November 5, 2010

Researchers Unravel a Secret of HIV Controllers

Five amino acids—tiny fragments of a protein called HLA-B—are what separate an elite group of HIV-positive people who naturally do not progress to AIDS from those living with the virus who will invariably develop AIDS without lifelong antiretroviral treatment, according to an important paper published November 4 on the website of the journal Science.

Under the direction of Bruce Walker, MD, from the Ragon Institute of Massachusetts General Hospital in Boston, a team of researchers sorted through 1.4 million bits of DNA to determine the rare gift of HIV control and immune system health among untreated long-term nonprogressors (LTNPs). The hope is that once researchers identify this gift, they can then replicate it in HIV-positive people with progressive disease. 

“HIV is slowly revealing its secrets, and this is yet another,” Walker said. “Knowing how an effective immune response against HIV is generated is an important step toward replicating that response with a vaccine. We have a long way to go before translating this into a treatment for infected patients and a vaccine to prevent infection, but we are an important step closer.”  

It has been known for almost two decades that a small minority—about one in 100—of individuals infected with HIV are able to live with HIV infection without showing any symptoms of disease progression, despite having a detectable viral load. Even more unique is a subset of LTNPs known as HIV controllers, who maintained undetectable viral loads, in the absence of treatment, without any obvious signs of immune system damage.  

In an effort to better understand this rare ability, researchers have been exploring genetic differences between LTNPs and HIV progressors. This led to the creation of the International HIV Controllers Study in 2006 by Florencia Pereyra, MD, of the Ragon Institute and her colleagues. The initial goal was to enroll 1,000 HIV controllers from medical clinics and research institutes around the world. That goal was expanded to 2,000 controllers in 2008, and thus far more than 1,500 controllers have been enrolled.

Early research suggested that certain genes involved with the HLA system—molecules that help the immune system differentiate between “self” and “invaders”—were important for HIV control. “But they couldn’t tell us exactly which genes were involved and how they produced this difference,” explained Paul de Bakker, PhD, of the Brigham and Women’s Hospital in Boston and a coauthor of the study. “Our findings take us not only to a specific protein, but to a part of that protein that is essential to its function.”

The current investigation began with a genome-wide association study (GWAS) of almost 1,000 controllers and 2,600 individuals with progressive HIV infection. The GWAS, which tests variations at a million points in the human genome, identified some 300 sites that were statistically associated with immune control of HIV, all in regions of chromosome 6 that code for HLA proteins. Further analysis narrowed the number of gene sites to four but could not indicate whether those differences actually affected viral control or were just located near the causal variants. Fully sequencing that genome region in all participants was not feasible, but a process developed by Sherman Jia—a medical student in the Harvard-MIT Health Sciences and Technology program—pinpointed specific amino acids; and directly testing those sites associated five amino acids in the HLA-B protein with differences in viral control. 

HLA-B is essential to the process by which the immune system recognizes and destroys virus-infected cells. Usually HLA-B grabs onto viral protein segments called peptides that are inside the cell and carries them to the cell membrane where they essentially flag the infected cell for destruction by CD8 “killer” T cells. The portion of the HLA-B protein that grabs and displays viral peptides is called the binding pocket, and all of the five identified amino acid sites are in the lining of the binding pocket.

“Amino acid variation within the HLA-B binding pocket will impact its shape and structure, probably resulting in some peptides being presented effectively and others not,” de Bakker says.  “Our work demonstrates that these variants could make a crucial difference in the individual’s ability to control HIV by changing how HLA-B presents peptides from this virus to the immune system.” 

This research’s ultimate goal is to clarify the mechanisms in which nonprogressors naturally control HIV and then to use that information to design a vaccine. “If we can replicate the natural phenomenon seen in HIV controllers (low levels of virus loads without medication) then we can impact the epidemic by decreasing HIV transmission and disease progression,” said Paul McLaren, a postdoctoral fellow at the Broad Institute in Cambridge and another coauthor of the study. “There are a lot of steps between now and then, but that’s the ultimate goal.”

Search: HLA-B, major histocompatibility complex, MHC, long-term nonprogressors, LTNPs, elite controllers, HIV controllers, Bruce Walker, Ragon Institute, vaccine

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Previous Comments:

Jose Diaz, San Juan, Puerto Rico, 2010-12-28 22:18:06
The impact of HIV and other factors like the protein HLB-B is important to understand the progress from HIV to AIDS.Congratulations for a good job.

Bruce, Blue Ridge Mountains, NC, 2010-12-18 06:59:50
Hi-new poster here-controller since '87-Partner since'79.Sent 20 tubes of blood to MGH 2 years ago and now they want us to go up. Would prefer to go to SCOPE but living on SSI makes it impossible to relocate. From MA originally-all friends dead. They just found my labs from 2004 and according to the Zephyr Foundation I am 1 of 6 controllers that they are aware of that has tested at the 2,000+ T-Cell mark globally. I have to do something? Ideas on relocating to CA appreciated. Happy Holidays!

