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Author Topic: CD8 new meds in the works, cd8 naturally eat up the infected cd4s  (Read 8628 times)

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Offline bimazek

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GOOD NEWS IN THEFIGHT AGAINST HIV   

For the first time in History new drugs to treat the CD8 cells in HIV Disease
The discovery... the existance of the PD-1 hi HIV-specific CD8 T cells
   
Amazingly Scientific Discovery
Effective New Potential Treatment Of HIV As Well As Cancer.

Scientists have recently discover why the CD8 T cells "turn off" in HIV disease.   Researchers have found a switch on the HIV-specific CD8 T cells, a receptor, called PD-1, that turns the cell off.           

In 1986 scientists discovered that in people infected with the human immunodeficiency virus (HIV), the immune system's activated cytotoxic CD8 T cells (HIV-specific killer cells) becomes disfunctional.  In 1983 scientists discovered that CD4 T cells were infected by HIV and destroyed.
Mysteriously, the HIV-specific CD8 T cells become exhausted, turned off, disabled.  CD8 T cells have CD8 receptors which recognize antigens virus-infected cells, bind to the infected cell and kill them.  In the case of HIV the CD8 cell binds to the CD4 T cell.  Called Killer T cells and HIV specific these do the dirty work of the immune system.  They function well during the first week or two of an HIV infection when fever was present but then they stop working properly.

Now for the first time in history scientist understand why they stop working. When the PD-1 switch on the surface of the cell is turned on they call it:  PD-1 hi HIV-specific CD8 T cells.  And that is the reason why CD8 T cells stop attacking the HIV virus.

PD-1 hi HIV-specific CD8 T cells are turned off and disfunctional and this state  can persist throughout the course of
infection. This is advantageous for the virus, because it hampers
the renewal of functional HIV-specific CD8 T cells by accumulating a
functionally impaired population and preventing the re-establishment of
a billions of functionally competent HIV-specific CD8 T cells.
PD-1 hi HIV-specific CD8 T cells also do not express a costimulatory molecule which could further contribute to theirreduced growth potential and their lack of IL-2 production

This is an earthshaking discovery (with application in HIV, cancer, and dozens of diseases.)   And critical because normally, CD4 and CD8 cells are trained to attack viruses. CD8 cells learn what exact 'bug' they should attack.  With the CD8 cells turned off, the CD4 cells destroyed, the body become more defenseless against HIV.

CD4 cells are destroyed, but CD8 cells were still present in large numbers. No one knew why the CD8 T cells stopped functioning, or how to turn the CD8 T cells back on, or if they would even function again if they were turned on.  Scientists knew only that CD8 cells stopped functioning and stopped attacking the HIV virus. 

Now they know why it stops and how to start it back up again.

Twenty two years of hard work by thousands of scientists and a group at Harvard, and in Montreal Canada, have discovered why the HIV-specific CD8 T cells turn off.  The discovery came by analysizing the human genome one sequence at a time to see what kind of molecule was produced by each group sequence then doing tests on that molecule.  Eventually they found a sequence that produced a protein molecule and this lead to learning of the existence of the PD-1 receptor pathway on the   CD8 T cell.  This genome research has finally paid off big time.

Researchers have found a pathway-like switch on the CD8 T cells, a receptor, called PD-1, that turns the cell off.  That discovery is the first part of the good news.

The second part is that they have also discovered the exact shape of the molecule, called anti-PD-1, a new monoclonal antibody molecule unknown until recently that will block the action and allow the cell to turn on again.  The anti-PD-1 monoclonal antibody blocks the functioning of the PD-1 therefore turning the cell back on.

The third part of the good news is the discovery that when the action of PD-1 is blocked, the CD8 cell reactivates, undamaged in any way, and it still has its memory to attack HIV.  Also, the CD8 cell is still a good cloner and can multiply thousands of times and do its job.   PD-1 is an inhibitory key so when the action is blocked the CD8 T cell turns back on.

Fourth came the discovery that the reactivated CD-8 cell retains a memory that it should attack HIV.

Finally, and this is the best news of all because it can take a decade to create a new drug and another decade to approve it, there is already a anti-PD-1 monclonal antibody molecule that has been approved for another use that will fit in the pathway and turn the CD8 cell back on!  Researchers are hoping to start larger HIV trials in Montreal and in Boston at Harvard's Massachusetts General Hospital.  One company in New Jersey has MDX-1106 has the anti-PD-1 antibody already in existence.  And the entire PD-1 pathway gives scientists lots of targets for new small molecule medicines that turn PD-1 off both outside the cell and many possibilities inside the cell where it is built and moved to the surface.

In Cancer and HIV the constant presentation of antigen to the immune system exhausts the CD8 T cells and
this has only recently been discovered. 

a new medicine needs to inhibit the ligation of PD-1
or inhibit PD-1 at the surface or inside the cell

A new drug which must inhibit molecules inside the cell that specifically are involved with the PD-1 pathway inside the cell as specificly as possible

PD-1 is produced inside the cell and moves to the surface in great numbers and stays on the surface the PD-1 molecule is up on the surface of the cell, it is up regulated, always up and remains up.  This is called PD-1 hi.

after trigger PD-1 res. inside the cell

signalling pathways

what needs to happen now is screening molecules that bind to PD-1,and
screening molecules that interfeer with PD-1, to find potential drug candidates that can be used for treatment of
HIV and Cancer.

so there are many targets for new drugs including, PD-1 effects both on the surface of the cd8 cell and inside the cd8 cell.

more excited and hopeful now
this is a huge huge discovery
it means that new meds can be given which will work on the CD8 cells

Currently  HAART treatment of today and all medicines that are available, of the triple cocktail all of them only works on the cd4 cells. 

There has never been a medicine until now that works to stimulate the CD8 T cell.

Soon there will be new medicines that will work on the CD8 T cells.

And these medicines that will work for cancer
because cancer is a chronic infection turning off the cd8 cells just like HIV!
That is another part of the amazing new discoveries. 

