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Fixing the Body: An Immune-Based Approach to HIV

February 2010

1. It's the Virus, Stupid

By now most people know HIV causes AIDS. But this is actually inaccurate. To understand why this is inaccurate helps explain why there are two different ways scientists are trying to figure out how to treat AIDS.


2. What Causes AIDS

AIDS is a condition in which a person is not able to fight off many illnesses that the body generally can get rid of or can learn to live with. The illnesses that kill people with AIDS are called "opportunistic infections" because they take advantage of a problem HIV sets in motion -- the slaughter of many different types of T helper cells.

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Before turning attention to how the T helper cells are killed off, let's look at how these T helper cells protect us in the first place.


3. How T Cells Protect Us

The immune system is our protection against disease and it has many parts.

The simplest parts of the immune system are barriers that stop germs from getting into important parts of our body, for example, our skin. Other parts are cells that are pre-programmed to kill off certain illness causing germs the body already knows about.

Then there is a third part that is much more creative and adaptable. This is the part of the immune system that can recognize a new enemy germ, and in response raise an army of fighter cells that are taught exactly what the enemy looks like and then gun down the enemy, attacking it either directly with chemical weapons like 'neutralizing antibodies' (stuff that sticks to the germ like glue and kills it or stops it from working), or indirectly by killing cells that hide it or help make more of it. In other words, by killing off infected cells that have been hijacked by the virus.

Infected cells hijacked by the HIV are reprogrammed by the HIV to manufacture more bad virus. To get rid of that kind of infection, we have to kill off those infected cells.

T helper cells are the part of the immune system that recognizes the new kinds of intruders, trains an army and hunts down infected cells. After 'learning' that a virus is an enemy, the T helper cells send out messages that get killer cells to investigate cells to see if they are infected and if so to destroy them. This, in most cases, eventually can cure us of an illness or at least hold it in check.


4. How Do Helper T Cells Learn a Virus Is an Enemy?

It turns out that all living things are made up of chemicals that we understand pretty well. The same set of chemicals which -- when you break them down -- form long chains of simple things called peptides.

T helper cells can tell which peptides are parts of you and which belong to something that should not be inside of you.

When T helper cells 'recognize' a peptide or a bunch of peptides that don't belong in you, they mobilize the immune system in a lot of different ways to get rid of the virus that the foreign peptide(s) are part of.

T helper cells are all born different, and recognize different specific peptides. Every T helper cell recognizes a peptide, as if it were a letter. The "z" T helper cells, for instance, are the ones that recognize "z" peptides, and know that they do not belong inside of you. They know right away that a virus with a "z" part -- in this case the so-called "zebra virus" -- is a bad guy. They alert every cell in the immune system that fights enemy viruses to kill off viruses that contain the peptide "z".

These cells recognize the viruses because they know that anything containing "z" -- including the cells hiding the zebra virus -- does not belong in your body. This way the immune systems clears out the virus and the cells that manufacture more of it from your body.

Sometimes this system of identifying these enemy "z" viruses stops working -- the question is why?


5. How Do the T Helper Cells Lose This Ability to Know That a Certain 'Zebra Virus' Attacked You?

If something is killing off T cells, and if there are only a limited number of T cells that can recognize this zebra virus, the result is that when none of those T cells are left, if the "zebra virus" attacks you, it will be very hard for your body to fight this zebra virus.

For one thing, it will take your body a long time even to realize that the "zebra virus" is there doing damage If you lose all the T cells that recognize the letter "z".

In the case of late stage HIV progressing to AIDS, your cells lose this ability to recognize enemy viruses. T helper cells have disappeared from your repertoire; your alphabet of T cells is missing important letters that makes you vulnerable to "zebra virus" if it attacks.

As one T cell after another disappears, and therefore T cells lose their ability to recognize letters, that is, to recognize those peptides that do not belong inside of you, you become less and less able to fight more and more illnesses and this condition is called "AIDS".

Importantly, the HIV is not directly making the T helper cells vanish -- the disappearing act is being caused by something else.


6. What Is Killing Off the T Helper Cells?

It has been known for a long time that the T cells (the "killer" T cells) -- whose job it is to kill off infected cells -- also kill off uninfected cells that look a lot like the infected ones. We might call them 'bystander' T cells. Scientists call the killer T cell a 'CD8+ cytotoxic lymphocyte' and these cells become hyperactive when HIV is around. In fact, they become so hyperactive, that for every cell actually infected with HIV, they kill hundreds or thousands of uninfected T helper cells and they slowly reduce your total healthy cell repertoire. It is actually this overkill from hyperactive CD8 cells that causes you to get AIDS, not the actual virus.

