  • Posts: 4,034
  • Protected phone sex
Bimazek,

don't get me wrong, every new discovery is a great thing. But saying things like this:

"so the disease is actually a disease of the uninfected cells dying
the cd4s that are dying ARE NOT INFECTED
we loose cd4s that are not even infected!!!
this is a huge breakthru if you ask me..."

Is declaring that the cause of the disease has been found that makes me uncomfortable. It may be true! But it may not. My feeling is that posting this is a great thing to keep people aware of new discoveries, but not everyone can understand exactely how the virus goes from point A to point B and how the body works, so they will read the post then see this sentence, and think "omg they found the cause!".

"nef protein ... no nef, no hiv, no aids, no sickness, no disease, hiv produces nef, they are working on this and have made many discoveries"

nef protein has been talked about since 1986. This is 2007 and there has been no "nef protein destructor" found for 11 years. What makes it difficult to figure out is the difference between its behavior against SIV compared to HIV, and this is extremely complex stuff ! So what i'm saying is just that it's great to discover, it doesn't mean that it's the end of hiv.

Trust me, I want to get rid of this as fast I got it. I'm sorry if my post was a bit overreactive.

Milker.



mid-dec: stupid ass
mid-jan: seroconversion
mid-feb: poz
mar 07: cd4 432 (35%) vl 54000
may 07: cd4 399 (28%) vl 27760
jul 07: cd4 403 (26%) vl 99241
oct 07: cd4 353 (24%) vl 29993
jan 08: cd4 332 (26%) vl 33308
mar 08: cd4 392 (23%) vl 75548
jun 08: cd4 325 (27%) vl 45880
oct 08: cd4 197 (20%) vl 154000 <== aids diagnosis
nov 2 08 start Atripla
nov 30 08: cd4 478 (23%) vl 1880 !!!!!!!!!!!!!!!!!!!!!!!!!!
feb 19 09: cd4 398 (24%) vl 430 getting there!
apr 23 09: cd4 604 (29%) vl 50 woohoo :D :D
jul 30 09: cd4 512 (29%) vl undetectable :D :D
may 27 10: cd4 655 (32%) vl undetectable :D :D

Now accepting applications from blowjob ninjas™

Offline bimazek

  • Member
  • Posts: 781
What is so giant about these new discoveries is that before they didnt understand the disease very well, now with the CD8 and the homing signal some very important things are understood.  Before when they made mathmatical computer models of all the viruses and all the cells and what they did and what the meds did, it never worked out exactly right so they had to use some math tricks, now they have greatly increased idea of the mechanisms and how to fight them and as the top researcher told me on the phone, the great thing is they already have

an     anti-pd-1 and anti-ctla monoclonal antibody developed so they can start testing it right away

if it works then they can work on some new meds for homing and for CD8



Offline pinkadam

  • Member
  • Posts: 76
Bimazek

You are great. Do your thing buddy.
We need people like you. We are counting on you !!!

Pink

 


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