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Author Topic: B*5701+ Elite Controllers & Immune Control of HIV: New Findings Published Today  (Read 4590 times)

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Offline zephyr

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    • Zephyr L.T.N.P. Foundation, Inc.
Greetings,

Very important news has been published today on findings related to Elite Controllers (ECs) who carry the B*5701 allele known to suppress HIV-1 infection. [Estimates are that 40% of  participants of the International HIV Controller cohort at the Ragon Institute - Boston, Massachusetts and approximately 63% of the participants in the LTNP Study at the National Institutes of Health (NIH) - Bethesda, Maryland test positive for this specific allele. Source: Power Point slides from presentations, Dr. Doug Kwon - Ragon & Dr. Stephen Migueles - NIH, Zephyr L.T.N.P. Foundation Symposium, "Unlocking the Mystery of the HIV Controller", San Francisco, October 13, 2009].

On a personal note, Zephyr is alive and well in Sacramento, and still donating samples of blood, cells and tissues to a variety of clinical research studies. My efforts to maintain the HIV Controller topic in the public view continue, as the work with the Zephyr L.T.N.P. Foundation does, too.

Peace to you,
Zephyr

Published online 5 May 2010 | Nature | doi:10.1038/news.2010.219

Well-trained immune cells keep HIV in check

Differences in T-cell development may explain why some infected people do not develop AIDS.

By Alla Katsnelson

A computer model proposes a solution to a long-standing mystery in HIV research — why a small percentage of people infected with the virus never develop full-blown AIDS. The answer lies in how the immune cells that recognize invaders are educated, and suggests new strategies for designing an HIV vaccine.

The human immune system detects foreign cells with the help of cell-surface proteins called human leukocyte antigens (HLAs). Each person's cells carry a particular set of HLA molecules — the person's HLA type — which bind fragments of virus or bacterial protein and 'present' them to T cells, the immune cells that recognize and attack infected cells. But before T cells are ready to perform their killer function, they are in effect trained on fragments of the body's own proteins — self-peptides — in an organ called the thymus. To 'graduate' from the thymus, a T cell must be able to recognize at least one combination of HLA molecule and self-peptide, which provides the template for its subsequent immune response against a foreign peptide bound to that HLA molecule. T cells that bind to self-peptides very strongly, however, are rejected, as they would attack the body's own cells.

Researchers in Massachusetts and California began with two observations. First, HIV-infected people who manage to keep the virus in check — so-called 'elite controllers' — often carry a particular HLA gene variant, HLA B571. Second, people with this gene also have a higher risk of developing autoimmune diseases, in which the immune system does produce a harmful response against the body's own proteins.

Arup Chakraborty, an immunologist at the Massachusetts Institute of Technology in Cambridge, and one of the lead authors of the new study, published online in Nature today2, thought the two observations might be related. He had not previously studied HIV, but he had studied how T cells are selected in the thymus by their ability to recognize specific HLA molecules and the peptides bound to them. He surmised that the HLA molecules of elite controllers might be binding a relatively small number of self-peptides.

Indeed, a look through a database of the binding properties of HLA molecules revealed that HLA B57, along with HLA B27 — which also protects against HIV — binds a much smaller proportion of self-peptides than HLAs that are not protective. The researchers then used a computer algorithm to predict how this would affect T-cell maturation.
T cells that develop in people with the HLA B57 gene would be presented with a smaller variety of peptides in the thymus. Their model showed these cells have broader activity and would be likely to recognize HIV even if the virus mutates, allowing the immune system of elite controllers to keep the infection under control. But that same property would also make them more likely to turn on the body's own cells, explaining why HLA B57 leads to a higher risk of developing autoimmune diseases. "If you have a smaller diversity of self-peptides in the thymus," explains Chakraborty, "there's a higher probability that T cells with a stronger reactivity and cross-reactivity" might be released.

Train gain
The mechanism of protection identified by the study was a complete surprise, says Bruce Walker, director of the Ragon Institute for HIV research at Massachusetts General Hospital in Boston, who is also a lead author of the study. "I actually had to pull out text books," he says, to recall the process of T-cell selection in the thymus, which has not previously been associated with the immune response to HIV.

