Immuology Primer, Part 2, Text

Immuology Primer, Part 2, Text
THIS IS A DRAFT ONLY.
The Dance of the Cytokines
In order to coordinate their activities among and between each other, there is a complex "messenger" system that the cells use (like passing notes to each other). These messengers are called cytokines. Some that may be familiar to you are the interleukins (IL-2 is one of these that has been used as a therapy in some people), the interferons (alpha, beta, gamma and tau) and others like tumor necrosis factor (TNF), macrophage inhibitory protein (MIP), RANTES, and many others. (Don't freak out: you don't have to figure them all out at once! See Table of Cytokines at the end of this section)

Depending on the type of infection (or injury), different patterns of cytokines are secreted. They work very locally, at the site of infection. Sometimes, cytokines may excite the very cell that excreted it (autocrine) or maybe one right nearby (paracrine). Each cytokine matches a "receptor" (like a lock and key). For example, interleukin-2 is the key and the IL-2 receptor is the lock. Once the receptor and the cytokine bind together, this causes a cascade of reactions to occur in the cell. The reactions may do any of a number of things from telling the cell to produce more of certain proteins, secrete less, possibly for the cell to divide and make copies of itself (clonal proliferation) or to "chill out" and do nothing (anergy) or even to kill itself (programmed cell death or apoptosis). Thus, the different cell types and cytokine messengers are coordinated in a complex and remarkable dance that helps heal wounds and clear infections. Unfortunately, like any system, things can go awry.

The cellular and humoral arms of the immune response are regulated by distinct subsets of CD4+ and CD8+ T-helper (Th) cells, termed Th1 and Th2 cells. Each is associated with a particular pattern of cytokine production with Th1 cells mostly secreting interleukins 2 and 12 (IL-2 and IL-12), tumor necrosis factor-beta (TNF- ), and interferon-gamma (IFN-). This characterizes the cell mediated immunity responsible for controlling intracellular infections including HIV.

Th2 cells produce IL-4, IL-5, IL-6, IL-10 and IL-13. IL-4 stimulates IgE antibody production (associated with allergies). IL-5 is an eosinophil-activating factor, which relates to skin or allergic related disorders. (See the tables at the end of these sections for a breakdown of cytokines, cell types and so forth). Elevations of these cytokines may indicate that you are in a Th2 type immune response which controls HIV and other lethal opportunistic infections poorly. This Th2 response helps to, in simplified terms, control extracellular type infections living outside cells, while suppressing Th1 cell mediated immunity. Both Th1 and Th2 cells produce TNF-alpha (TNF-), interleukin-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF).

Several groups of researchers have reported that persons with HIV disease have a reduced capacity for macrophages to produce IL-12, which is an important Th1-inducing cytokine as well as reductions in IL-2 as HIV disease progresses. It has been suggested that a switch from a protective Th1 type immunity to an inappropriate Th2 type might play a role in the progression toward full-blown disease. Some studies suggest that Th2 type immune cells are more efficient supporters of HIV growth than Th1 cells. Others provide test tube evidence that the Th2 pattern of cytokines may shut down the Th1 response. However, research is accumulating that casts some doubt as to the relevance of these patterns to humans.

It is important to emphasize that these patterns of Th specific immune responses are extremely complex and variable. The cytokine patterns that characterize cellular and humoral immunity are much clearer in mice than they are in humans. Th1 and Th2 should be considered as the two functioning subsets of Th cells but rather either extreme of a range of responses. Thus, CD8 cells can excrete a Th1 or Th2 profile of cytokines and their behavior is modified by that pattern. Similarly, CD4 cells also may behave as B-cell stimulatory helper cells or as cytotoxic cells that identify and kill other infected cells. In addition to Th1 and Th2, there is also a complex variant known as Th0. The Th0 pattern is a hybrid mix of Th1 and Th2 that was originally thought to be a precursor to Th1/Th2 cells. This theory has been largely abandoned. Obviously, many questions remain.

Surface Markers on Cells
A cell is like a bag full of fluids and tiny organs known as organelles (see the Biology 101 section). Cells need to perform a lot of tasks in their lives. The cytokines are their little notes to other cells. But once the message arrives, it needs to be translated. So each cell has dozens of different types of receptors that help translate these various messages. T-cells are characterized by the CD4 receptor. The other type of T cells that are featured in cell mediated immunity are characterized by CD8 receptor molecules.