HIV discoveries may lead to the best treatments for cancer in history. 
Many diseases are chronic infections of viruses or bacteria that the body cannot properly clear.

Hiv attacks cd4 cells and lives and reproduces inside the CD4 cells but Hiv turns off cd8 cells which stops the body from being able to fight off the hiv, in the CD4 cells.

Hiv attacks cd4 cells and lives there but turns off cd8 cells which stops the body from being able to fight off the hiv, in the  CD4 cells.

cancer attacks certain cells and lives and reproduces inside these tumor cells but turns off cd8 cells which stops the body from being able to fight off the cancer in a similar way...

A blockade of PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity.   expression of PD-1 is widely expressed in cancers.  "Contemporary approaches for vaccination and immunotherapy are often capable of eliciting strong T-cell responses against tumor antigens. However, such responses are not parallel to clinical tumor regression. The development of evasion mechanisms within tumor micro-environment may be responsible for poor therapeutic responses," researchers in the United States report.


HOW OTHER ANIMALS SUPRESS VIRUS     
     
Nine percent of all cats in the USA have the feline version of HIV and they do not progress to disease.  The cats natural immune system suppresses the virus.  Just like how the human body suppresses a cold sore or small pox virus.  Also monkeys, chimps and some great apes who get their version of the HIV virus do not progress.  This is because the HIV specific CD8 T cells in these animals never get exhausted and fight it off just fine, repressing the virus for the life of the animal.  Their own immune system, because the PD-1 switch is not turned on, takes care of the virus on its own without medicines.  Now scientists know how and why. And how and why human's immune system is different and how to stimulate the human immune system or how to unblock and excite the exhausted CD8 T cells.


PD-1 is turned on in a chronic human viral infections. Scientists examined PD-1 expression on HIV-specific CD8 T cells in 71 infected people.  PD-1 on CD4 T cells showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count. The higher the viral load the higher the PD-1 the higher the CD4 count the lower the PD-1.  Blockage of the pathway increased CD4 and CD8 T-cell function. The immunoregulatory PD-1 pathway is operative during a viral infection in humans, but has a reversible effect in HIV-specific T-cell function and can enhance the function of exhausted T cells in chronic HIV infection.  Analysis reveals that PD-1 was induced by interferon-g but not by growth factor-a and IL-1ß.

The biotech company Medarex does research and drug development in New Jersey and has developed a fully human anti-PD-1 monoclonal antibody for the treatment of cancer. Medarex President and CEO Dr. Donald L. Drakeman believes that MDX-1106 (the anti-PD-1 antibody) is part of an emerging new group of immunopotentiators -- antibodies that target immune regulatory pathways, such as CTLA-4, PD-1 etc. that are designed to boost a patient's immune response to eliminate cancer and chronic [viral] infections.  Medarex is not presently doing any trails for this new immunopotentiator on HIV patients only on cancer patients, but they are collaborating with the Harvard team and the Montreal Canada scientists. Currently, MDX-1106 the anti-PD1 is in Phase I Cancer trails.   
 
     
     FIRST THE MOUSE
     
     Of course the scientists in 2005 and 2006 first researched this breakthrough discovery of PD-1 and its role using mice to see how they did with chronic viral infections.  Now remember, PD-1 had not even been discovered it was unknown to anyone on earth until a short time ago.  They gave some poor mice a bad viral infection, and they found that the anti-PD-1 treated mice resolved the viral infection and remained healthy, and did not exhibit any overt signs of disease.
     
     The scientists treated persistent virally infected mice with anti-PD-1 blocking antibody and monitored T-cell responses and viral control by the mouses own immune system. They found that virus-specific CD8 T-cell responses were enhanced both in number and quality by the anti-PD-1 blockade. The treated mice showed significant increases in the numbers of virus specific CD8 T cells.   And, these T cells  functioned better following anti-PD-1 treatment, and more of the CD8 T cells were capable of producing interferon IFN-gamma and TNF-alpha compared to untreated mice. Two natural molecules that do good things in the immune system to fight off things.
     
     PD-1 blockade resulted in a substantial reduction in virus levels; the treated mice had cleared infectious virus from the blood, spleen and liver, while untreated mice still had high levels of virus in these tissues and died. Also, the anti-PD-1-treated mice that resolved the viral infection remained healthy, and did not exhibit any overt signs of disease.
           
     Importantly these discoveries have huge implications for therapeutic vaccination and T-cell immunotherapy.  Because despite their enormous potential, therapeutic vaccines have had minimal to no success in eliminating chronic viral infections. The main reasons for their failure is the very limited cell population reproduction and growth potential of the exhausted cd8 T cells.
     
     Meaning that even when a vaccine for treatment has been given to a virally infected body in the past and many have been tried, the CD8 T-cells do not proliferate, and increase and divide thousands of times to fight the virus because they have been turned off already by the PD-1 switch.  They have been exhausted by the PD-1.  This is one main reason why vaccines have not been effective for treatment. This provides a powerful new strategy for improving the effectiveness of therapeutic vaccinates against viruses by combining it with anti-PD-1 treatment.
     
     Similarly, the efficacy of T-cell therapy for chronic infections or even cancer tumors may be enhanced by anti-PD-1 treatment.  Also very importantly, after stopping the anti-PD-1 treatment T-cell numbers remained stable and more functional for several weeks. This important breakthrough hints at future anti-PD-1 treatments that could be intermittent.  The expanded number of virus-specific CD8 T cells does not suddenly decline after the antibody treatment has been stopped.
     
       
     The triple cocktail saving lives today called, HAART, a miracle in itself, has a down side because there are so many long term side effects, and the HIV virus mutates around the drugs over a period of a decade leading to many drug resistant strains which are being spread in the community too often.  The anti-PD-1 treatment either alone or with a vaccine or with another drug treatment may one day finally allow the human body's immune system to naturally suppress the virus and give patients long healthy lives without toxic drugs as many other animals immune systems do naturally.
 
