Gene Hope from HIV Controllers

posted: 05/11/2010

Scientists are closer to understanding why a tiny proportion of people with HIV can live for many years without treatment and without developing AIDS. New scientific insights could boost HIV vaccine and treatment prospects by exploiting natural immunity to the virus. But a UK HIV expert said there is still a "long way" to go before a vaccine or any new drug for HIV can be developed.

Natural immunity

About one in 300 people with HIV do not develop AIDS because of natural immunity. Their immune systems keep the virus in check, preventing HIV from overwhelming the body's immune system defences, and reducing the risk of passing on HIV.
 

People who stay healthy are described as "HIV controllers". Their bodies are able to control HIV by suppressing it so far that the viral load can be undetectable.
 

Genes of 1000 compared with 2,600

The latest study involved an exhaustive genome-wide genetic scan involving a million measurements of the DNA of 1000 HIV controllers from around the world. These were compared with the genomes of 2,600 other people with HIV. The comparison revealed significant differences in the DNA responsible for one of the immune system's vital proteins, called HLA-B. This is already known for defending the body against viruses.
 

Small differences
The study found that the ‘Controllers’ version of this protein has differences in only five of the amino acids – the building blocks of proteins. These differences are at the "binding pocket," which locks on to invading viruses, before warning the immune system that it is under attack.
 

HLA-B is part of the process by which the immune system recognises and destroys virus-infected cells. Part of the protein called a binding pocket "drags and drops" peptides from inside the virus onto the cell membrane. These then mark out the cell for destruction by CD8 "killer" T cells of the immune system.
 

"We found that, of the three billion nucleotides in the human genome, just a handful make the difference between those who can stay healthy in spite of HIV infection and those who, without treatment, will develop AIDS," said Bruce Walker, director of the Ragon Institute at the Massachusetts General Hospital in Boston.
 

Paul de Bakker of the Broad Institute in Cambridge, Massachusetts, said: "Earlier studies showed that certain genes involved with the HLA system were important for HIV control. But they couldn't tell us exactly which genes were involved and how they produced this difference. Our findings take us not only to specific protein, but to a part of that protein essential to its function."
 

One step closer

Dr Walker emphasised that the discovery just one of the major differences that increase people’s chance of living healthily with HIV.
"We've not identified the precise mechanism to explain HIV controllers, but we know that of all the genetic influences involved, this is by far the most important," Dr Walker said.
 

Doug tells us why he's involved
Doug Robinson, 46, from Truro, Massachusetts, is one of hundreds enrolled in the study of "HIV controllers". He was diagnosed in November 2003 but is still healthy and well. Normally by this stage of HIV infection, and without anti-HIV drugs, Mr Robinson would be expected to have a high level of HIV in his bloodstream – a "viral load" of about 50,000 copies of HIV. Instead, Mr Robinson has under 50 copies, which is undetectable.
 

"After my diagnosis, a friend told me that I am here for a purpose, that I could be a link to something that could be beneficial, and I felt like I had a responsibility to put myself out there," Mr Robinson said. "I feel it's my responsibility, no matter what I do, to put that to use. When I'm long gone, and the dust has blown over me, I hope to leave something, a positive contribution."

Hope but a long road
Gus Cairns, editor of HIV Treatment Update of the UK's National Aids Manual, said: "This research opens the door to the development of a vaccine that could encourage the body to mimic the most effective kind of immune response, or to drugs that could interfere with HIV's ability to infect cells and derange the immune system.
"Nonetheless there is still a lot we don't know about why some genetic variants provide a much less welcoming environment for HIV than others and, although we are becoming clearer about what kinds of specific immune response are effective against HIV, we are a long way from being able to make them happen, or even knowing what we must do to make them happen."
 

Sources and reference
Independent
BBC
HIV Controllers study

Science article (pay to view)

Treatment - Learning from Exceptions

posted: 10/07/2009

Rare people among the many living with HIV, have HIV but never seem to become ill with it. What can they teach us about new ways to strengthen the body’s natural defences against HIV and for developing new HIV drugs?
 