There are many other markers beside CD4 and CD8. For example, CD3 is found on all T cells. In fact, there are over a hundred molecules identified by the CD designation (which means "clusters of differentiation"). For some of these, especially those associated with CD4 and CD8 cells, there is increasing evidence that their expression (or lack of expression) is strongly associated with how fast a person progresses to opportunistic infections and AIDS. Thus, it may be a good idea to discuss with your primary healthcare provider the subject of getting a more refined analysis of your blood work, including some of the less commonly assessed CD4 and CD8 subsets discussed below.

The CD designations are broken down partly by the cell type on which they are predominantly found or the function with which it is associated. Thus, some are grouped with T cells, others with B-cells, platelets, cells that line blood vessels and other organs (endothelial cells) and so forth. In terms of function, they may be group as to whether they help cells attach to vessels (adhesion), whether they are activated or not and so forth. (A good chart that lists these different types may be acquired from Immunotech, 1800-458-5060 called "Leucocyte Surface Markers").

Both CD4 and CD8 cells also express another marker called CD28. As CD4+ hooks up with MHC class II (or CD8+ with MHC-I), CD28 hooks up with a molecule called B7/BB1. B7/BB1 and CD28 are known as costimulatory molecules. Thus, it is the connection of CD28 with B7 and the coupling of the T-cell receptor with the antigen presented by MHC that tells the cell to become activated and "proliferate" (or make copies of itself). There are several such connections between the two cell types that are required in order for the immune system to recognize and fully respond to what is perceived as a threat to the body. CD28 is also expressed sometimes on activated B cells, thymocytes and peripheral T cells (Knapp, 1989).

However, in people with HIV, this CD28 molecule begins to disappear even early on. With progression, increasing numbers of CD8+CD28- cells appear. [When cells are referred to as CD8+, the + means "positive" or, rather, that the cells expresses this receptor. Cells that do not express a receptor are negative, for example CD8-.] Over 90% of CD4+ T cells and around 47% of CD8+ T cells express the CD28 molecule in HIV-negative, healthy controls. (Choremi-Papadopoulou, 1994; Saukkonen, 1993). A variety of studies of people with HIV have noted increased numbers of both CD4+ and CD8+ cells that lack CD28 (i.e., CD4+CD28-), even in infants. (Borthwick, 1994; Lewis, 1994; Jennings, 1994; Choremi-Papadopoulou, 1994; Choremi 1993; Miedema, 1991; Miedema, 1990). Conversely, HIV+ people who maintained expression of CD28+ were healthy. (Levy, 1993).

The effect of this loss of CD28+ expression is that when CD8+CD28- meets with an APC, it does not become activated. Rather, it becomes "anergic" or unreactive. This may then later lead to a type of programmed cell death called apoptosis (identified by a characteristic destruction of the cell's genetic material). The cell then dies. (Ameisen, 1991; Ledbetter, 1992; Borthwick, 1993).

This was further demonstrated by Baylor College researchers who examined the blood of asymptomatic people with HIV. CD8+CD28- cells tended to die in culture after 3 days, regardless of any stimulation used--and they died by DNA fragmentation. Normally, cells can survive longer. The authors suggest that these cells are end-stage cells undergoing a process of proliferation, anergy induction and apoptosis. (Rodgers, 1994). To wit, they're activated, then they're signaled to go to sleep (anergy) and then, the next time they're prodded, they commit suicide (apoptosis) out of sheer boredom.

[PICTURE NOT YET AVAILABLE ON INTERNET VERSION]

Some of this work has been done prospectively. That is, Dutch researchers followed an individual from presumed initial infection forward (before he seroconverted). They noted that CD8+ cells were expanded from the moment of conversion, and an increase in CD8+CD38+, CD8+CD27+ and CD8+CD28- cells were noted. CD8+ cell expansion (lymphocytosis) paralleled a high rate of programmed cell death. This patient showed all these immunologic variations before actually seroconverting. (Don't forget: there is a lag time of around a few weeks to 6 months between the moment of infection to the moment of seroconversion--an antibody response to HIV). In addition, there was a drop in CD4+ counts along with high plasma p24 and HIV-1 RNA levels. Ten days after seroconversion, viral load had dropped significantly and proliferative response was restored. (Miedema, 1994). This is a possible explanation for the post-infection T cell dip seen in the "standard course of HIV infection" cartoon (above). (Lymphocytosis is an increase in cell numbers associated with a chronic infection or inflammatory response.)