     This part is for all budding young geneticists (remember,  gene-splicing is now taught in high school):  The binding site is called PD-1, a type I transmembrane glycoprotein of Ig superfamily, 55 kDa , 55 times the size of a hydrogen atom approximately, with a single extracellular IgV-like domain containing an immunoreceptor tyrosine-based inhibitory motif, it is induced in lymphocytes and monocytic cells following activation.  Blockage of this pathway using antibodies against the PD ligand 1 (PD-L1) restores CD8 T-cell function and reduces viral load.  There is also a PD-L2 with similar related function.  Over the past few years, several new members of the glycoprotein B7 family have been discovered, including B7h, PD-L1, PD-L2, and B7-H3. Although their precise roles in T cell regulation are just now being learned, they have distinct, although partially overlapping functions.    How was PD-1 discovered?  CD28 and inducible costimulator (ICOS) were discovered by the functional effects their monoclonal antibodies had on increasing T-cell proliferation.  PD-1 and Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and B- and T-lymphocyte attenuator (BTLA) were discovered by screening for genes differentially expressed in cytotoxic T lymphocytes (CTLs) or in cells undergoing apoptosis, or overexpressed in T helper cells
     
     Exciting new cancer therapies from medarex:
         
     MDX-1106 (ONO-4538) anti-PD1    Cancer    Phase I    Ono Pharmaceutical     
     
     MDX-010 (ipilimumab)  anti-CTLA4    Melanoma, Other Cancers     Phase III    Bristol-Myers Squibb
       
     HuMax-CD4 (zanolimumab) anti-CD4    Cutaneous T-cell Lymphoma    Phase III    Genmab/Serono


Offline Cheo63

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  • Posts: 35
Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #1 on: February 05, 2007, 11:25:16 PM »
Wow, this certainly sounds like a great break through!  I hope trials will begin on HIV+ people soon!!
Thanks for the info!

Offline ronaldinho

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  • Posts: 79
Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #2 on: February 06, 2007, 07:47:50 AM »
This sounds so great that i wonder why this information have not made headlines in the newspapers. Is this information very recent?? Could you provide the link for the text ?

Offline dingowarrior

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #3 on: February 06, 2007, 10:37:54 AM »
Can someone explain this article in short for the scientifically challenge?

Offline ronaldinho

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  • Posts: 79
Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #4 on: February 06, 2007, 12:32:58 PM »
This information seems to have appeared in the internet in august 2006, as the result of a study in which Bruce Walker was the leading investigator. This link has some information on the subject:

http://www.sflorg.com/sciencenews/scn082106_01.html

So, these news are not so "new".

The botton line seems to be that HIV does not destroy the defense cell suposed to fight it, HIV only desactivate them, so that it might  be possible to reactivate these defense cells so that they may resume  their work fighting HIV. Although the theory is exciting , i have not been able to find if there are clinical trial going on based upon these findings.





« Last Edit: February 06, 2007, 01:42:41 PM by ronaldinho »

Offline Ihavehope

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  • Posts: 1,366
  • Yes, I'm a cry baby, AND WHAT?
Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #5 on: February 06, 2007, 01:05:36 PM »
Good Good News. Yay! More drugs more drugs.
Infected: April 2005
12/6/06 - Diagnosed HIV positive
12/19/06 - CD4 = 240  22% VL = 26,300
1/4/07 - CD4 = 200 16% VL = ?
2/9/07 = Started Kaletra/Truvada
3/13/07 = CD4 = 386 22% VL ?

Offline bimazek

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #6 on: February 06, 2007, 03:24:00 PM »

The new-ness is that they are actively working on this in many places in world, harvard, montreal in lab of one of the top virologist in world, and currently in trials for cancer by company in new jersey, it is new because each week more work is being done. 

Here are some links to look at:

http://scholar.google.com/scholar?q=anti-pd-1+hiv&hl=en&lr=&btnG=Search

http://www.google.com/search?hl=en&q=anti-pd-1+hiv&btnG=Google+Search

http://www.nature.com/nature/journal/v439/n7077/abs/nature04444.html

CTLA is a similar receptor with similar function to pd-1

http://scholar.google.com/scholar?hl=en&lr=&q=anti-ctla+hiv&btnG=Search

These are very active areas of research for virus, cancer, etc so there will be new papers every few months for many years. 

I wish that medarex would at least find some hiv positive Melanoma patients to add to their melanoma trial, perhaps there would be some results to the hiv chronic infection.  If anyone has Melanoma and hiv it might be a great thing to enter the trial of anti-pd-1 for melanoma.

pd-1 and ctla are an area of current research probably there will be major developments in this area over next few years and these scientists will win nobel prize, in my opinion, it took 20 yrs to find and mapping the entire human genome and then seeing what protein each sequence produced and that is how they stumbled on it.

I have personally spoken with PhDs in the labs at harvard and in montreal for an article, it would take dozens of hours to write what is in their minds and possible areas of breakthru, they are actively experimenting. 

there are also studies here where they use these new monoclonal antibodies together with vaccines in hiv treatment 

Responses by Simultaneous Administration of Liposomal Peptide Vaccine with Anti-CD40 and Anti-CTLA- … -
... we demonstrated in this paper that anti-CD40 mAb and anti-CTLA-4 mAb ... clinical treatment
of human cancer, but also applicable to patients with HIV infection who

I am also very excited about this new discovery in 2007 ... emerin ... i did a search for articles only in 2007 on hiv
found this new protein that hiv uses to insert into cells, a gene produces this protein and it is same gene involved in Muscular dystrophy and then after some digging i found that this gene gets turned on in animals that are difficient in selenium ... it is interesting how it is all connected..
http://forums.poz.com/index.php?topic=8475.0

Offline bimazek

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Offline bimazek

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  • Posts: 781
Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #8 on: February 06, 2007, 08:26:02 PM »

There are no clinical trials at this time that I have found, but there is an anti-pd-1 antibody in trials for melanoma, by medarex in new jersey, perhaps some activism might help.  If there were hiv positive people who also had melanoma this might be the fastest route to some trials.  Perhaps the best thing is to contact Mass. General and ask them if there is a trial starting.