Testing their model on data from 1,900 HIV-infected individuals with known HLA types, 1,100 of which were elite controllers, the researchers found that the progression of the disease was strongly correlated with the number of self-peptides an HLA molecule was able to bind.

"I think it's a remarkably interesting hypothesis," says Sarah Schlesinger, an HIV vaccine researcher at the Rockefeller University in New York. It "explains clinical observations made for over a decade", she adds.

Extra-reactive T cells are more numerous in carriers of HLA B57, says Walker, but everyone has them in low numbers so it might be possible to design a vaccine that actively selects them. "What we need to do with a vaccine is train bigger T-cell armies that will be there when a person first encounters the HIV virus."

How researchers might design such a vaccine is unclear, but the study's findings are likely to be helpful, says Schlesinger. In the mid-1990s, she notes, scientists identified another mechanism that provides a degree of natural immunity to HIV — a mutation resulting in the lack of a receptor that HIV commonly hijacks to enter a cell. "It was not entirely clear how that was going to be clinically useful," she says, but it resulted in a drug called maraviroc, made by the pharmaceutical company Pfizer, which prevents the virus from binding to this receptor and entering the cell.

"I think it's becoming more and more apparent that conventional ways of designing vaccines are not going to work for HIV," says Helen Horton, an HIV vaccine researcher at the Seattle Biomedical Research Institute in Washington state. Studying the body's own tricks for controlling infection could provide just the shot in the arm that HIV vaccine efforts need, she says. "I think this is definitely where we need to be headed."

http://www.nature.com/news/2010/100505/full/news.2010.219.html

    *
      References
         1. Migueles, S. A. et al. Proc. Natl Acad. Sci. USA 97, 2709-2714 (2000).
         2. Kosmrlj, A. et al. Nature advance online publication doi: 10.1038/nature08997 (2010).


New insights into the mystery of natural HIV immunity

May 5, 2010 by Anne Trafton   Physorg.com

When people become infected by HIV, it's usually only a matter of time, barring drug intervention, until they develop full-blown AIDS. However, a small number of people exposed to the virus progress very slowly to AIDS -- and some never develop the disease at all.

In the late 1990s, researchers showed that a very high percentage of those naturally HIV-immune people, who represent about one in 200 infected individuals, carry a gene called HLA B57. Now a team of researchers from the Ragon Institute of Massachusetts General Hospital, MIT and Harvard has revealed a new effect that contributes to this gene's ability to confer immunity.

The research team, led by MIT Professor Arup Chakraborty and Harvard Professor Bruce Walker at MGH, found that the HLA B57 gene causes the body to make more potent killer T cells — white blood cells that help defend the body from infectious invaders. Patients with the gene have a larger number of T cells that bind strongly to more pieces of HIV protein than people who do not have the gene. This makes the T cells more likely to recognize cells that express HIV proteins, including mutated versions that arise during infection. This effect contributes to superior control of HIV infection (and any other virus that evolves rapidly), but it also makes those people more susceptible to autoimmune diseases, in which T cells attack the body's own cells.

This new knowledge, published online in Nature on May 5, could help researchers develop vaccines that provoke the same response to HIV that individuals with HLA B57 muster on their own, says Walker, who is director of the Ragon Institute and a professor at Harvard Medical School.

"HIV is slowly revealing itself," says Walker. "This is another point in our favor in the fight against the virus, but we have a long way to go."

Most killer T cells are genetically unique and recognize different pieces of foreign proteins, known as epitopes, attached to the surface of cells that have been infected by viruses or bacteria. After a killer T cell grabs hold of such a protein, it becomes activated and starts sweeping the body for more cells that express the same protein, so it can kill them. It also clones itself to produce an army of T cells targeting the invader.

http://www.physorg.com/news192282594.html
"It is character that communicates most eloquently."

Offline Inchlingblue

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Thanks for all your work and dedication, Loreen.

