Some HIV/AIDS info

Chuck Grimes cgrimes at tsoft.com
Sat Jan 27 01:26:20 PST 2001


You know, I've written two long posts on this AIDS thread and deleted them, because first I figured everybody knew the basics, and then on a second round, decided the thread would die off. It seems I was wrong. So here is another. What follows makes no argument either way and doesn't reflect any of the larger social, political, and economic questions. It accepts the science `as is'.

HIV stands for human immunodeficiency virus and AIDS stands for acquired immune deficiency syndrome. Notice that HIV is a virus and AIDS is a syndrome, or a collection of symptoms. The tests used to diagnose exposure to HIV are the ELISA (enzyme linked immuno-sorbent assay) and the Western Blot. Here is how they work.

In the ELISA, a blood sample is taken and placed on a plastic surface with HIV virus proteins embedded on it. If there are HIV antibodies in the blood they will bind to the viral proteins. The surface is then washed with the enzyme linked immuno-sorbent solution to reveal the presence of HIV antibodies that have attached to the viral proteins. It is deduction that the presence of antibodies in the blood implies a previous exposure in which the body has manufactured anti-bodies.

In the Western Blot, blood proteins are separated out and placed on a gel. The gel is electrically charged and the proteins migrate and segregate themselves into bands depending on their physical size under electrophoresis. The gel is then blotted onto paper containing HIV antibodies. Because the size of each HIV protein is known, the binding of any protein in the blood sample to HIV antibodies on the paper is considered a positive test for the presence of that viral protein.

These are very standardized tests used through out bio-science labs for every kind of protein. The basic screening is adapted to the particular protein one is looking for and the Western blot is a basic test for both the presence of the protein and its identification. Since every protein is different, these tests are modified for each type sought. So a Western blot is a catalogue of hundreds (thousands?) of different tests that all use the same procedure. For example I found a reference for both the ELISA and Western blot used in the detection of Lyme's Disease, and Western blots for identifying neurotoxins.

By standardized, I mean the methodology and practice is well known and understood. Every instance however, is still a lab test, and lab tests do fail all the time. However, part of the methodology is to specify under what conditions the tests are to be considered positive, what conditions are they considered negative, and what conditions are indeterminant. Part of the FDA trial process for medical and drug applications is supposed to determine these criterion and then certify them (usually as an industry consensus). These kinds of tests are now manufactured as kits and completely systemized. Blood (or protein samples) go in, results come out. At this point there are probably have machines that do hundreds an hour. (The only Western blots I've ever seen were all hand done looking for very special proteins. The method for getting antibodies is to inject lab animals with possible protein samples and harvested the resultant anti-bodies. Then test for the presence of a binding protein in sequence. This identifies the specific protein in question. However, so many proteins are classified that there is usually some kind of kit available for them.)

Both tests are indirect in the sense they test for the presence of an antibody or a viral protein, and do not test directly the presence of the virus. In this restricted sense, the presence of HIV in the blood is inferred from the presence of some of its component proteins and their antibodies.

Notice it is also an inference that HIV causes AIDS. However strong that inference might be, it remains open to some question. This inference is complicated by several possibilities. First, since AIDS is a collection of symptoms, infections, and cancers, then anything that can depress the immune response system by attacking T-cells will result in a similar collection of symptoms and diseases.

It turns out that some myelomas, or cancers of the bone marrow result in AIDS symptoms and associated diseases. The reason is that the T-cells are either reduced, malformed or inactive. Myelomas can be tested for and eliminated as a causative factor thorough blood screening for the presence of various marrow cell proteins.

When large numbers of cells die, they dump their contents into the blood. This makes it possible to isolate which cell types are dying off through tests for the presence of their various kinds of proteins and other components. Some of these are cell membrane components, which are used by other cells to identify each other. Large quantities of some proteins indicate certain types of cell deaths and that is interpreted as evidence for certain cancers and infections.

So it is always possible that some AIDS is not caused by HIV. However, most of these alternatives can be eliminated through other tests and diagnostic tools.

HIV has been isolated and there are numerous electron microscope photos of it on the surface of T-cells. It is a moderately small virus, about the same size as Herpes simplex, which is smaller than Mumps or Cowpox, and much larger than Polio or the common cold virus.

The infection cycle in the blood begins when HIV attaches to the CD4 receptor protein on the surface of a T4 lymphocyte and enters by endocytosis (encapsulation). T-cell recognition is accomplish by HIV through its cover glycoprotein which matches the T-cell surface protein CD4. Once in the cytoplasm, HIV RNA is released along with an enzyme, reverse transcriptase which conducts the synthesis of complementary DNA. The HIV DNA is transported to the T-cell nucleus and incorporated into its genome.

At this point, the HIV copy can remain dormant, or it can also be permanently turned off by the T-cell DNA. This occurs in some individuals who have been infected, have tested positive and may never manifest AIDS. It is rare but it happens and is one focus of research, since if it were possible to duplicate this ability, that would be essentially a cure.

More usually, the next step after a latency period is an active phase when HIV DNA enlists the cell metabolic systems to replicate HIV and the virus is budded out of the T-cell to infect other cells. It is possible that the active phase is triggered by other assaults on the immune system, like a cold or infection and therefore stresses T-cells and T-cell production.

Two therapies are directed at two different parts of this infection cycle: reverse transcriptase inhibitors and protease inhibitors.

Proteases and other hydrolytic enzymes are components of the lysosomes, tubular like organelles of cells which are the principal sites of intracellular digestion. Large molecules like proteins, fats and carbohydrates are cut up into smaller components in the lysosomes by enzymes: proteases, nucleases, glycosidase, lipases, and so on. Once HIV RNA has been complemented and that DNA has been incorporated into the chromosomal component of the nucleus, the manufacture of new HIV begins. Part of the later HIV replication process enlists the cell lysosomes and their protease in the HIV replication process.

Protease inhibitors work by blocking the action of the lysosomal proteases and therefore HIV protein formation is flawed. Later replicants of HIV are then malformed and ineffective.

Reverse transcriptase inhibitors (like AZT) work by blocking the action of RNA to form HIV DNA during the initial phase of the cytosol infection cycle.

These two therapies are used together in tandem to inhibit replication of HIV and force a drop in the total quantity of HIV in the blood. Neither one cures HIV because there are always some T-cells which contain HIV in some inappropriate phase. Also these inhibitors have no direct path to free HIV in the blood that has not yet entered the T-cells. So, there is always a potential reservoir of HIV somewhere that is effectively immune to the treatment regime. In addition the PI's attack the protease enzyeme which has been coded for by HIV. However, the HIV RNA pool contains enough variation in the protease codon, so that some are resistant to the inhibitors. These variations under pressure develop as PI resistant strains.

[Some of this I knew before hand, and some of the detail I had to look up from JAMA, Molecular Biology, Intro to Bio. and other sources.]

I hope this helped.

Chuck Grimes



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