Work at the lab of director, Anthony Fauci, of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), suggests that the loss of CD8+ function is specifically HIV related. Broader CD8+ response to other pathogens is not necessarily disrupted. (Pantaleo, 1990). (Remember: each CD4 and CD8 cell responds to a unique pathogen). What they suggest happens is that the ability to recognize and destroy HIV-infected cells is selectively inhibited both by a decrease in the pool of such cells as well as a decreased ability to proliferate on stimulation. Understanding why selective HIV targeting is lost (if this occurs) and determining how it can be corrected may yield a novel, immunomodulatory antiviral strategy.

The CD8+CD28+ subset of cells appears to take over some of the functions of the CD4 cells (more likely they had it all the time) and help keep persons with advanced HIV (below 150 CD4 cells) disease-free, except for PCP (which is controlled primarily by CD4+ cells). So even though a certain number of these CD8 cells are suppressor cells (CD28-), they may only make one more susceptible to disease for those with between--perhaps--150-350 CD4 cells or when their CD4 percentage drops below 20% (see CD4/CD8 ratio above) during the course of HIV disease.

Many doctors are still not aware of these facts, even though there is no doubt the entire area of CD8 disease-controlling cells needs much more research and verification. Nevertheless, UCLA studies have found that persons with below 100 CD4 cells who maintained above 500 CD8 cells rarely developed opportunistic infections, while several well known HIV doctors have reported that persons with below 50 CD4 cells who have greater than 400 CD8 cells rarely develop such diseases as CMV or MAI (and sensibly consider CD8 levels as a guide for deciding when to initiate prophylaxis.).

One study has found that it is when a particular subset, CD8+CD11b- cells, decline below 200/mm3 that persons with advanced HIV disease (below 150 CD4) frequently reach the point of developing opportunistic infections. Thus CD8+CD11b- cells along with CD4+ may be an important combination of markers to help people decide if they should go on prophylaxis for MAC or CMV. This is a difficult decision due to toxicities, resistance and an overall lack of effect on mortality. Toxicities particularly affect the bone marrow where critical white blood cells are formed to fight infections. Measuring this subset may offer a more precise tool for determining the need for further prophylaxis at very advanced stages of CD4 cell loss.

As mentioned above, natural killer cells are involved with a non-specific immune response. They express either CD16 or CD56 molecules. Whether there is actually a decline in numbers is not clear. Some see an increase in numbers, (Valkova, 1993). while others see a decrease, at least in cells both CD8+ and CD16+. (Rouger, 1990). Others observed a circadian rhythm, with higher levels in the morning, lower at night. (Bourin, 1993). One possible explanation comes from one lab that found CD16+CD56- did not vary over time, while CD16+CD56+ did decline in numbers. (Kimura, 1994). Another arises from differences between gay men and IVUs. Gay men had on average twice as high a percentage as the IVU population, suggesting the possibilities of viral phenotype variation (Robertson, 1994). or the suppressive effects of morphine on NK cell activity. (France, 1993). Yet another lab finds evidence for increased expression of CD16+ on certain activated monocytes (CD11b+45+DR+). (Wilkinson, 1992; Wahl, 1991). (Monocytes are transported to various tissues like liver or lung where they become macrophages.)

Most labs report a decline in functional capability of natural killer cells, increasing with severity over time. (Moretta, 1994; Rinaldo, 1990). One study suggested that NK activity was stable only in people with AIDS Related Complex (ARC), but not in people with AIDS (PWAs). (Gritti, 1994). Stress and higher basal cortisol levels were shown to correlate with lower levels of CD16+ and an even stronger decline in the number of CD56+ cells. (Evans, 1994). The structure of the NK cells is dysregulated (microtubule rearrangement does not occur after activation) and "there appears to be a diminution of the NK pool (CD16+ cells) involved in cytolytic function, while there is an elevation of the NK pool that co-expresses NK (CD57+ or Leu 7+) and CD8+ cell markers, which show little or no involvement in cytolytic function." (Wainberg1989). Still another lab reports that while NK cells can bind to their target, they don't kill it. They suggest this is a result of lowered expression of the initial activation marker, CD69 and a concurrent defect in responding to IL-2. (Pena, 1993).

In a study investigating why some people with very low CD4+ T-cell counts nonetheless had high levels of IgE (the antibody class associated with allergic reactions which are stimulated by CD4+ cells), they found some peculiarities in CD8+ profiles. The cells expressed CD40 and produced higher levels of IL-4, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF)--a Th2 cytokine expression profile more akin to CD4 cells. In addition, about a third of these cells expressed either CD16 or CD56. (Cassone, 1994).