Here's another article about this:

http://news.bbc.co.uk/2/hi/health/8663239.stm

Offline madbrain

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I just found out yesterday that I have the HLA B*5701 mutation (1 copy), thanks to some genetic tests from Navigenics. I guess it makes sense that my VL was low and tcells not declining.

Offline Inchlingblue

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I just found out yesterday that I have the HLA B*5701 mutation (1 copy), thanks to some genetic tests from Navigenics. I guess it makes sense that my VL was low and tcells not declining.


Is this test covered by insurance?  If not, is it expensive?

Is it safe to assume that those who have two copies are elite controllers?

Offline madbrain

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The Navigenics set of tests is not covered by my insurance (HMO), but it's eligible for reimbursement through a Flexible spending account, ie. tax-free payment. I already got reimbursed from my FSA. The regular cost of the complete set of tests is $999, but I only paid a $199 corporate discount introductory price. There are a lot of other interesting tests in the package that I'm still going through. It's in a 78 page report.

Offline zephyr

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    • Zephyr L.T.N.P. Foundation, Inc.
Thank you for your kind comment, Inchlingblue, it's much appreciated! I hope everything is going well for you. :)

And hello to 'madbrain', nice to see you here, too. As Dr. Connors says (below), "The B*5701 gene may only be part of the explanation (re: control of HIV)...."

Wanted to post an update to this story, published on Bloomberg.com, that presents comments by Dr. Mark Connors, Chief, HIV-Specific Immunity Section, Laboratory of Immunoregulation, NIAID/NIH.

Zeph

Hunt for HIV Vaccine Renewed by Insight on Protective Gene, Scientists Say

By Adi Narayan - May 05, 2010

Insights into a gene that helps some people fight HIV may revive the hunt for vaccines against the deadly virus behind AIDS, said researchers at Harvard University and the Massachusetts Institute of Technology.

The gene, HLA B57, enables the body to produce more-potent killer T cells, the white blood cells that fight infections, the scientists said today in the journal Nature. The killer cells linked to the gene can attack even the mutant cells that arise to escape T cells, according to the research.

About 1 in 200 patients infected with HIV have natural immunity to the virus, and scientists discovered earlier that many of the protected people carry the HLA B57 gene. In the new study, the researchers said the gene affects an immune-system organ called the thymus, leading to the stronger array of T- cells. Vaccines one day might provoke the same reactions in people without natural immunity, the scientists said.

“HIV is slowly revealing itself,” said Bruce Walker, one of the study leaders and a professor of medicine at Harvard Medical School in Boston, in a statement. “This is another point in our favor in the fight against the virus, but we have a long way to go.”
The researchers used computer models to simulate the function of the thymus and tested the performance of the HLA B57 gene compared with others.

In 1999, scientists at the National Institutes of Health, in Bethesda, Maryland, linked the HLA B57 gene to the ability to control HIV without drugs. Since then, researchers have been using a variety of tools, including clinical experiments and mathematical modeling, to understand how the gene works.

‘Attractive Idea’

The latest study isn’t consistent with earlier findings, and may have shortcomings because it was “completely done on a computer,” said Mark Connors, chief of HIV-specific immunity at the National Institute of Allergies and Infectious Diseases, part of NIH, in a telephone interview.

That HLA B57 increases the variety of T cells is “an attractive idea that needs to be confirmed by experimental data,” said Connors, who first found the link between the B57 gene and HIV immunity. Connors wasn’t involved in the new study.

The B57 gene may only be a part of the explanation, and physiological or environmental elements may influence immunity to HIV, Connors said.

“B57 tilts the odds in your favor, but it doesn’t guarantee anything,” Connors said.
More than 34 million people globally have HIV, and about 2 million lost their lives to AIDS in 2008, according to the World Health Organization, based in Geneva.

To contact the reporter on this story: Adi Narayan in New York at anarayan8@bloomberg.net

http://www.bloomberg.com/apps/news?pid=20601124&sid=aZoaJHXyudsU




"It is character that communicates most eloquently."

