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Author Topic: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID  (Read 4903 times)

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Offline zephyr

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    • Zephyr L.T.N.P. Foundation, Inc.
LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« on: December 04, 2008, 12:47:21 PM »

Greetings to the AM Community -

Today is a very exciting day for all PLWHA's, as a new paper from the NIH has just been released that identifies a specific mechanism of control in those individuals categorized as LTNP's (Long-Term Non-Progressors), or, HIV Controllers.

I have cut and pasted a summary paragraph from the paper, as well as a link to an article published on the abstract on Cosmos.

http://www.cosmosmagazine.com/news/2389/why-some-people-are-immune-aids?page=0%2C0

Well-Armed Immune Cells Help Long-Term Non-Progressors Contain HIV

 WHAT:  To help develop an effective HIV vaccine, researchers are trying to better understand how the immune systems of a small minority of HIV-infected people known as long-term non-progressors (LTNPs) contain the virus naturally. CD8+ T cells, which kill cells infected with HIV, enable LTNPs to control HIV, but it has been unclear how CD8+ T cells mediate that control so effectively. A new report shows that the ability to stockpile two molecular weapons makes the HIV-specific CD8+ T cells of LTNPs superior cellular killers.
 
 Lead author Stephen Migueles, M.D., senior author Mark Connors, M.D., and colleagues at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, used cutting-edge technology to examine individual CD8+ T cells for their killing prowess. The study included new techniques to measure how many HIV-infected cells each CD8+ T cell destroys, and how rapidly. In laboratory experiments, the scientists found that CD8+ T cells taken from LTNPs efficiently killed HIV-infected cells in less than 1 hour. In contrast, the CD8+ T cells of progressors, or individuals who do not contain the virus without antiretroviral therapy, killed HIV-infected cells inefficiently, even when the CD8+ T cells were present in high numbers or came from progressors being successfully treated with antiretroviral therapy.

 When CD8+ T cells kill HIV-infected cells, a protein, perforin, made by the CD8+ T cells punches holes in the infected cells. Then a second protein, granzyme B, penetrates those holes and causes the cells to die. Previously, the researchers found that HIV-specific CD8+ T cells of progressors, unlike those of LTNPs, make little perforin when they encounter an HIV-infected cell. It remained unclear, however, whether this deficiency explained why HIV-specific CD8+ T cells of progressors are poor killers. The current study demonstrates a direct relationship between the quantity of both perforin and granzyme B that CD8+ T cells accumulate over time and the ability of CD8+ T cells to eliminate HIV-infected cells. This discovery significantly advances the understanding of the cellular mechanisms unique to LTNPs that explain why their immune systems, unlike those of the majority of HIV-infected people, can control HIV without antiretroviral therapy.

 According to the NIAID scientists, their results also suggest that an HIV vaccine might control virus replication if it could stimulate HIV-specific CD8+ T cells to robustly stock and rapidly deliver perforin and granzyme B to HIV-infected cells. 
 
ARTICLE:         SA Migueles et al. Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity DOI 10.1016/j.immuni.2008.10.010 (2008).


I consider this a major breakthrough, and have no doubt that this valuable information will influence the development of new therapies for HIV infection within a short time.

Keep the faith, people, keep the faith!

My best to you,

Zephyr
"It is character that communicates most eloquently."

Offline HALOO

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Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #1 on: December 04, 2008, 01:13:12 PM »
This really make me feel very excited!!
If they can successfully apply both concept that is this CD8+ killer and CCR5 delta-32 gene therapy, than I guess I will have high chance to get old.

Offline veritas

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Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #2 on: December 04, 2008, 01:22:18 PM »
Zephyr,
I think your spot on with respect to the importance of cd8's in any future vaccine. I found this link to another study:


   http://www.pnas.org/content/97/25/13812.full#xref-ref-30-1

My gut tells me a therapeutic will not take 10-20 yrs. At least I pray it doesn't.

veritas

Offline freewillie99

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Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #3 on: December 04, 2008, 02:43:00 PM »
Zephyr:

Great stuff.  Although different, this reminds me a bit of the recently published article here "HIV Can’t Hide From Specially Engineered CD8 Cells"

http://www.aidsmeds.com/articles/hiv_engineered_cd8_1667_15598.shtml 

It's a brave new world, baby.
Beware Romanians bearing strange gifts

Offline veritas

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Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #4 on: December 05, 2008, 08:09:58 AM »

Here is the release from the NIH----- good find Zephyr



http://www3.niaid.nih.gov/news/newsreleases/2008/LTNPs.htm

Offline georgep77

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  • Posts: 144
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #5 on: December 05, 2008, 09:03:17 AM »
Awesome !!!!