At first Karen Pancheau figured her son Tyler’s nasty rash came from friction on the mats at judo class. But when the rash became much worse, his dad took the teenager for tests, which revealed he had HIV. Karen, too, then tested positive for HIV, which she’d acquired from a blood transfusion in 1982 and to which she exposed Tyler during childbirth and breast-feeding. Yet while Tyler’s health deteriorated, Karen remained well.
 

Treatment worked for Tyler, but left him constantly tired, and he killed himself aged 23. Remarkably, 26 years after her HIV infection, his mother is still well.
 

She isn’t alone. Bruce Walker, now director of the Partners AIDS Research Center at the Massachusetts General Hospital and director of the Center for AIDS Research at Harvard University, first became aware in 1992 that there were others who seemed somehow protected from HIV. He learned about the phenomenon from Susan Buchbinder, an epidemiologist in San Francisco who was analyzing blood samples from gay men taken many years earlier to understand how HIV infection develops. She found men whose samples showed they had been infected with HIV in the late 1970s; many had already died, but some weren’t even sick. Then, in 1994, Walker met a haemophiliac in Boston named Bob Massie, who had become infected with HIV through a blood transfusion in 1978. “People keep telling me I’m going to die, and I keep living,” Massie told Walker. Walker immediately began to study his immune system.
 

“Non-progressors” or “Elite controllers”

A few years later, speaking before several hundred doctors at an HIV conference in New York, Walker asked how many doctors saw people who were unaffected by their HIV. At least half the audience raised their hands. Walker realized that people like Massie represented a real opportunity for research. He also came to realise why these rare individuals — no more than one in every 300 cases — had remained under the radar: “They weren’t sick. They weren’t coming to the hospital.”
The rare individuals whose HIV does not progress are clumsily called either “non-progressors” or “elite controllers”. They offer hope for HIV research.
 

Since 1981 AIDS has claimed more than 25 million lives, and today some 33 million people worldwide are infected with HIV. Though treatment improvements mean most people who start treatment now at the recommended point when the CD4 count is 350 can expect to live into their 70s.
Many scientists have openly questioned whether conquering HIV with a vaccine or a cure is even possible. In 2008, after pharmaceutical manufacturer Merck announced the failure of its latest attempt at a vaccine, the Independent surveyed more than 35 leading HIV researchers in the USA and UK. About two-thirds said an HIV vaccine wouldn’t appear within the next decade. Several predicted a vaccine would never be developed.
 

Learning from people who’s HIV doesn’t do damage
Against that gloomy outlook stand these rare people, who, somehow, have managed to do what medicine’s best efforts have been unable to accomplish.
No one yet knows how their bodies keep HIV at bay. Are their immune systems exceptionally strong and effective? (One recent study says their immune systems are far better at killing HIV-infected cells.) Do they have genetic protection? Is it a combination of still-unknown factors that makes the difference?
 

As more and more of these “non-progressors” emerge — 500 in the USA have volunteered to help — scientists hope to reveal the HIV protective shield. And perhaps in the process they’ll find a way to safeguard everyone else as well.
 

HIV at work
Like many other viruses, the human immunodeficiency virus does its damage by entering healthy cells, reproducing and releasing copies of itself that then infiltrate other cells. The immune system fights back with several mechanisms, including B cells, which produce antibodies that coat invading viruses, thus preventing them from entering other cells; and T cells, which find and dispatch infected cells. (There are two main types of T cells: CD4+ cells, which oversee the immune response, and CD8+ cells, or “killer” T cells, which do most of the actual killing.)
 

In the typical progression of HIV, a person’s viral load—the number of viral copies of HIV per milliliter of blood — rises while the number of immune system CD4+ cells falls. If the CD4 count falls to about 200, “opportunistic” infections become very likely.
People with low CD4 counts and opportunistic infections may have viral loads of several hundred thousand copies per milliliter. In contrast, the viral loads of “non-progressors” range from barely detectable to undetectable by even the most sensitive tests.
 

Virus bad, Retrovirus worse
Two characteristics of HIV make the condition an immense challenge for the body — and vaccine s — to combat. Most viruses attack particular parts of the body, with, for example, the common cold virus going after the nasal passages, and hepatitis infecting the liver. But HIV targets the immune system’s T cells, weakening the body’s defences. It turns these infected cells into highly efficient HIV factories. What’s more, HIV mutates rapidly into countless variations within a single person, making it extremely difficult to develop an effective vaccine.
 

