The Institute for Applied Biomedicine is an agreement with a growing number of AIDS researchers around the world who believe that the key to a full understanding of exactly how HIV causes AIDS is an examination of the immune system. This section describes an immune-based model of the biochemical steps between an HIV infection and full-blown AIDS. According to this model, an HIV infection induces something similar to an autoimmune disease, in which the body attacks its own cells as if they were foreign invaders. Many of the definitive experiments one would perform to test this model have already been done and are universally consistent with its predictions.
The Human Immune System
The task of the immune system is to recognize foreign material when it shows up in the body, and then to raise an overwhelming attack against that particular material. The immune system attacks both foreign organisms, such as bacteria, fungi, and viruses (if they can be called organisms), as well as foreign substances, such as proteins. The immune system is complicated and contains many cell types, as well as non-cellular components. Immune system cells circulate in the blood and are collectively known as white blood cells. There are two cell types most relevant here - B cells and T4 cells.
T4 cells regulate the entire immune system in several ways. They produce hormones that activate and control other parts of the immune system. They also give the confirming signal to other immune system cells, assuring them that the material they have encountered is indeed foreign and they may go ahead and attack it. Without functional T4 cells, the other components of the immune system are unable to attack any new materials, although ongoing immune responses can continue.
B cells circulate in the blood scouring it for foreign materials. Each B cell is sensitive to a very particular type of material. Most proteins can be recognized by only about 0.01% of all the B cells in the body. When a B cell encounters a protein of a type it recognizes, it internalizes the protein. After receiving confirmation from a T4 cell that the protein is indeed foreign, the B cell begins making antibodies to the protein.
The B cell releases antibodies into the bloodstream where the antibodies bind specifically and tightly to the same type of protein the B cell recognized. The antibodies stay bound to that protein and act as a red flag to other parts of the immune system. Anything bound by antibodies is labeled as a foreign invader and destroyed.
Once a B cell begins making antibodies to a specific protein, it will continue to do so, without additional signalling, as long as that protein is present in the bloodstream. In addition, the activated B cells will divide, and most of the daughter cells will also make antibodies. It is therefore possible for the body to make a large amount of antibodies in a fairly short time. When the protein has been eliminated from the bloodstream, the B cells quit producing antibodies.
HIV to AIDS - the gp120-Mediated Autoimmune Model
Each human immunodeficiency virus (HIV) bristles with almost 300 copies of a protein called gp120. This protein serves to hook the virus to the cells it infects. gp120 binds to a protein called CD4 on the surfaces of T4 cells, and this brings the virus and the cell together.
There are two remarkable features of gp120. First, gp120 is only loosely attached to the viral coat, so it tends to fall off in a process called shedding. Shedding occurs not only from the surface of HIV particles, but also from infected cells, which also bristle with gp120. All this gp120 floats loose through the bloodstream. (32)
Second, gp120 triggers an impressively large antibody response from the B cells. It binds to and activates about 6.4% of all the B cells in the body, a response some 640-fold larger than normal. (48) This causes an over-production of anti-gp120 antibodies, which is characteristic of people who are HIV-positive. (55) (It is the presence of this antibody that is tested for in an HIV blood test. Eventually, gp120 and antibodies are found in huge quantities in the blood of a person with advanced AIDS. In fact, these substances can even do mechanical damage to membranes that filter blood, e.g. the kidneys.) All of these antibodies are released into the bloodstream where they seek to bind to gp120. Once bound by antibodies, the gp120, and anything associated with it, is red-flagged for destruction.
It would be nice, of course, if the antibody found only HIV particles and infected cells and bound to them - as is the case with normal pathogens. These would then be destroyed by other parts of the immune system. Unfortunately, when the antibody binds to gp120 on HIV and on infected cells, the gp120 often just falls off. (36) The antibody and gp120 stay bound and float together through the bloodstream, while the HIV or infected cell remains untouched. (38, 62, 63) Thus, the antibody component of the human immune system is not very effective at controlling an HIV infection. (3, 5, 6) The body's best defense against HIV is another component of the immune system, the T8 cells (also called killer T cells, cytotoxic T cells, or CD8 cells), which locate and destroy cells infected by viruses or bacteria. (13, 22, 114)
Meanwhile, the gp120 floating through the bloodstream is still capable of binding to CD4, found primarily on T4 cells. Antibody then binds to the gp120 on the CD4. This antibody flags the (uninfected) T4 cell for destruction. (64, 65)
The antibody does more than flag T4 cells for destruction by the rest of the immune system. Each antibody can bind to two molecules of gp120 attached to a single T4 cell. Such an antibody holds the two CD4 molecules bearing their gp120's close together on the surface of the cell in a process called crosslinking. (See diagram next page.) Even one instance of crosslinking destroys a T4 cell's ability to function normally. (Crosslinking of CD4 has dramatic, but very different, effects on the other types of cells that contain it.) The hormone Interleukin 2 has been shown to reverse the effects of gp120 binding to CD4, but no medication can reverse the effects of crosslinking. (84-95)
In summary, the gp120-mediated autoimmune model asserts that it is the combination of gp120 and antibodies against gp120 which acts to disable T4 cells, not the direct infection of T4 cells by HIV. After initial infection, the concentrations of gp120 and antibody in a person's body slowly rise. HIV continues to infect more cells and spread, shedding more and more gp120, and B cells continue to multiply and produce anti-gp120 antibodies. Finally, the number of T4 cells that are disabled by the gp120 and antibody reaches critical levels, and the immune system starts its collapse.