[A technical note: In the early 1990s, the researchers Joyce Zarling, Leonard Adelman and Allen D. Allen, working independently, proved to a scientific certainty that it was the cytotoxic CD8 T cells that were indiscriminately killing off CD4 T cells. This was published in prominent medical journals, such as Journal of Immunology, AIDS, etc. and led Allen to invent an agent known as Cytolin (a mouse anti-human monoclonal antibody.]


7. How Could We Stop This From Happening?

Your killer defense CD8 T cells would calm down if the amount of HIV in your body would be reduced. This is what antiretrovirals (the medicines that stop HIV from making more HIV) accomplish. However, there are several problems with this approach, even though it has worked wonderfully keeping millions of people alive for many, many years.

The problems are: the HIV medicines are expensive, have side effects and the virus can sometimes get resistant to them.

For this reason, it would be useful to have a medicine or a group of medicines which the virus would not get resistant to, which are not too expensive and which would help calm down the killer cells a little.

Different chemicals like steroids act like a brake on the immune system, and a particular monoclonal antibody called "Cytolin" (mentioned above) acts like a brake on the hyperactivity of the CD8's -- it calms them down. It down regulates their hyperactivity, which would help the body keep healthy T cells around to do their work preventing opportunistic infections, and therefore avoiding AIDS.

We have known for some time that this approach of calming down the immune system would work to slow down AIDS because we have had medicines that calm down or slow down the immune system. There are immune tranquilizers, such as cyclosporine A for example, which makes CD8s less panicky and lets them shoot at the enemy with an accurately pointed pistol instead of what is more like a machine gun shooting down every cell that is near an infected T cell.

When you use these types of drugs on people with HIV, you can show that T cells are no longer being killed off and the amount of virus is actually reduced.

However these early immune tranquilizers were just as over reactive as the CD8 cells we are trying to calm down, and made the immune system unable to protect us from many illnesses.

But now there are some drugs known as 'immune modulators' that make the killing CD8 cells less hyperactive, but allow them to still kill off the already infected cells, and allow them to still protect against other infections as the body gets attacked.

One of these immune modulators, mentioned above, is called "Cytolin." It is what scientists call a 'monoclonal antibody' and it makes the killer cells less crazy -- that is, less likely to kill off all the cells near an infected cell but instead focuses just on the infected cell.

During the height of the AIDS pandemic, before the antiviral cocktails were available, activist doctors used Cytolin to rescue a few hundred patients. [Data from 188 patients treated with Cytolin for 18 months were reported to the FDA (check www.searchforacure.org). A Phase I(b)/II(a) study of Cytolin was reported at the 2002 and 2005 CROI national conferences by Donald W. Northfeld, MD.]

Cytolin -- which is given as an intravenous infusion -- is being developed by a west coast company called CytoDyn and is being studied by Eric Rosenberg, M.D., a researcher at the Massachusetts General Hospital. It is hoped that within a year we can get more information on how the medicine works on people with HIV.


8. Why Would We Think This Drug Might Work?

We think that this medicine may work because before 1996 (when HIV/AIDS antiviral drugs were invented), doctors used this drug on 188 HIV-positive people of them) and we know from the records of those patients that the drug seemed to help them.

In general, using the antibody showed some return in their ability to fight illnesses, an increased number of T cells, and a drop in the amount of HIV.

The way scientists measured this was to use a test of the body's ability to recognize enemy germs, a skin test showing if the body recognized illnesses it was exposed to in the past. It was clear that people who were not able to fight some illnesses got this ability back after using the antibody.

Some of the well known scientists who worked with this antibody years ago were contacted by the non-profit organization Search for a Cure and interviewed. All of them indicated that they would like to see Cytolin studied because they felt it had potential.


9. What Is Happening Now?

Search for a Cure has researched this drug and helped to get a clear strategy for studying it underway. The testing will first happen in vitro (in the test tube) and later in people.

There are several ways studying the drug might be helpful:

  1. It would protect antivirals from resistant strains of HIV emerging since HIV cannot get resistant to Cytolin.
  2. To see exactly how Cytolin protects T cells and through this to better understand the errors made by the immune system that leads to AIDS.
  3. To see if some version or amount of Cytolin might be able to help people avoid needing the use of antivirals for long periods of time.

The research will take a good deal of time, but many specialized scientists are convinced that a monoclonal antibody such as Cytolin is a good way to help the body fight against its own over reaction to HIV and protect its immune system. This would make Cytolin the first immune-based therapy in existence for HIV. There are others like Interferon alpha for hepatitis C for example, but none for HIV.


12. How Can I Get More Information?

For more information:

Contact us at hope@sfac.org and we can send you more information. If you are interested in technical materials, we can e-mail them too you. You can also check the CytoDyn website where a good deal of data is available. Eventually the results of the studies will be available to everyone.



  
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This article was provided by Search for a Cure.
 
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