“This isn’t just one virus,” says Dennis Burton, an immunologist at the Scripps Research Institute in La Jolla, California. “You’re talking about tens of thousands of different viruses.” Even worse, neutralizing one HIV variant simply creates a niche for other opportunistic mutations to fill. “HIV is really an elegant replicating machine built to evade almost every defence humans have against pathogens,” explains Steven Deeks, an HIV specialist at San Francisco General Hospital.
Early on, researchers discovered that these rare individuals don’t have a weakened version of HIV – it is just as strong as in everyone else. But little else about their condition is certain, and that’s a situation Deeks, Burton, Walker and a growing number of other researchers are determined to change.
 

International study
Since 2006, Walker and his colleagues have been organising an international contingent of more than 250 researchers and more than 200 physicians who have “non-progressors” as patients. Initially funded by a gift from the Mark and Lisa Schwartz Foundation and recently boosted by a $22 million grant from the Bill & Melinda Gates Foundation, the International HIV Controllers Study is working to identify “non-progressors”, collect samples of their blood and DNA, and distribute the samples to labs for analysis.
 

Burton, at Scripps, is studying the immune systems of HIV-positive people, some of whom are “non-progressors” but most of whom simply have low viral loads, whose antibodies are capable of acting against many different strains of the virus. At the MGH, Marylyn Addo investigates regulatory T cells, which prevent the immune system from destroying healthy cells in its quest to quell invaders. Though her work is at an early stage, she is hopeful the comparison will eventually yield clues about how “non-progressors’”regulatory T cells maintain the delicate balance between doing too much and too little.
Some blood samples have made their way to the Massachusetts Institute of Technology, where scientists versed in nanotechnology—the study of very small structures—are examining how the immune system fights off disease at the most basic level. Along with his research group, J. Christopher Love, a chemical engineer whose specialty is building structures out of metal rods as small as one one-thousandth the width of a human hair, is trying to dissect the immune system to discover what might be different about “non-progressors”.
 

Immune system defenses
The immune system uses an array of defenses—broadly classified into innate and adaptive immunity—to fight off viruses, bacteria and other invaders. Innate immunity refers to defenses humans are born with; the skin and mucous membranes, for example, help keep out most attackers. But it’s adaptive immunity that is compromised by HIV. That subsystem depends on B cell antibodies and killer T cells that not only seek out and destroy intruders but also remember them the next time they attempt to invade, thus providing adaptive immunity.
Vaccines normally work by introducing a dead or harmless piece of virus that stimulates the adaptive immune system to attack. In that way, the body builds defenses capable of destroying the real virus. But HIV has resisted every effort to develop a vaccine.
 

T cells with that bit extra?
Love and his team want to know whether the T cells in “non-progressors” have special properties that enable them to fight off HIV. The answer will require a much more detailed understanding of just how T cells function, so the team has developed a system to examine T cells destroying infected cells. They start by moulding cell-size wells into a piece of polymer similar to a laboratory slide. Then they trap a single T cell along with a single cell infected with HIV—with as many as 300,000 specimens fitting onto a single three-inch slide. That allows researchers to watch T cells attacking infected cells and to compare the action of “non-progressors’” cells with those of patients whose HIV has developed into AIDS. By examining the differences, they hope to understand the qualities in the “non-progressors’” cells that enable them to ward off the disease.
 

Extra proteins clue
One clue may already have emerged. In the December 19 issue of the journal Immunity, researchers at the National Institute of Allergy and Infectious Diseases concluded that the killer T cells of “non-progressors” accumulate more of two important proteins—perforin and granzyme B—than do those of other people with HIV. Perforin released by the T cells punches holes in the infected cell through which granzyme B enters and destroys the cell. In studies of cells taken from “non-progressors” and from people with AIDS, controllers’ T cells killed 68% of infected cells in an hour, compared with just 8.1% for those with AIDS. It’s a promising find, but to discover many of the hows and whys of the phenomenon needs more study.