Research Evidence for the gp120-Mediated Autoimmune Model
There is an impressive assortment of evidence for this new model. Experiments have been performed both in vitro (i.e. in test tubes) and in living systems which confirm the predictions this model makes. Furthermore, this model is consistent with and explains known physiological facts about AIDS.
T4 cell failure with gp120 and antibody in vitro: When T4 cells are grown in vitro with these additions to their medium, the following is observed:
These results confirm that the combination of gp120 and antibodies does indeed disable healthy T4 cells. (These experiments were performed with concentrations of gp120 and antibody lower than physiologically relevant.) (44, 81, 96)
T4 cell failure with gp120 and antibody in mice: Researchers have found a way to create mouse T4 cells with human CD4 on their surface. Mice with such cells were injected with gp120 and anti-gp120 antibodies. The T4 cells with human CD4 were eliminated, despite never having been exposed to HIV. (B cells expressing human CD4 in these mice were not eliminated, demonstrating that T4 cell anergy upon CD4 crosslinking is due to cell signaling pathways.) The elimination of T4 cells did not occur when only gp120 or antibody was used. (112, 127, 128)
Failure of T4 cells when exposed to anti-CD4 antibody: OKT4, commercial antibody to human CD4, has been used for years to cause temporary collapse of the immune system by direct crosslinking of CD4 on T4 cells. This is an exact parallel to the mechanism of immune collapse proposed by the gp120-mediated autoimmune model. The only difference between the action of OKT4 to disable T4 cells, and the action of gp120 and antibody, is that OKT4 crosslinks the CD4 directly without an intermediary. In an HIV infection, gp120 acts as the intermediary allowing anti-gp120 antibody to crosslink the CD4.
(Furthermore, in AIDS patients there is a shift in expression from Interleukin 2 to Interleukins 4 and 10. CD4 crosslinking induced by treatment with anti-CD4 antibody induces similar cytokine hormone defects. (84-86, 92-95)
Increase in anti-gp120 antibodies correlated with decreased health: Studies have shown a slight, but reproducible, negative correlation between the health of HIV-positive people and both their overall antibody titer, and their anti-gp120 antibody titer. In other words, greater levels of antibodies are correlated with poorer health, as would be expected if anti-gp120 antibodies were a main contributor to T4 cell failure. (97, 109-111)
Infected T4 cells protected: When a T4 cell is infected by HIV, it stops expressing CD4 on its surface. Therefore, gp120 can no longer bind to the cell, and the cell is safe from antibody flagging and crosslinking. This explains why infected T4 cells are not found to be dying - they can carry on their normal immune system tasks, produce more viruses, and eventually die of old age. (77, 78) (gp120 expressed by infected cells is also a potential target, but it is shed when antibody binds to it, as discussed above.)
Uninfected T4 cells targeted for destruction: Natural killer cells are one part of the immune system that destroys anything labeled with antibodies. In vitro experiments with natural killer cells have shown that uninfected T4 cells are 100 fold more easily recognized and targeted by natural killer cells than infected T4 cells, presumably because infected cells stop expressing CD4 on their surfaces. gp120 concentration is 80 times higher in AIDS than necessary for maximal recognition and targeting of healthy T4 cells by natural killer cells. (64, 65)
T4 cells healthy during initial infection: After a person is first infected with HIV, it takes a minimum of three to four weeks for B cells to produce large amounts of antibodies. During this first stage of infection, the T4 cells are mostly healthy, and the T8 cells are able to control the infection. This explains why, even though more cells are infected with HIV during this initial infection than during advanced AIDS, the body is still able to defend itself.
Failure of T Cells to Mature: Naive (new, unconditioned) T cells being produced by the bone marrow do not mature properly even when the viral level is kept low with anti-viral drugs. Consequently, the immune system does not regain its ability to respond to new pathogens. Crosslinking of CD4 on T cells and T cell precursors (thymocytes), even at very low frequencies, blocks cell division. (85) After being produced by the bone marrow, thymocytes undergo several rounds of cell division in the thymus before becoming mature and functional. Since these precursors express CD4, and the CD4 is subject to crosslinking by antibody, they are blocked from maturing properly. This prevents the body from restoring a fully functional immune system. (129, 130)
Increase in B cell activity causes a loss of T8 cell activity: There is an inverse relationship between the antibody and cytotoxic (T8 cell) arms of the immune system. As the B cells become more and more over-stimulated producing anti-gp120 antibodies, the T8 cells are down regulated and become less numerous and less effective. This explains, in part, the decline of T8 cells observed in AIDS. (This shift in immune system function has many different potential negative effects. For example, HIV-positive people are at an increased risk for B cell disorders including antibody-based autoimmune diseases and B cell cancers. Please contact us for more details.)
The gp120-mediated autoimmune model makes sense of a tremendous variety of phenomena, demonstrated by different labs exploring widely different questions. This model proposes a biochemical cause to interpret clinical, as well as in vitro, results. (If you are interested in more details on the research summarized above, please see Literature Excerpts.) Many of the results which the model explains were previously unexplainable. In addition, this model has correctly predicted the outcomes of new experiments. And most excitingly, the model offers entirely new options for therapy. For an explanation of one such therapy, see the next section, Details of Immudel-gp120.
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