Offline bimazek

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #9 on: February 17, 2007, 10:16:01 PM »
what is new in what i wrote above is i actually called harvard and spoke with one of the researches for 45 min to write the above info, also i read every article over a 12 years period and tried to put it into simple words, also i called the lab in montreal that works with the harvard group, it is the lab of supposedly the top virologist in world (told to me by an MD) and spoke with one of the PHD MD types for 40 min with questions to understand

sometimes i feel that all the newspapers and such just re print the press release

i also called medarex the company in new jersey 7 times to get a quote from their chief scientist

is that quote in the version i posted

anyway it took months of calls to get a publicly traded biotech company to make a statement on the record

i was writing all this for a so cal gay magazine but article has not hit news stand cause of space limits,

medarex has the anti-pd-1 human antibody but they are not yet testing in humans, also they have anti-ctla which is similar to pd-1

if anyone is in new jersey or so. penna and has melanoma they are using,
medarex has the anti-pd-1 human antibody, they are in trials for melanoma cancer so call them and try to get in the trial if you have

MELANOMA



Offline bimazek

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #10 on: March 27, 2007, 04:16:52 AM »

This article suggests that the reason vaccine trials in past, 5 10, 15 years ago failed is because, this CD8 exhaustion.  Does this mean the trial must be repeated with a CD8 stimulant also to prove that it may work?

Offline bimazek

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #11 on: March 30, 2007, 10:13:49 PM »
Chinese in Bejing building on harvard breakthrough prove that LTNP is because of the CD8 cells...
have special quality to their CD8 killer cells...
Blocking PD-1/PD-L1 pathway may represent a new therapeutic option for this disease.
looks like they just proved that CD8 cells in LTNP long-term non-progressors  are somehow , well they do not have this immunoreceptor PD-1 upregulated on CD8(+) T cells so their CD8 cells do not become exhausted

LTNP exhibited functional HIV-specific memory CD8(+) T cells with lower PD-1 expression.

Progressors showed up-regulated PD-1 expression correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load.

Importantly, PD-1 upregulation was also associated with reduced perforin and IFN-gamma production, as well as decreased HIV-specific effector memory CD8(+) T-cell proliferation in TP but not LTNP individuals.

Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8(+) T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 upregulation mediates HIV-specific CD8(+) T-cell exhaustion. Blocking PD-1/PD-L1 pathway may represent a new therapeutic option for this disease, and provide more insight into immune pathogenesis in LTNP individuals



Chinese in Bejing... have you seen their city buildings.... makes USA look like a slum


1: Blood. 2007 Feb 1; [Epu
    PD-1 upregulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors, but not in long-term non-progressors.

        * Zhang JY,
        * Zhang Z,
        * Wang X,
        * Fu JL,
        * Yao J,
        * Jiao Y,
        * Chen L,
        * Zhang H,
        * Wei J,
        * Jin L,
        * Shi M,
        * Gao GF,
        * Wu H,
        * Wang FS.

    Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.

    The immunoreceptor PD-1 is significantly upregulated on exhausted CD8(+) T cells during chronic viral infections like HIV-1. However, it remains unknown whether PD-1 expression on CD8(+) T cells differs between typical progressors (TP) and long-term non-progressors (LTNP). In this report, we examined PD-1 expression on HIV-specific CD8(+) T cells from 63 adults with chronic HIV infection. We found that LTNP exhibited functional HIV-specific memory CD8(+) T cells with markedly lower PD-1 expression. TP, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 upregulation was also associated with reduced perforin and IFN-gamma production, as well as decreased HIV-specific effector memory CD8(+) T-cell proliferation in TP but not LTNP individuals. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8(+) T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 upregulation mediates HIV-specific CD8(+) T-cell exhaustion. Blocking PD-1/PD-L1 pathway may represent a new therapeutic option for this disease, and provide more insight into immune pathogenesis in LTNP individuals

Offline bimazek

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  • Posts: 781
Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #12 on: April 18, 2007, 02:36:37 AM »
LTNP have now been proven to be because of pd-1 on the CD8 cell by Univ of beijing


Offline hahaha

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  • Posts: 123
Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #13 on: April 23, 2007, 11:48:44 AM »
Is there any grey market that allows us to buy this anti-Pd-1 thingee?
I really would like to give a try on my ownself. 
Maybe i am too tired of keep taking the med.

 :-\
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 thirtysomething

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  • Posts: 124
Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #14 on: April 28, 2007, 12:18:56 AM »
I'm wondering if HIVWorker has read this post and what's his take on this.

Offline HIVworker

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  • HIV researcher
Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #15 on: May 09, 2007, 09:07:28 PM »
I think LTNPs are LTNPs for a variety of reasons. PD1 might well be one of them...but it would be wrong to think that there was one mechanism that made someone a LTNP.

PD1 is an area worth keeping an eye on.
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline bimazek

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #16 on: May 10, 2007, 05:34:28 PM »
 
In Med school lecture about HIV... they noted that in 2004 that "DILS is usually associated with long term non-progression and a favorable outlook"   diffuse infiltrative lymphocytosis syndrome
 (DILS) stimulating Sjogren’s syndrome isa associated with long term non-progression and a favorable outlook"

WHY?  Well upon 400 hours of searching over 9 months and reading every article about DILS stimulating Sjogren’s syndrome I found an article that stated that the latest research showed that

DILS stimulating Sjogren’s syndrome was caused by a CD8 PD-1 issue.  Then few months later the chinese prove "long term non-progression and a favorable outlook"  =  CD8 PD-1 issue

if
DILS = "long term non-progression and a favorable outlook"
and
DILS =  CD8 PD-1 issue
and
Chinese two months ago prove that
"long term non-progression and a favorable outlook"  =  CD8 PD-1 issue

the equal sign should have a dot above it to indicate related to..