Inspirator, Russian River, 2010-11-29 03:31:06
Now 30+years, I had bloods testing + from the late '70s (I helped start the MAC studies)! No ARVs, diminished but stable CD4s, almost undetectable vl, only 2 head-colds in the last 10 years, but even I won't get out of this life alive ... though I've now been HIV+ for over 1/2 of my life (now 55). In SCOPE study at UCSF. ;)

mannysf, San Francisco, 2010-11-23 19:30:09
I have been a viremic controller for about 11 years now with no meds and relatively high Tcell count and low vl. I've participated in the study mentioned above. I also have had my share of partying and still drink just for some perspective.

Mandy, London, 2010-11-23 15:06:37
I was diagnosed at the age of 22 in 1999,it's now 11 yrs ever since.I don't live my life in any special way,don't hav any healthy habits.I must say am blessed with stress free job and that realy helps cause I don't worry much. I thank God for such a blessing and encourage people not to lose any hope one day we will all be free from the stigma attached.

grace, USA, 2010-11-23 01:02:12
This is another reason why Test & Treat approaches are harmful and inappropriate medicine. I am a nonprogressor, with no change after 5 years. Some have had no change or need for meds after 25 years. Putting people on ART right away does not allow time to see if it is even necessary, and nonprogressors are important to NOT medicate, because in their bodies are answers for a vaccine. For those that advocate for TNT approaches, please think again.

DamienRocks, Los Angeles, 2010-11-21 04:05:29
I am an elite controller - 6 years as undetectable without any medications. I also adhere to a highly spiritual regiment and healthy lifestyle and don't use drugs or alchohol, which i'm sure, helps.

Brad, Anderson, IN, 2010-11-18 15:11:32
-Continued from first comment- This discovery, and or subsequent work, might make the the single choice of Vaccine over Cure irrelevant!!!

Brad, Anderson, IN, 2010-11-18 15:07:35
Hurrah to the HLA-B studies! In this age of prevention knowledge, come biases of contributory blame, and subsequent apathy to long term survivors. Some empathy to newly infected, and financial restraint from the powers that employ a Judge, Jury and Executioner' mentality. Spectrum wide disparities in prevention efforts, treatment, and funding make this discovery the largest ray of hope I have heard in some time-When asked if I would favor a vaccine, or cure,(with only one choice) a vaccine!!!

photojack53, San Diego, 2010-11-18 10:20:11
I'm another long-term nonprogressor, diagnosed in 1986 & never had any side-effects from meds, & have been off my meds for 2 years now, with no changes. My earlier medical treatment was from a clinical drug study that saw two newer drugs approved for HIV treatment. I'd gladly go through another clinical trial or testing to enable researchers to determine if new therapies or vaccines could be developed using my blood chemistry or amino acids. I revere those dedicated, humanitarian scientists!

Olivier, Washington D C, 2010-11-13 18:49:24
Very interesting story..One key factor is missing. The names of the five amino acids are never identified in this article. Please disclose the five amino acid types. With out this the article is incomplete. Thank you ...I do really appreciate POZ and all the work you do.

Jeff, , 2010-11-12 09:09:11
James Ozmun dude you need to settle down and get off your high horse

Ray, Pasadena, 2010-11-11 12:58:29
Regarding your article on "HIV Controllers", I believe this completely. I am an HIV individual, diagnosed since 1987, and have been disease-free, now undetectable, with an extremely low T-Cell count. I have tried to explain to my doctor that "I believe there is in my body, something that is helping my immune system other than my low T-Cells." I think she "could care less", but I think this is very important. I thank God for keeping me healthy. Of course, I also do my part with diet and exercise.

James Ozmun, Benton,Tennessee, 2010-11-10 09:59:16
I want to hear from others on this opinion of mine. Please read my initial comment on this article and make efforts to contact me. I believe more people like myself are out there, and we need to band together, take a stand with hard facts that have been at our disposal and just give the MACHINE a piece of our collective minds. This viral creation has been allowed to linger for too long. People are still taking their own lives due to this epidemic. it's rediculous! Scream and shout!!!!!!!!!!

James Ozmun, Benton,Tennessee, 2010-11-10 09:46:22
I've learned a lot about pure health since discovering the name Max Gerson. Upon my diagnosis I was told to "read,read,read". The best advice those SOB's ever gave me. I refuse to praise the AMA or FDA any further. Humans are viewed as disposable guinea pigs. The cure is with us people. Stand up, demand it. Speak out against the bureaucracy. Otherwise succumb to their elitist aristocracy and sit around and wait to die. It's time to stand up for ourselves! Noone else is. It's 28 plus years now.