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)

'Assassin Cell' Treatment?

posted: 27/11/2008

Researchers have developed a new "assassin cell" therapy for treating HIV which involves engineering the patient's own immune system to fight the virus more effectively. It could be used to boost the defences of people with advanced HIV infection.

The therapy – which has proved effective in laboratory tests using human cell cultures – will be tested in a USA clinical trial of 35 patients with advanced HIV infection that is due to start next summer.

Efforts to find a traditional vaccine against HIV have so far drawn a blank. "HIV mutates so quickly," said Dr Bent Jakobsen at Adaptimmune, the company in Oxford that is developing the new approach. "Gradually it gets better and better at escaping the detection of the immune system."

unusually resistant man

Jakobsen and his colleagues began to pursue a different approach after investigating a patient who had resisted his HIV infection particularly effectively. "When we tested the T cells from this patient, it looked as if he was responding to a number of those variants that normally escape the immune system," he said.

T cells are part of the immune system and attack and destroy cells within the body with any infection. They can recognise parts of HIV – antigens – on the outside of infected cells. In this patient, the T cell receptor protein seemed particularly good at recognising HIV antigens.
 

How they did it

The team isolated his receptor protein and then improved its ability to recognise HIV further by randomly mutating it. Treating patients will involve taking a blood sample and adding an engineered virus containing genes for the improved T cell receptor. The patient's own T cells then take up the genes and so are equipped with the improved receptor. These cells are then injected back into the patient. The result was a T cell receptor that binds to HIV 450 times more strongly. The study was published yesterday in Nature Medicine.

"In the face of our engineered assassin cells, the virus will either die or be forced to change its disguises again, weakening itself along the way," said Prof Andy Sewell from Cardiff University.
"Because the immune cells work so much better when they have this modified antigen receptor they can eliminate the virus. And the mutants that normally escape detection are also recognised and eliminated," Jakobsen said. "That's not to say that will happen in patients. HIV is incredibly difficult to deal with. But it does give hope that it will do much more than the immune system does against the virus."

The search for a vaccine has not gone smoothly. Last year a major trial of an experimental vaccine developed by Merck was abandoned and during the summer work on another vaccine candidate was shelved.

The clinical trial of 35 patients next summer will take place at the University of Pennsylvania in Philadelphia. There have been many false dawns before and this is just the start of a long process before this potential method can be adopted more widely. This is a process that is highly complex requiring experts and laboratories. It is not going to be cheap either. However it does offer a prospect for some people with advanced HIV infection who may have few other choices.

Source