 Excessive anti HIV CD8 response may result in diffuse infiltrative lymphocytosis syndrome
 (DILS) stimulating Sjogren’s syndrome
 T cell infiltration leads to dry eyes, loss of salivary gland secretions
 Disabling autoimmune disease with autoantibodies resembling those found in
 lupus patients       DILS is usually associated with long term non-progression and a favorable outlook, but it is also associated with a type of B cell lymphoma that occurs early in the course of HIV infection,
 reflecting chronic cell stimulation (begin in lacrimal gland or salivary gland)





Anti HIV Immune Response
 With onset of CD8 response viremia falls from5X10
 6 /mL to <10n4 /mL, sometimes undetectable
 CD4 count rises from400 to  800/µL
 A key concept that isn’t fully understood: Degree of viral suppression and return of CD4
 levels (set point) varies and correlates with the length of the asymptomatic period; there have
 been attempts to treat with retrovirals and other means to manipulate the set point
 HIV species begin to diversify, viral variants appear reflecting successful attempts to escape the
 suppression of CD8 response, body brings in another CD8 type (concept of epitope war)
 The virus mainly persists in monocytes and macrophages
 5
 Page 6
 Experimental infection
 with SIV (Simian) of
 intact and CD8 depleted
 monkeys illustrates role
 of CD8 T cells in
 controlling viremia
 CD8 Response to HIV-1
     Establishes asymptomatic phase of infection
     CD8 responds to HIV peptides by activation, clonal expansion, and differentiation to effectors
     2 Critical Events:
 1. Specific lysis of HIV-infected target cells (macrophages and CD4 cells) via perforin
 pathway and/or apoptosis via upregulation of fas ligand
 2. Strong inhibition of viral infectivity by release of chemokines (MIP-1a/ß, RANTES) that
 bind to CCR5 and block coreceptor dependent entry of R5 HIV-1
     Lastly, release of IFN-? and secondarily TNF-a ?? LTR-driven transcription
     Excessive anti HIV CD8 response may result in diffuse infiltrative lymphocytosis syndrome
 (DILS) stimulating Sjogren’s syndrome
 T cell infiltration leads to dry eyes, loss of salivary gland secretions
 Disabling autoimmune disease with autoantibodies resembling those found in
 lupus patients
     DILS is usually associated with long term non-progression and a favorable outlook, but it is also
 associated with a type of B cell lymphoma that occurs early in the course of HIV infection,
 reflecting chronic cell stimulation (begin in lacrimal gland or salivary gland)
 Thwarted Immunosurveillance
 No expression of viral peptides
 Also inaccessible to Rx
 6
 Reasons for failure of CD8 cells to totally eliminate HIV-1
 1. HIV may integrate into a region of the
 heterochromatin (e.g. in memory CD4 T cell) where
 it remains undetected and inaccessible to therapy for
 as long as that CD4 T cell is quiescent; activation of
 CD4 cell leads to reexpression of HIV
 2. Nef and vpu diminish MHC class I expression, thus
 avoiding infection surveillance, especially when in
 monocytes
 Extra credit: Nef is particularly clever since it decreases
 HLA-A and HLA-B, but not HLA-C and HLA-E, thus
 avoiding most NK cell surveillance; what goes on in the
 placenta
 3. Dendritic cells are used as a  Trojan Horse
 Immature DCs typically located in the
 submucosa express a C-type lectin CD-SIGN
 HIV-1 envelope binds to CD-SIGN with high
 affinity
 The virions are internalized and remain in acidic
 endosomal compartments while the DC matures
 Intact infectious virions are reexpressed on the
 surface when the CD enters the lymph node



Chinese in Bejing building on harvard breakthrough prove that LTNP is because of the CD8 cells...
have special quality to their CD8 killer cells...  Blocking PD-1/PD-L1 pathway may represent a new therapeutic option for this disease.  looks like they just proved that CD8 cells in LTNP long-term non-progressors  are somehow , well they do not have this immunoreceptor PD-1 upregulated on CD8(+) T cells so their CD8 cells do not become exhausted  LTNP exhibited functional HIV-specific memory CD8(+) T cells with lower PD-1 expression.  Progressors showed up-regulated PD-1 expression correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load.  Importantly, PD-1 upregulation was also associated with reduced perforin and IFN-gamma production, as well as decreased HIV-specific effector memory CD8(+) T-cell proliferation in TP but not LTNP individuals. 
Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8(+) T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 upregulation mediates HIV-specific CD8(+) T-cell exhaustion. Blocking PD-1/PD-L1 pathway may represent a new therapeutic option for this disease, and provide more insight into immune pathogenesis in LTNP individuals

Offline milker

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #17 on: May 10, 2007, 05:56:44 PM »
Or you could just have cited the two links:

http://www.cumc.columbia.edu/dept/ps/2007/immuno/2006/IM23.pdf (which has nice graphics too, and is easier to read) and http://www.im.ac.cn/UserFiles/File/Zhang%20J-proof%20BLOOD.pdf for the chinese study, with a short paragraph that would say something like this:

"Those two studies, one from Columbia University, and one from China, seem to confirm that the PD-1 regulation may have something to do with long term progression, which may be related to CD8 exhaustion".

That would be a lot easier to decide if this is something we want to read, and be sure that we have the complete documents if we do.

It is, indeed, interesting.

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 J220

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #18 on: May 10, 2007, 07:15:29 PM »
Yes, these encouraging news are from late last year. In Sept. 06 I actually wrote an email to Dr. Walker, and he replied that they were "cautiously optimistic" about the discovery, which was done simultaneously by different researchers- yet another reason for hope that this could someday translate into a treatment, or who knows, even a cure.

