Scientists unmask key HIV protein

[datdude]

Scientists unmask key HIV protein, open door for more powerful AIDS drugs
New U-M discoveries on how HIV evades immune system could one day eliminate the need to take antiviral drugs for a lifetime

 
ANN ARBOR, Mich. — University of Michigan scientists have provided the most detailed picture yet of a key HIV accessory protein that foils the body's normal immune response. Based on the findings, which appear online in the journal PLoS Pathogens, the team is searching for new drugs that may someday allow infected people to be cured and no longer need today's AIDS drugs for a lifetime.

"There's a big hole in current therapies, in that all of them prevent new infection, but none attack the cells that are already infected and hidden from the immune response," says Kathleen L. Collins, M.D., Ph.D., the study's senior author and a U-M associate professor in both internal medicine and microbiology and immunology.

In people infected with HIV (human immunodeficiency virus), the virus that causes AIDS, there's an unsolved problem with current anti-viral drugs. Though life-saving, they cannot root the virus out of the body. Infected cells are able to live on, undetected by the immune system, and provide the machinery for the virus to reproduce and spread.

"People have to be on the existing drugs, and when they're not, the virus rebounds. If we can develop drugs that seek out and eradicate the remaining factories for the virus, then maybe we could eradicate the disease in that person," Collins says.

Research details:

The new research details the complex actions of a protein, HIV-1 Nef, that is known to keep immune system cells from doing their normal jobs of detecting and killing infected cells.

Collins and her team show how Nef disables two key immune system players inside an infected cell. These are molecules called major histocompatability complex 1 proteins (MHC-1) that present HIV antigens to the immune system, and CD4, the cell-surface receptor that normally locks onto a virus and allows it to enter the cell.

Collins likens MHC-1 to motion detectors on a house, which send the first signal to a monitoring station if an invader breaks in.

"The immune system, especially the cytotoxic T lymphocytes, are like the monitors who get the signal that there's a foreign invader inside the cell, and send out police cars," she says. "The 'police' are toxic chemicals produced by T lymphocyte cells, which kill the cell that harbors the invader."

By in effect pushing the MHC-I proteins into an infected cell's "trash bin" so they fail to alert the T lymphocytes, Nef's actions allow active virus to hide undetected and reproduce. Also, once a cell has been infected, Nef destroys CD4. The result is that this encourages new virus to spread to uninfected cells.

Nef's activities are variable and complex. But the research team's findings suggest that the many pathways involved may end in a final common step. That could make it possible to find a drug that could block several Nef functions.

Implications:

Collins' lab is now screening drug candidates to find promising Nef inhibitors. Such drugs, which are at least 10 years away from use in people, would supplement, not replace, existing anti-viral drugs given to HIV-infected people. The new drugs would target the reservoirs where the virus hides.

In developing countries, the new drugs could have a huge impact, Collins says. Today, children born with HIV infection start taking the existing anti-HIV drugs at birth. It's very hard to continue costly treatments for a lifetime. But if children could be cured within a few years, global HIV treatment efforts could spread their dollars further and be much more successful, she says.

http://www.eurekalert.org/pub_releases/2008-09/uomh-suk092608.php

[leit]

Isn't it the usual re-re-re-breakthrough (see "Nef inhibitors")?

[bimazek]

no, actually this is very very important because, no one understood why the infected cd4 cells did not present something outside the cell some kind of bio-marker some Info to the body's immune system out in the blood, --- that hey immune system -- this cell is infected by a virus please destroy it as soon as possible--- this information was never known or discovered before today   and this also apples to the reservoir cells that many on these boards are worried about clearing...  any other body cell for that matter,   --- any  infected body cells not presenting something outside itself to the body's immune system ---  this is done by MHC    this is major-ly important cause it solves that huge mystery --- imagine science did not know that the cd4 receptors were RETRACTED by hiv until today after the cd4 cell was infected, that alone is amazing breakthru piece of info part  of the puzzle, and it makes perfect sense if you read the links below -- like why wouldnt the hiv particles clump onto the cd4 receptors of the cd4 cell that it was manufactured in, even i had that thought, why dont they get stuck on the cd4 of an already infected cd4 cell, also

the Major HC complex  Major Histoical complex  MHC  -- the is a BASIC part of the immune system and immune presentation of viruses to immune system so now, for first time in history science knows that the   MHC (the most important part of presenting an invader to immune system) is retracted and put in trash bin of cell by hiv

this is a big big FEAT, and both of these together are doubling up the fooling the immune system, so it could be a nice step in right direction

read all these links entirely and you will see

There's a big hole in current therapies, in that all of them prevent new infection, but none attack the cells that are already infected and hidden from the immune response," says Kathleen L. Collins, M.D., Ph.D., the study's senior author and a U-M associate professor in both internal medicine and microbiology and immunology.
In people infected with HIV (human immunodeficiency virus), the virus that causes AIDS, there's an unsolved problem with current anti-viral drugs. Though life-saving, they cannot root the virus out of the body. Infected cells are able to live on, undetected by the immune system, and provide the machinery for the virus to reproduce and spread.
"People have to be on the existing drugs, and when they're not, the virus rebounds. If we can develop drugs that seek out and eradicate the remaining factories for the virus, then maybe we could eradicate the disease in that person," Collins says.

http://www.sciencedaily.com/releases/2008/09/080926100638.htm Collins' lab is now screening drug candidates to find promising Nef inhibitors. Such drugs, which are at least 10 years away from use in people, would supplement, not replace, existing anti-viral drugs given to HIV-infected people. The new drugs would target the reservoirs where the virus hides.
In developing countries, the new drugs could have a huge impact, Collins says. Today, children born with HIV infection start taking the existing anti-HIV drugs at birth. It's very hard to continue costly treatments for a lifetime. But if children could be cured within a few years, global HIV treatment efforts could spread their dollars further and be much more successful, she says.