Important cell types also include CD45RA (naive) and CD45RO (memory) cells. Naive cells are ones that cruise the system and then respond when they encounter a new pathogen for the first time; once bitten though, twice shy and some cells become memory cells for a quick secondary response in case the offending pathogen should try to renew its acquaintance with your body. In HIV infected people, naive cells decline in number over time while memory cells increase. (Jennings, 1994; Choremi-Papadopoulou, 1994). In fact, specific increases in CD8+45RO+ subpopulations indicate that a shift occurs from naive to memory cells. This suggests immunological memory becomes exhausted. A correlation has been noted with a reduction in the levels of naive CD45RA+ cells with an increase in beta-2-microglobulin (B2M) and neopterin (discussed more fully in the section, How To Monitor Your Bloodwork). In addition, the same lab noted a correlation between increasing levels of HLA-DR+ cells and both B2M and soluble receptors of interleukin-2 (IL-2R, a/k/a CD25). (Prince, 1990). Other researchers have shown that the increase in memory (RO+) cells occurs both in CD4+ and CD8+ cells, as well as CD45RO+CD38+, CD45RO+DR+ and other phenotypes. Their research also found a negative correlation between activated cytotoxic CD8 cells and CD4+ cells (that is, more of one to less of the other). (Fernandez-Cruz, 1994).

HLA-DR is a sub-class of human MHC class II. Others include DP, DQ, etc. MHC-class II is the antigen presenting cell molecule that helps CD4 cells identify foreign invaders. In HIV-negative controls, DR expression accounts for about 10% of CD4+ cells. Belgian researchers have noted that this level increases in asymptomatic and symptomatic people living with HIV. Additionally, a subtype, HLA-DR+CD38+, found in only 2% of healthy controls, is 11% in asymptomatic and up to 22% in symptomatic HIV+ people. (Vanham, 1993).

Understanding AIDS and the immune system is complicated by the various features that distinguish babies, children, adolescents and adults. Infants were found to have higher median absolute counts of CD8+DR+ which persisted over 24 months. They also had higher CD8+ counts and lower CD3+CD4+ counts (3201 down to 2727 after 2 months; kids have a higher average T-cell counts than adolescents or adults). CD8+38+ were noted as elevated by 4 months as were counts of CD8+57+ (indicating a cytotoxic CD8) by one year. The differences persisted through 24 months of age. (Moye, 1993). Other unchanged markers in this study included CD19+ (B cells) or natural killer cells (CD56+).

CD38 is an indicator of activated but immature cells and is found co-expressed on CD8+ cells. About 62% of CD4+ cells in uninfected controls also express CD38. (Vanham, 1993). The expression of this molecule increases and seems to correlate with progression in adults and infants. (Jennings, 1994; Choremi-Papadopoulus, 1994; DePaoli, 1993). These cells also sometimes express HLA-DR. As people age, it has been noted that the standard direction of these cell types is for CD45RA+ and CD38+ to decline in numbers while activation markers like HLA-DR+CD8+ cells and CD3+CD25+ (CD25 is the IL-2R) to increase in absolute numbers. (Hulstaert, 1994). Researchers have, however, noted increased expression of HLA-DR (and, incidentally, IL-2R on CD3+ cells). Others have also noted an increase in CD8+CD38+CD45RO+ which correlated well (p<0.001) with HIV disease stage; this subtype is rarely seen in healthy controls. (Medina, 1993). Other work shows a decline in CD25+ expression on CD8+ cells. (Pantaleo, 1990).

Interpreting what these variations in cell subpopulation means is not clear-cut. For example, CD38 is generally thought of as a marker of activation of an immature cell. Vanham, et al., suggest that in HIV infection, this expression may not be a marker of immaturity. Rather, these cells are shown to destroy infected cells--but in addition, they also tend to destroy healthy cells, suggesting a possible "autodestructive" role (i.e., autoimmunity). (Vanham, 1991). It has been clear for some time that AIDS has an autoimmune component. This is exemplified by the presence of a variety of clinical phenomena like Sj�gren's syndrome. (Morrow, 1991; Aranda-Anzaldo, 1991; Hoffman, 1991). Further evidence for this autoimmune component arises from work that shows a CTL--and not an NK cell--identifies and destroys uninfected CD4+ cells. The phenotype of this cell was CD3+CD8+CD16-. (Moran, 1990). (see below).