Needle in a haystack search for gene differences
One theory about “non-progressors” holds that they possess special genetic traits, beyond any differences in their immune systems, that better equip them to battle HIV. Geneticist Paul de Bakker of Brigham and Women’s Hospital in Boston is combing through the human genome to find those characteristics. But it’s a daunting endeavour. The genome comprises 3 billion coded pieces of information that determine who a person is. Some 99.9% of these pieces are the same in all people, but there are points of difference—known as single nucleotide polymorphisms (SNPs, pronounced snips)—that set apart one individual from the next.
 

In his search for SNPs along the 3 billion-link chain, de Bakker isn’t looking for an HIV-causing gene but rather for something more subtle and elusive, a predisposition that empowers “non-progressors” to keep HIV from taking hold. Though at the outset of his quest he had no idea where to look for such crucial differences, de Bakker insists that may actually be an advantage. “We don’t have to make any assumptions about how HIV works, or about the immunology behind it,” he says. “We just let the data tell us what is important.”
 

To conduct his experiments, de Bakker uses powerful DNA scanners at the Broad Institute in Cambridge, Massachusetts, a joint Harvard and Massachusetts Institute of Technology research centre devoted to genomics studies. Researchers deposit DNA samples on a “SNP chip” and insert it into a machine that produces colour-coded maps of a subject’s DNA.
 

Researchers can now examine as many as a million SNPs at once, but de Bakker thinks that within five years scanners will be able to compare the entire code of thousands of people to find points of variation. Somewhere in there, he thinks, will be clues to how “non-progressors” fend off AIDS; early indications signal a cluster of genes that involve the immune system.
 

De Bakker’s goal, like those of dozens of other scientists focusing on controllers, is to learn secrets that could lead to a vaccine or even a cure. “Non-progressors” themselves are as mystified as anyone about what makes their bodies special. For many, including Karen Pancheau, survival is bittersweet—their own good health is counterbalanced by the pain of having lost friends or family to the disease. “I have my glass-half-empty days, but I try not to dwell on those,” Pancheau says. She thinks that an answer to the disease, derived in a way from her own blood, would be a fitting tribute to the son she lost. “That’s why I do this.”
 

Edited from Source
abridged version here
 

Predicting Non-Progression

posted: 14/01/2009

A very small number - 3-5 out of every 100 - people with HIV don’t experience HIV disease progression. Even with treatment, over a lifetime, most people will face a gradual fall in their CD4 cell count and the rising risk of developing infections and ill-health.
 

Non-progressors are different - their CD4 cell count remains high (over 500) and their viral load remains very low for years after HIV infection – without needing HIV treatment. People who stay like this for at least eight years are sometimes described as ‘long-term non-progressors’.
 

Predicting non-progression

French researchers have found that it’s possible to predict who will be long-term non-progressors very soon after HIV infection.
 

They studied people who had a CD4 cell count of at least 500 at the time of their diagnosis. 
They then looked at what was different about people who had no HIV symptoms and whose CD4 cell count stayed above 500 for at least eight years without treatment, compared with those whose HIV progressed normally.

Non-progressors had higher CD4 cell counts at diagnosis (840 vs 670), were younger, and were more likely to have an undetectable viral load and undetectable levels of HIV DNA at diagnosis, than people whose HIV progressed. People who had undetectable levels of HIV DNA at diagnosis were found to have the best chance of experiencing no HIV disease progression for up to 16 years.
 

What’s the point of this research?
Firstly, it shows that we can predict who is likely to be among the few people whose HIV won’t progress for a long time.
 

Lessons for most

But it also affects the vast majority of people with HIV whose CD4 cell count will fall.
It shows that long-term non-progression is beyond anyone's control. If you don't luck out with the protective genes, your key to a long and healthy life is in good HIV treatment and care. And looking after your general health is important.

Thanks to treatment, people with HIV can expect to live a long time - most people can now expect to collect a state pension and be around even longer - so it makes very good sense to visit your HIV clinic for regular check- ups, start taking HIV treatment when you need to,  and to take your treatment properly, not to smoke, eat a good diet, exercise and look after your sexual health.

Source