Offline veritas

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zephyr,

An exciting find ! This latest find seems to be building on another report by Carrington et al. back in Nov. 2009. See this:

http://www.nature.com/ng/journal/v41/n12/abs/ng.486.html

Another exciting development with respect to HLA-C gene, shows that information is being shared as CHAVI was certainly aware of the progress being made with respect to Carrington et al.'s work. This was reported on Dec 9 of last year.

https://chavi.org/modules/announcements/index.php?id=7

Thanks for posting.


v

Offline Boze

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Inching,
Similar test is offered by 23andme (also ancestry information). They are normally $500 but on 4-23 they offer a $99 special. You just missed it - but it should be back next year :)
==========
Aug08 - Seroconversion
Mar10 - Diagnosis; cd4 690 - VL 19,000
Apr10 - cd4 600
May10 - VL 4,500
Jun10 - started Atripla ; VL 113
Jul 10 - UD vl, CD4 590
Aug 10 - UD, CD4 810, 52%
Nov 10 - UD, CD4 980

Offline Inchlingblue

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Inching,
Similar test is offered by 23andme (also ancestry information). They are normally $500 but on 4-23 they offer a $99 special. You just missed it - but it should be back next year :)

That's good to know, thanks. ;)

Offline zephyr

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    • Zephyr L.T.N.P. Foundation, Inc.
Hi veritas,

Thanks so much for linking me to Dr. Carrington's paper from December - I really appreciate this.

I have been following the genetic aspects of HIV Controller research for several years now, and find it absolutely fascinating, to say the least. Dr. Carrington and I met each other last year, when I attended the NIAID/NIH Genomics Workshop in Bethesda, Maryland. She is an extraordinary person, and has been instrumental in furthering my knowledge-base on this subject. In addition, she sits on the Scientific Advisory Panel for Dr. Walker's study and has informed me recently that we can expect publication of the HIV Controller Genome Wide Association Scan (GWAS) paper very soon.

Keep your eyes peeled for this paper, as I'm sure it will be quite interesting and full of specific information in regard to Class I alleles (HLA- A, B, C) as well as Class 2 alleles (HLA-DRB1, DQB1 and DRB), loci equated with  suppression of HIV (or being considered as such).

My best to you,
Zephyr
"It is character that communicates most eloquently."

Offline stealthy81

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The Navigenics set of tests is not covered by my insurance (HMO), but it's eligible for reimbursement through a Flexible spending account, ie. tax-free payment. I already got reimbursed from my FSA. The regular cost of the complete set of tests is $999, but I only paid a $199 corporate discount introductory price. There are a lot of other interesting tests in the package that I'm still going through. It's in a 78 page report.


Hi Madbrain!

Isn't HLA-B*5701 the same genetic polymorphism routinely screened to detect hypersensitivity to abacavir? Why did you have to take a special test? Thank you!

Offline madbrain

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Hi Madbrain!

Isn't HLA-B*5701 the same genetic polymorphism routinely screened to detect hypersensitivity to abacavir? Why did you have to take a special test? Thank you!

Yes, it's the same test.
I didn't have to take a special test, it was included in the Navigenics package. Actually this test is something they recently added to the package, between the time I ordered and the time I received my results.

Offline veritas

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zephyr,

A strong killer T cell response is certainly what we are going to need for a vaccine or cure and genetics seems to be the ave to pursue with respect to obtaining that objective. However, the genetic aspect has always giving me pause due to the potential for auto-immune disease and possible cytokine storm.
When I saw the genetic study on CHAVI's website and your update, I remembered that anti-ps has the potential to quelle a cytokine storm and could possibly contribute to the control of auto-immune disease.
(I would have to dig for the reference.). Should this combination work synergistically (and I'm hoping that's what CHAVI is looking to do), some real progress could be made toward the "goal".

Please keep us updated on this fine work ,since you are the resident expert on genetics. I 'll try to do my part with anti-ps.
 By the way ,did the good doctor give you any indication as to which journal the GWAS paper will be published? I take it that 'Genetics' is the obvious candidate. Will keep a look-out.


Thanks,

v

 


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