      Thanks for the information Zephyr

                             :D
Come on Sangamo,  Geovax,  Bionor immuno, ...Make us happy !!!
+ 2008

Offline leit

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  • Posts: 236
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #6 on: December 05, 2008, 06:56:44 PM »

Thank you for the news, Zephyr!

...However, I don't get the link between this undoubtedly very important discovery and a possible vaccine: vaccines stimulate an immune response AGAINST antigens they contain, while here we need to stimulate HIV-specific CD8 to produce more perforin and granzyme B - so what antigens could be employed?


OT for Zephyr (I hope the other users will forgive me):
I'd like to know whether are elite controllers' (like you) immunological parameters (CD3, CD4, CD8, CD4/CD8 ratio, activated T cells, inflammation markers and so) like the ones of healthy people or do they worsen, though very slowly. ...And do you feel as before you were infected (no lack of energy, sense of premature aging or other "strange" ailments)?
Thank you very much!



Offline freewillie99

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Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #7 on: December 05, 2008, 08:18:06 PM »
I don't get the link between this undoubtedly very important discovery and a possible vaccine

leit:

Wasn't the link when the NIAID scientists said that an HIV vaccine might control virus replication if it could stimulate HIV-specific CD8+ T cells to robustly stock and rapidly deliver perforin and granzyme B to HIV-infected cells - as a LTNP like Zephyr's CD8 cells do?  Cheers. 
Beware Romanians bearing strange gifts

Offline leit

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Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #8 on: December 05, 2008, 09:46:03 PM »

Thank you, "freewillie99", but I didn't mean the "Web link" (where the NIAID scientists said "that an HIV vaccine might control virus replication if it could stimulate HIV-specific CD8+ T cells to robustly stock and rapidly deliver perforin and granzyme B to HIV-infected cells"), but the "logical link"!


Offline veritas

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Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #9 on: December 06, 2008, 05:59:16 AM »

leit,

This attached might help:

http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0003481

No question the science is complicated but it looks like they are making some good progress. Trying to understand all this stuff is tuff.

veritas

Offline freewillie99

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  • Posts: 303
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #10 on: December 06, 2008, 03:43:46 PM »
Thank you, "freewillie99", but I didn't mean the "Web link" (where the NIAID scientists said "that an HIV vaccine might control virus replication if it could stimulate HIV-specific CD8+ T cells to robustly stock and rapidly deliver perforin and granzyme B to HIV-infected cells"), but the "logical link"!

Hmmm...scientists observe the way LTNP's control virus replication via their CD8 cells delivering perforin and granzyme B to other HIV-infected cells.  They theorize and deduce that they could replicate this ability in non-LTNP's modified CD8's via vaccine.  Technology aside, seems logical to me.
Beware Romanians bearing strange gifts

Offline oaktree

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  • Posts: 9
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #11 on: December 13, 2008, 03:52:08 PM »
I don't know of anyone that works harder than Dr. Migueles. I am proud that I am part of the ltnp study.

Offline OzPaul

  • Member
  • Posts: 410
  • a very blessed 29 year ltnp
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #12 on: December 13, 2008, 06:44:41 PM »
Hey Oaktree

Great to see you back here at the Forums !

I agree with you. Dr. Migueles is a hardworking and dedicated researcher. He's also a super nice and congenial person. I'm proud and humbled too to be in this ltnp study.

Cheers
Paul

Offline leit

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  • Posts: 236
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #13 on: December 14, 2008, 12:00:45 PM »

Hi "oaktree" and "OzPaul"!

Could you please answer my above questions ("OT for Zephyr")?
Thank you very much!
« Last Edit: December 14, 2008, 12:08:18 PM by leit »

Offline oaktree

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Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #14 on: December 14, 2008, 12:36:09 PM »
Leit,

I have no idea about the T cells being like healthy people. I do know that mine seem to very only a little. Sometimes up a little sometimes down a little. They are always in the "normal" range.