T-cell receptors (TCR) engage (along with either CD4 or CD8) with the MHC proteins found on antigen-presenting cells (APCs). Often, TCRs are composed of two chains, an alpha and a beta (/) for the most part. TCRs are associated also with a complex of proteins designated CD3. Each chain, comprised of various amino acids, has a part that stays pretty much the same (a constant or C region). The tips of each chain vary depending on the antigen they uniquely identify (the variable or V region). There is also a "J" or joining region that connect the constant and variable regions.

However, there is another variety of TCR that has a role in activating the initial immune response. These have gamma/delta chains instead of alpha/beta. They are fundamentally different from alpha/beta cells in several ways: (Ziegler, 1994).

These chains are broken down into subsets. For example, Vgamma9/Vdelta1 (because we can't use Greek letters, Vg9/Vd1) chains are found in 60-70% of healthy donors, with 20-30% expressing Vd1 chain (usually in the form of g1/d1). Some research has shown an elevation of the V1 expression in people with HIV as early as stage II. These same cells also expressed the activation marker, CD38. These are important cells that play a role in fighting infections in an un-MHC restricted fashion. (Gougeon, 1994). These cells are the first in line and these experiments suggest they do respond to HIV infection. Experiments with mice depleted of these cells showed they died rapidly to sub-lethal exposure to Listeria parasites or bacteria; such cells also tend to proliferate more rapidly under certain conditions (e.g., IL-1 + IL-7 or IL-2 + IL-12) (Ziegler, 1994).

There are many other cell surface markers that have been identified as becoming dysregulated in HIV/AIDS. The appended table 1 summarizes some of these. Since there is a lot of mixing and matching described below, I urge you to review the table--have it handy--to refer back to in order to recall what each of the different "CD's" represents. I wish I could make it simpler, but nobody said this was going to be easy! Remember, too, sometimes cell phenotypes are characterized by multiple CD antigen expression.

Infection, Inflammation and Oxidative Stress
An infection occurs when the body is exposed to a virus, bacteria, fungi or what have you. Very often, this is associated with a condition called inflammation, which is characterized by the features of redness, swelling, pain or discomfort, heat and a disruption of local function. The acute phase response is the initial immune response to infection, and involves the activation of many different immune cells and the production of many different compounds, many of which cause free radical production (see discussion in the next section). When the crisis is passed, the damage is healed and the inflammatory response subsides. If the damage is serious, however, scar tissue may form at the site. Such damage occurring to the liver, pancreas or other organs that become riddled with scar tissue means their ability to function properly is seriously compromised.

With HIV infection, there is a sustained, pathological (disease-inducing) inflammatory response that is a chronic (ongoing) condition. In this process, the body's natural defenses are fighting HIV but are also causing local damage to tissues. While people often think of HIV as a blood disease, it is not. Most of the virus is to be found in the lymph system, lymph nodes, spleen and in other tissues; what is seen in the blood is "spillover" from these other areas. The lymph system is the "other" circulatory system (besides blood) that helps to remove foreign material and helps white blood cells to migrate to the site of infections.

Unfortunately, HIV targets the very cells that are used to fight it. This includes not only the CD4+ T-lymphocyte (T cell) but also, extremely critically, a cell known as the monocyte. Monocytes help to identify invading organisms that need to be controlled by the body's defense mechanisms. They are transformed into cells called macrophages, follicular dendritic cells and Langerhans cells, depending on where they wind up. (That is, the tissue to which they migrate). Some researchers have evidence that the monocyte/macrophage is the first cell to be infected (Ho, 1993). when HIV is transmitted sexually through the mucosal tissue (as opposed to by blood transfusion or shared needles).

This causes a welter of confusing signals to be sent by the immune system which not only results in the death of infected cells but uninfected ones as well. The body's alarm signals are being emitted in a chronic way, recognizing the presence of an uncleared infection. So while it seems paradoxical to talk about an acute phase response as a chronic condition, what is meant is that the acute phase response is normally meant to be transient (temporary) but winds up becoming sustained or chronic. Inflammation is therefore sustained and, over a period of time, the damage increases to many organ systems from the intestines to the brain and central nervous system. And, as we will see in the following discussion, this inflammatory response fosters an environment favorable to the growth of new HIV. (For a discussion on some of the ideas about why uninfected T cells are killed, review the Immunology Primer in TIP).