http://www.medpagetoday.com/HIVAIDS/HIVAIDS/tb/11080
In a second step, nef binds the MHC I molecules to another protein, ß-COP, that initiates a process of degradation, eventually destroying the MHC I molecules entirely.
ß-COP "puts them in a trash bin" where they are destroyed, Dr. Collins said.
Interestingly, the same protein, ß-COP, also plays a key role in another important nef function, the researchers found.
Once a cell has been infected by HIV, no fewer than three viral proteins -- including nef -- have the job of locking the door after themselves, Dr. Collins said. In other words, they take the HIV receptor CD4 off the cell surface.
For nef, the process is "similar but different" to the way it prevents MHC I activity, she said.
The CD4 molecules are allowed to reach the cell surface, she and her colleagues found, but then nef quickly binds them to another trafficking molecule, this one called AP-2.
The AP-2-bound CD4 molecules are whisked into the interior of the cell, where nef binds them to ß-COP, which -- as in the case of the MHC I molecules -- starts the process of degradation, the researchers showed."It's counter-intuitive to think that HIV would want to remove its own receptor," Dr. Collins said, but in fact it's vital to viral replication.
For one thing, the lack of CD4 receptors means viral particles outside the cell go on to infect other cells, spreading HIV instead of re-infecting the same cell.

But a more subtle point, she said, is that when the crop of new viral particles is ready to leave the cell and start looking for new targets, they will interact with the cell surface.
If CD4 receptors remain, the new particles will bind to them, essentially forming a clump of HIV that is not infectious, Dr. Collins said.   She said that current HIV therapies are aimed at stopping HIV replication or infection of new cells but can do nothing about removing infected cells.
Blocking nef, on the other hand, might have that effect.

[leit]

no, actually this is very very important because, no one understood why the infected cd4 cells did not present something outside the cell some kind of bio-marker some Info to the body's immune system out in the blood, --- that hey immune system -- this cell is infected by a virus please destroy it as soon as possible--- this information was never known or discovered before today   and this also apples to the reservoir cells that many on these boards are worried about clearing...  any other body cell for that matter,   --- any  infected body cells not presenting something outside itself to the body's immune system ---  this is done by MHC    this is major-ly important cause it solves that huge mystery --- imagine science did not know that the cd4 receptors were RETRACTED by hiv until today after the cd4 cell was infected, that alone is amazing breakthru piece of info part  of the puzzle, and it makes perfect sense if you read the links below -- like why wouldnt the hiv particles clump onto the cd4 receptors of the cd4 cell that it was manufactured in, even i had that thought, why dont they get stuck on the cd4 of an already infected cd4 cell, also

the Major HC complex  Major Histoical complex  MHC  -- the is a BASIC part of the immune system and immune presentation of viruses to immune system so now, for first time in history science knows that the   MHC (the most important part of presenting an invader to immune system) is retracted and put in trash bin of cell by hiv

Sorry, "bimazek", but I can't see any big news in comparison with what was already known and reported by "aidsmap" ("Nef inhibitors"):

Nef down-regulates the expression of CD4 receptors on the surface of cells in order to allow virions to bud out from the cell wall more efficiently.
[...]
Nef also down-regulates the expression of major histocompatibility complex 1 (MHC-1) molecules. These molecules present viral antigens to the immune system so that infected cells may be cleared by natural killer (NK) cells. Down-regulation of MHC-1 may be partially responsible for maintaining the reservoir HIV-infected cells, by preventing their elimination by NK cells.

[bimazek]

http://www.eurekalert.org/multimedia/pub/10087.php?from=122436

did you actually look at the new discovery and this photograph

down regulate is NOT completely retract and put in the garbage can of the cell which is what has been discovered

yes, you are correct science thought that nef did some down regulation but it is an entirely different big step to find out and realize that it completely retracts all the MHC from the cell surface

what you are missing is that before this discovery science knew that there was some effect

now they see that it is complete and could be how

reservoirs exist without immune system finding them

it is similar to -- there was a time in science when they did not know something -- some thought it some experiments showed something in that direction

but to show that all the MHC gets pulled INSIDE cell and put in the part of the cell which is the genetic garbage can and that those genes (of hiv and MHC cannot get out of the garbage can of the cell) this is a big step

it solves a fundamental question of why immune survailence does not find hiv infected cells

before this discovery it could have been hundreds of reasons

they only knew that entry was effected --

that is a big big difference in science

if you asked 1000 hiv scientists who MHC does not present viral particles to immune system before this discovery you would have hundreds of guesses, if they would even have been willing to say why

now they know why and there is a photo

this technique of the photo of genes and parts of cell becoming common place is relatively new
yes perhaps they had it 5 ten twenty or more years ago but it was very expensive

now all these tech. are becoming affordable by a individual scientist in the lab (where before they had to get funding just to do the experiment)

now there is NEVER a point where science can say, well the MHC does present the latent infection to immune system so it has to be something else

now all science knows HOW exactly, remember there could have been millions of combinations of reasons on how this was done,

remember the immune system has a trillion different parts, it is difficult to even imagine its complete function

down regulate VS. complete retraction is a big difference in my book

if it was just ONLY down regulate then the immune sys could find the infected cells on its own

check CTLA and cd8 etc

science is going down ninety thousand paths of research and some are turning up big steps

this is one of them    --- yes the path was known down reg was known but not completely retraction and moving all MHC into a sequestered part of the cell, hidden from the body

big step in my book, remember
you would have to read all the papers to even know how they thought that nef down reg-ed MHC