As far a how I feel before I was infected...I don't really know. I am hardly ever sick ( cold etc.) I think I  have been infected for 25 years...so I do feel older. What I do feel is blessed.

Offline OzPaul

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  • Posts: 410
  • a very blessed 29 year ltnp
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #15 on: December 14, 2008, 10:13:42 PM »
Leit,

My numbers are up and down though remain within the 'normal' range. I likely became infected in 1983 (tested positive in 1985) when I was a much younger man. Today at 50 I feel great though perhaps a bit slower than those bygone days. I have more problems with sustaining my energy because of the medications I take for bipolar disorder.

Like "oaktree", I feel very blessed to have been well all these years while living with HIV. 

Paul

Offline leit

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  • Posts: 236
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #16 on: December 21, 2008, 01:36:12 PM »

Thank you for your answers and for your generous commitment, "oaktree" and "OzPaul"!


Offline zephyr

  • Member
  • Posts: 459
    • Zephyr L.T.N.P. Foundation, Inc.
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #17 on: January 02, 2009, 04:55:44 PM »
Hi leit –

Please excuse my delayed response to your questions from December 5th – it was a very busy month for me!

In my mind, the ‘logical link’ between the Migueles paper on the findings re: LTNP CD8 production of higher levels of perforin and Granzyme B proteins and the development of a potential vaccine for HIV infection is the discovery of one piece of the complex puzzle that is the ability of LTNP’s (or, HIV Controllers, as we are now known) to spontaneously control HIV infection.

Imagine the implications of these findings if science could synthesize or manipulate the increased production of these two proteins in progressors – to actually create a method by which the CD8 cells are stimulated to manufacture higher levels of perforin and Granzyme B in all humans infected with the virus?

To answer your other questions – I will share my most recent labs from November 13th – at 16 years and 4 months of infection with HIV. ( Dx’d in July 1992.)

Test Name                             In Range                 Out of Range           Reference Range

CD3 % POS                              73                                                              57 – 85 %
CD3 ABS POS lymphocytes   2794                                                         840 – 3060 cells/uL
CD4 % POS                              48                                                              30 – 61 %
ABS CD4 Count                                                       1837                        490 – 1740 cells/uL
CD8 % POS                               24                                                              12 – 42 %
ABS CD8 Count                       919                                                           180 – 1170 cells/uL

T-Lymph Help/Supp
CD4/CD8 Ratio                         2.0                                                             0.86 – 5.00

I have not inquired about my ‘inflammatory markers’, but will ask Dr. Stephen Deeks (University
of California, San Francisco – S.C.O.P.E. Study) as this is his area of expertise.

I have never registered a Viral Load; in September, during a visit with Dr. Migueles, he indicated that his team was successful in extrapolating one-half of a copy of HIV (yes, 0.5) from my body –
something they’ve been attempting to do since 2006. They actually have an assay machine that will register down to 0.25 copies/mL now – Amazing!

As far as my general health goes – I feel great, have plenty of energy, and have no ‘strange ailments’ to complain about. I am approaching my 55th birthday in the spring and feel like I’m in my mid-30’s.

Happy New Year!

Zeph
"It is character that communicates most eloquently."

Offline leit

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  • Posts: 236
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #18 on: January 02, 2009, 08:49:37 PM »

Thank you very much for answering, "zephyr"!

Imagine the implications of these findings if science could synthesize or manipulate the increased production of these two proteins in progressors

Sure, but I have difficulty in understanding how could a vaccine do that. Some genetic manipulation seems a more suitable way to me... but I'm nothing.

Quote
I will share my most recent labs from November 13th – at 16 years and 4 months of infection with HIV

After more than 16 years, CD4=1,837, CD4%=48%, CD4/CD8=2.0. I'm simply AMAZED!!! I believe no doctor in the world could have even the slightest suspicion that you are HIV-infected!

Quote
I have not inquired about my ‘inflammatory markers’, but will ask Dr. Stephen Deeks (University
of California, San Francisco – S.C.O.P.E. Study) as this is his area of expertise.