Below is the original article I posted in the other thread, I think it's pretty good because it describes the whole process pretty specifically yet in resonably easy terms. In addition, there is a note at the end about a concern about blocking PD-1 altogethe: auto-immune disease. Apparently PD-1 does have an important function in keeping the immune system from attacking the healthy system, so blocking PD-1 alogether may not be the answer. Maybe just slowing it enough to allow CD8 cells to to their job may be the way to go (speculation here).

Or, maybe we need to find out how the virus activates PD-1 in CD8 cells, and block whatever enzyme or protein it uses, so that the over-production of PD-1 doesn't happen in the first place, thereby allowing CD8 cells to kick ass. Anyway, it's still good news.

_______________________________________


Detailed studies of white blood cells have revealed how HIV relentlessly wears down the immune cells by exploiting the body’s built-in protection against autoimmune diseases. The new understanding should lead to ways to overcome this "Achilles heel" and treat HIV infection.

As HIV accumulates in the blood, specific immune cells that target viruses – called CD8 – begin to over-produce a receptor molecule called Programmed Death-1. As this PD-1 builds up on the surface of the CD8 cells, the immune cells became weaker and produced fewer virus-killing chemicals, such as cytokines.

Instead of functioning as sentinels of the immune system, the CD8 cells gradually burn out, becoming clogged-up with PD-1. “The immune cells are there, but they have been turned off in persons with high viral loads,” says Bruce Walker at Massachusetts General Hospital in Boston, US, who led the research.

The biological function of PD-1 is not fully understood, but it is thought that it may be involved in preventing autoimmune reactions – where the white blood cells attack the body’s own cells.

Walker and his collaborators examined CD8 cells from 71 untreated HIV-positive patients in Durban, South Africa. They found that the more virus the patients had in their bodies, the more PD-1 they had on their CD8 cell surfaces.

But when Walker massively suppressed the amount of virus circulating in their blood by giving the patients antiretroviral drugs, the amount of PD-1 on their CD8 cells went down too, suggesting that the two rise and fall in tandem.

The same phenomenon was demonstrated in 19 North American individuals by a team led by Rafick-Pierre Sekaly at the Central Hospital of Montreal in Canada.

In lab experiments, though, Sekaly showed that even after antiretroviral drugs were given, the CD8 cells continued to weaken despite the fact that the drugs drove down the amount of PD-1. “The drugs didn’t correct the dysfunction, and the cells got more and more tired and burnt out,” he says.

But the two teams were able to help the cells to recover using antibodies that block the PD-1 receptor molecules. In cell culture, these CD8 cells resumed their normal activity when exposed to HIV, producing chemicals such as interferon gamma, for example, which targets viruses including HIV.

And experiments in mice treated with similar antibodies also blocked the production of PD-1.

The teams, whose results were both published at the same time, in the journals Nature and Nature Medicine respectively, are delighted that each others' findings have been mutually confirmed.

Now, Sekaly wants to try the same thing in people. “We need to start a clinical trial as soon as possible,” he says.

Sarah Rowland-Jones, director of research at the UK Medical Research Council’s Labs in Fajara, Gambia, says that it would be interesting to know if the virus itself somehow triggers the CD8 cells to overproduce PD-1. “It wouldn’t surprise me in the slightest,” she says.

However, Rowland-Jones, who wrote a commentary piece accompanying the two studies, in Nature, warns that blocking PD-1 altogether could be dangerous. She says that in experiments on mice bred to lack the gene, the mice developed severe autoimmune disease.

This suggests that the protein plays an important role in stopping the immune system attacking itself. Perhaps, she says, HIV exploits this to blind the immune system to its presence.

Journal references: Nature (DOI: 10.1038/nature05115), Nature Medicine (DOI: 10.1038/nm1482)
« Last Edit: May 10, 2007, 07:17:24 PM by J220 »
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline powerpuff

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #19 on: June 14, 2007, 06:56:29 PM »
do you have the original link to this article?
Im' asking because i read somewhere that possible turning off pd1 can cause autoimmunity??

Offline JPinLA

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #20 on: June 14, 2007, 07:08:01 PM »
Powerpuff - I would guess that is indeed a possibility.  It has been shown that blocking of other regulatory receptors like CTLA-4, which acts very similalry to PD-1 in down regulation of activated immune cells, cause some autoimmune types of responses in study subjects (Medarex, MDX-10 CTLA-4 blocking mAb).  But, careful study and management of these side effects may be possible and may or may not occur with blocking PD-10. 

I posted a reference somewhere in another of bimazek's threads regarding MDX-10.  He has a link to thier findings.

JP
11/06 - Diagnosed - VL/5784 & CD4 326
2/07 - VL/6000 & CD4 290 2/07
3//07 -Began Truvada/Viramune 
4/07 VL/undetectable and CD4 320 22%
7/07 VL/undetectable and CD4 286 22%
11/07 VL/undetectable and CD4 302 26%

Offline bimazek

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #21 on: June 15, 2007, 08:34:12 PM »

Thanks guys, great additions, as I think about this I am completely surprised and happy that all LTNP seem to have something to do with PD-1 this is much much better than I ever hoped, I thought that there would be many different reasons, for LTNP, some genetic, some based on dozen of other factors I am completely happy and optimistic because it is a fundamental thing...

basically my long short story is, in 1985 or so, when i believe dr. walker, discovered that the cd8 cells where not fighting hiv, i remember reading the article in some paper or science mag., (back then i was young gay scared) and i read everything on hiv, when i read that i walked out of the place i was and was walking like down upper market st in sf, and it was a very black night and i thought, this virus is so unusualy that it has figured out a way to turn off the very cells that should be fighting against it, so i was flabergasted and i had had enough bio, and advanced bio to know that cd8 was important and that this was big, i thought to myself, this is going to be very hard to cure becuase i knew that it would be harder to design a vaccine, but i also thought on that night 22 years ago that the solution must be with the cd8 cell, ... not the cd4 cell, why because i thought back then  that the way to suppress it was somehow to get the body to naturally do it, i knew at the time that cats had hiv in fiv, because my x- was a phd, md, vet, and he knew all about retro viruses in 1981.  he knew alot, parents both dr.s, anyway, i thought it was important and i thought as i walked that the achilles heel of the virus was the cd8 the thing that was being turned off...

i also remember thinking , when i heard that they found azt as a substance that came from chemo area, and that it stopped the virus in the cd4 that this was the wrong thing to target adn i remember thinking i hope that does not cause the entire research industry to go down only that path, the cd4 meds, but i was glad and happy they found something, and i was trying to stay neg myself amid the death and devestation of loosing many friends.  In 1989 I tried to start an organization called   "Vaccines for AIDS" because even in my high school we learned that viruses could only be treated by vaccines and bacteria by other means.  I posted ads in gay papers with my own money and created a small mailing list of guys who were interested by my own life stopped that org. from getting any traction.

then when i got hiv and started reading non stop (some reading was done before 3 years ago when i was neg) then 14 month ago started reading tons,

I am going to post this now....

and it was the when I read this in august in an obscure med school lecture that I knew I was onto something big, "Excessive anti HIV CD8 response may result in diffuse infiltrative lymphocytosis syndrome
 (DILS) stimulating Sjogren’s syndrome  T cell infiltration leads to dry eyes, loss of salivary gland secretions
 Disabling autoimmune disease with autoantibodies resembling those found in
 lupus patients         DILS is usually associated with long term non-progression and a favorable outlook, but it is also associated with a type of B cell lymphoma that occurs early in the course of HIV infection,
 reflecting chronic cell stimulation (begin in lacrimal gland or salivary gland)"

I had noticed my skin was drier especially on my legs since getting hiv.

i think that yes
there can be a way to balance the auto immune problems with the fighting the virus issues

there are many animals who do that just fine

sjogren’s syndrome or DILS

DILS = diffuse infultrative lymph syndrome

when i read this

Sjogren’s syndrome or DILS Anyone had these Diseases? Please post
I found a pd-1 connection to this LTNP connection
 
http://forums.poz.com/index.php?topic=7708.0
http://forums.poz.com/index.php?topic=8215.0
 
 Experimental infection with SIV (Simian) of intact and CD8 depleted monkeys illustrates role of CD8 T cells in controlling viremia CD8 Response to HIV-1 Establishes asymptomatic phase of infection CD8 responds to HIV peptides by activation, clonal expansion, and differentiation to effectors 2 Critical Events: 1. Specific lysis of HIV-infected target cells (macrophages and CD4 cells) via perforin pathway and/or apoptosis via upregulation of fas ligand 2. Strong inhibition of viral infectivity by release of chemokines (MIP-1a/ß, RANTES) that bind to CCR5 and block coreceptor dependent entry of R5 HIV-1 Lastly, release of IFN-? and secondarily TNF-a ?? LTR-driven transcription Excessive anti HIV CD8 response may result in diffuse infiltrative lymphocytosis syndrome (DILS) stimulating Sjogren’s syndrome T cell infiltration leads to dry eyes, loss of salivary gland secretions Disabling autoimmune disease with autoantibodies resembling those found in lupus patients DILS is usually associated with long term non-progression and a favorable outlook, but it is also associated with a type of B cell lymphoma that occurs early in the course of HIV infection, reflecting chronic cell stimulation (begin in lacrimal gland or salivary gland) Thwarted Immunosurveillance No expression of viral peptides Also inaccessible to Rx 6 Reasons for failure of CD8 cells to totally eliminate HIV-1 1. HIV may integrate into a region of the heterochromatin (e.g. in memory CD4 T cell) where it remains undetected and inaccessible to therapy for as long as that CD4 T cell is quiescent; activation of CD4 cell leads to reexpression of HIV 2. Nef and vpu diminish MHC class I expression, thus avoiding infection surveillance, especially when in monocytes Extra credit: Nef is particularly clever since it decreases HLA-A and HLA-B, but not HLA-C and HLA-E, thus avoiding most NK cell surveillance; what goes on in the placenta 3. Dendritic cells are used as a Trojan Horse Immature DCs typically located in the submucosa express a C-type lectin CD-SIGN HIV-1 envelope binds to CD-SIGN with high affinity The virions are internalized and remain in acidic endosomal compartments while the DC matures Intact infectious virions are reexpressed on the surface when the CD enters the lymph node Page 7 Why don’t antibodies work? It takes too long for antibodies specific for a particular strain to develop The virus is evolving at a rate too great for the immune system to keep up with Immune Responses in Asymptomatic Phase: Depends on a relatively few CD8 clones Maintenance of <5-20 CD8 expanded memory/effector CTL clones, each comprising 1-5% of CD8 repertoire Clones each recognize different HIV peptides, great individual variation in number and particular peptide recognized Many clones = generally good outlook for long asymptomatic period ( 12 year), few clones = rapid progression of HIV infection (< 2 years) The number of clones and survival duration correlates with the viral set point established in the acute infection; set point reflects the adequacy of a person’s immune system to respond to HIV Long term non progresors Subset of infected individuals that remain asymptomatic for 12 years Particular HLA types, e.g. HLA-B27, B57 Low levels of plasma virions, CD4 counts 500/µL High CD8 counts, maybe 3000/ µL CTL response is against critical conserved region of HIV gag, env, pol that cannot readily be mutated without loss of viral function; This appears to be the key factor High chemokine release (RANTES, MIP) The particular peptide that is recognized in HIV by cytotoxic CD8 cells is critically important to whether the infection will be controlled If the recognized peptide encodes a region that is essential for HIV function, any mutation in that site will be lethal for the virus; for this to occur to conditions must be met: 1) The correct peptide must be presented. The individual’s class I MHC alleles are the major determinant of which peptide is recognized. They determine the particular peptides that are bound and presented 2) The peptide must be recognized by a T cell clone. Not all bound peptides are equivalently recognized by T cell clones in the repertoire. Only a few bound peptides are immunodominant, and readily recognized. The T cell ligand is a combination of peptide and class I MHC, and it demonstrates the importance of polymorphism in the HLA molecule The environment formed by peptide binding properties of MHC molecules influences evolution of the HIV infection. HLA alleles influence the number of peptides in a protein that can be recognized (e.g. HIV envelope protein) Allele: HLA-B*27052 HLA-B*3501 HLA-B*0702 Motif: XRXXXXXX[KRYL] XPXXXXXXY XPXXXXXXL Each allele is able to bind a number of different peptides 7 Page 8 Basis of outcome with HLA type HLA B35 Rapid Progression HLA B27 Slow progression PXXXXXY peptides recognized if any are in noncritical parts of HIV genome permitting mutations in MHC anchor residues Peptides are weak stimulators Rapid viral replication and evolution not restrained RXXXXXX[KRYL] peptides recognized are often in critical parts of HIV genome and mutations not permitted in MHC anchor or TCR recognition residues Peptides give strong stimulation Viral replication and evolution greatly slowed Immune Response Asymptomatic phase: Shifiting immunodominance in epitope war Near end of asymptomatic period Usually recurrent pattern of HIV escape from immunodominant CTL effect by mutation followed by regain of CD8 control via next HIV peptide that can be presented by MHC I and recognized by TCR in hierarcy of HIV peptide immunodomiance