I will be very grateful to you for that, because recently these parameters seem to have acquired a big importance in HIV-disease progression (in fact, for instance, my C-reactive protein is 7 mg/l, while its optimal value should be below 1.0 - there are other inflammatory markers, like D-dimer and interleukin 6, too, but they are not measured in the common clinical practice).

Quote
his team was successful in extrapolating one-half of a copy of HIV (yes, 0.5) from my body –
something they’ve been attempting to do since 2006

LOL!!! Poor HIV, it met the wrong person!  ;)

Quote
I feel great, have plenty of energy, and have no ‘strange ailments’ to complain about. I am approaching my 55th birthday in the spring and feel like I’m in my mid-30’s.

Zephyr, could I have your whole genome (except sexual chromosomes - I'm too old for such a big change)?  ;)

Thanks for your generous commitment and happy new year!


leit


P.S. The "Zephyr Foundation" link at page http://www.thebody.com/content/art49825.html must be wrong (errors 403-404).
« Last Edit: January 04, 2009, 12:00:04 AM by leit »

Offline zephyr

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    • Zephyr L.T.N.P. Foundation, Inc.
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #19 on: January 03, 2009, 09:37:52 PM »
Hello leit -

You are very welcome.

I did check that link to my Zephyr Foundation website, and it does work for me. (For anyone interested in learning more about HIV Controllers, feel free to visit http://www.zephyrfoundation.org).

In regard to genetic manipulation (in general), Dr. Bruce Walker's team in Boston is highly focused on the presence of the gene HLA B*5701 in 85% of all HIV Controllers involved in their particular study. They have no doubt that this gene has specific suppression ability. We should be reading some papers in the very near future on this topic, and, if you search the Research Forum for another of my posts from the fall, you can learn about a new Safety Pilot Study being launched by the NIH called "White Blood Cell Infusion to Treat HIV Infection", a study that will transfer lymphocytes from a B*5701 Elite Controller to a B*5701 Progressor. There are many of us who have been working hard to locate 3 recipients (progressors) who qualify for this procedure - I am hopeful that the study will launch in the spring.

Yes, as odd as my numbers are, I am definitely HIV-positive. And now that Dr. Migueles has extracted at least 1/2 of a copy of the virus from my body, there's absolutely no doubt at all.

I appreciate your comments, and will update you on the inflammatory markers at a future date.

Be well, and take good care.

Zeph
"It is character that communicates most eloquently."

Offline leit

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Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #20 on: January 04, 2009, 12:09:27 AM »

I did check that link to my Zephyr Foundation website, and it does work for me.

Nothing to do for me:
---------
Forbidden
You don't have permission to access / on this server.

Additionally, a 404 Not Found error was encountered while trying to use an ErrorDocument to handle the request.
Apache/1.3.41 Server at www.zephyrfoundation.org Port 80

---------

Quote
a study that will transfer lymphocytes from a B*5701 Elite Controller to a B*5701 Progressor. There are many of us who have been working hard to locate 3 recipients (progressors) who qualify for this procedure - I am hopeful that the study will launch in the spring.

I'm praying this experiment will be successful, since it would be a very simple and safe "cure".

Quote
will update you on the inflammatory markers at a future date.

Thanks again, Zephyr!


Offline zephyr

  • Member
  • Posts: 459
    • Zephyr L.T.N.P. Foundation, Inc.
Re: LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID
« Reply #21 on: February 10, 2009, 03:23:57 PM »
Hello AM Community -

Based upon the number of views to this thread - 1580 as of today - I thought I'd let you know that Dr. Migueles will be presenting an Oral Abstract of his paper at CROI (Conference on Retroviruses & Opportunistic Diseases) this afternoon in Montreal, at 4:00 p.m.

The webcast of his presentation may be posted on the CROI website later today (http://www.retroconference.org), and definitely tomorrow, if you are interested.

You can select 'Webcasts' on the far left hand menu from the home-page, and find the presentation under 'Oral Abstracts - Mechanisms of Immunologic Control of HIV/SIV Infection' under the title "Lytic Granule Loading of CD8+ Cells Is Required for HIV-infected Cell Elimination Associated with Immune Control", or by typing in Dr. Migueles' name.

All the best,
Zeph
"It is character that communicates most eloquently."

 


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