Offline bimazek

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #22 on: June 15, 2007, 08:44:35 PM »
thanks for the paper milker i liked it...
this part jumps out and also... it shows that perhaps more than one receptor will be involved...
PD-1/PD-L1  CD28 family  CD38
One report  illustrates that PD-L1 is up-regulated and B7-2 (CD86) is downregulated
on APCs during chronic HIV infection.

china paper that proves the LTNP is pd-1 dependent...............................................................
http://www.im.ac.cn/UserFiles/File/Zhang%20J-proof%20BLOOD.pdf

T-cell activation is a necessary component of an effective
acquired immune response against HIV infection, although hyperactivation
of T cells can cause autoimmune destruction in HIVinfected
patients.24 The CD28 family, in particular the PD-1/PD-L1
pathway, plays a prominent role in controlling T-cell activation.23-25
We found that PD-1 expression correlated with elevated CD38 and
HLA-DR expression in HIV-infected patients. In particular, PD-1
up-regulation was associated with high levels of CD38 and
HLA-DR expression in TP patients, whereas lower PD-1 expression
correlated with reduced levels of CD38 and HLA-DR in
LTNPs. Thus, PD-1 may act as a surrogate activation marker during
HIV infection. It is also likely that high levels of both CD38 and
PD-1 expression may act synergistically to induce HIV-specific
CD8 T-cell exhaustion and promote increased sensitivity to
apoptosis in TP patients.31 However, the regulation of T-cell
activation and expansion is a complex process that requires the
coordinated interaction of multiple signaling pathways. One report
illustrates that PD-L1 is up-regulated and B7-2 (CD86) is downregulated
on APCs during chronic HIV infection, providing
increased inhibitory and reduced activating signals for T cells.33 In
addition, a gene expression study has recently shown that in
addition to PD-1, a large number of other genes are altered in
exhausted CD8 T cells during viral infection (Dr E. J. Wherry,
personal communication). Furthermore, other immunoinhibitory
receptors, including PD-1, BTLA, and FcRIIB, may also cooperate
to induce HIV-specific CD8 T-cell exhaustion.20,32 Future
studies will be required to clarify these findings.
Consistent with recent studies in both mice and humans,28-31 our
data confirmed that blocking the PD-1/PD-L1 inhibitory pathway
could be exploited therapeutically, particularly for HIV-infected
patients with low CD4 T-cell numbers. Importantly, HAART
therapy is found to down-regulate PD-1 expression in TP patients,
29,30 suggesting that this treatment may partially restore the
innate and adaptive immune responses of the host to HIV-1.9,34-36
Future longitudinal studies should address the correlation between
PD-1 down-regulation and the recovery of host immune responses
in patients with AIDS undergoing HAART therapy.
Overall, we found that PD-1 expression was significantly lower
on HIV-specific memory CD8 T cells from LTNPs than TPs.
Furthermore, our study indicated that blocking PD-1/PD-L1 interactions
in vitro could, at least in part, revitalize some HIV-specific
CD8 T-cell functions in TP patients. These findings not only
extend our understanding of how the PD-1/PD-L1 inhibitory
pathway functions in LTNPs but also support the notion that
blocking PD-1/PD-L1 interactions may represent a potential therapeutic
strategy for HIV-infected patients.

Offline bimazek

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Re: CD8 new meds in the works, cd8 naturally eat up the infected cd4s
« Reply #23 on: June 15, 2007, 08:48:52 PM »
I just want to take a moment to thank these men and perhaps women, we may never know, who at Beijing, under a not so great govt system, they have labored tirelessly and helped patients and tested patients and done some great discoveries...  I want to thank them all as a poz person who can only thank them for thier effort and the extreeme sacrifice they may have made to first get educated to study learn read and dedicate themselves to helping all of us... esp. since it is a communist system...

Ji-Yuan Zhang, Zheng Zhang, Xicheng Wang, Jun-Liang Fu, Jinxia Yao, Yanmei Jiao, Liangen Chen,Hui Zhang,2 Jianan Wei, Lei Jin, Ming Shi, George Fu Gao, Hao Wu, and Fu-Sheng Wang

Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China; Research Center of Biological Therapy, Beijing Hospital, Beijing, China;

Department of Infectious Diseases, Beijing You-an Hospital Affiliated with Capital University of Medical Science, Beijing, China; 4HIV/AIDS Research Center,
Beijing Guang-An-Men Hospital, Beijing, China

 


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