Normally, the body has a capacity to offset the inflammation that occurs and limit the damage to healthy tissues. The molecules that dampen the flames of infection-fighting cells are known as antioxidants. While some are found from outside sources (like some vitamins), others are produced inside cells. The most well-characterized of these (especially for T cells) include glutathione (GSH) and the two types of superoxide dismutases (one containing copper and zinc, the other containing manganese). Glutathione, being so important to the process, is discussed below.

At the cellular level, a number of molecules are released in excess during HIV infection that are the real hell-raisers. Some of these are derived from a chemical called arachidonic acid that is found in cell membranes. When oxidants release this chemical, it is transformed into a variety of other chemicals, depending on what enzymes are around. This includes the prostaglandins, leukotrienes, HPETEs and several others. In an ongoing acute phase response, the worst of the lot can be produced which can cause significant damage to tissues. Prostaglandin E2 (PGE2) elevations have been noted in the fluid that surrounds the spinal cord (CSF) and have been implicated in the development of dementia in people with HIV. (Griffin, 1994). (In contrast, PGE1 is considered a "good" prostaglandin; its production is increased by fatty acids known as linoleic or gamma linolenic acid, GLA).

There are many ways to minimize the damage of this "chronic" acute phase response. Obviously, antioxidants like various vitamins (carotenes, C, E) and other nutrients (a very important one is alpha-lipoic acid) are all critical. Omega-3 fatty acids change the actual structure of the cell membrane, making the above inflammatory products become greatly diminished. Quercetin is a well-characterized anti-inflammatory which also strongly inhibits histamine release as well as HIV growth in the lab. However, it is poorly absorbed and probably should be taken in higher doses along with bromelain to increase its absorption. Other plant bioflavonoids have substantial anti-inflammatory capabilities like gingko biloba, curcumin, glycyrrhizin and silymarin. Even low-dose aspirin, or other over-the-counter anti-inflammatories, may very well be of some benefit with this generalized inflammation. There is a reasonable chance that by taking a mix of different types of natural anti-inflammatories PWHIV can strongly reduce the disease-causing effects of this acute phase inflammatory response to reasonable levels.

As with a lot of things, an appropriate amount of oxidative stress (see below) in the biological machinery can be good. It is necessary in fighting off certain kinds of infections. For example, when a bacterium is encountered, it may be killed by the release of free radicals that basically punch holes in the outer wall of the bacteria, killing it. The problem, of course, is that too much can be unhealthy, especially if it is chronic (ongoing). Like a fever is a good thing for a day or two if it is not too high. But a fever that is too high for too long can kill. Similarly an inflammatory response that goes on unchecked has been implicated in a variety of diseases. Among these are diseases of the muscle and skeleton system, some diseases where the immune system attacks the body (autoimmune disorders), rheumatoid arthritis and others. See the discussion in the next section.

Research at Dr. Luc Montagnier's Pasteur Institute and as reported at a National Institutes of Health (NIH) conference has clearly shown that there is a severe oxidative imbalance--excess of free radicals and depletion of protective antioxidants--in HIV infection, which worsens as the disease progresses. [The abstract book from this important conference is available at the DAAIR office.] Antioxidants are depleted in fighting free radicals which are excessively generated by four types of destructive compounds and processes in the body--HIV proteins, excess immune signaling messengers (cytokines), other immune system cell overactivation (inflammation), and substantially increased cellular energy utilization. (Passwater, 1995; Kaufman, 1990; Klein, 1990). In this section we review the role of free radicals and HIV proteins.

Free-radicals are molecules with unpaired single electrons (negatively-charged parts of a molecule normally balanced in twos) which, because of their instability, steal electrons from other molecules in order to keep things in balance. The robbed molecule is now deficient one electron and grabs one from somewhere else which then needs one and this results in a chain reaction. But this only works when a free radical meets a non-radical (like the molecules in a cell's membrane). When two radicals meet, they cancel each other out. The cascade of reactions occurring in the respiratory burst are known as oxidation-reduction reactions.

Free radicals have been shown to cause aging and have been implicated in several degenerative diseases, including cancers and immune system disorders. Some types of injuries like in a heart attack (myocardial infarction) may be worsened by the presence of free radicals. Antioxidants are also known as free-radical scavengers because they neutralize free radicals by donating available electrons and otherwise spare electron-stealing damage to human cells.

Free-radicals can have external environmental sources--such as drugs, pesticides, sunlight, x-rays, cleaning fluids, air pollution (including cigarette smoke) and certain foods (mainly fried, barbecued, additive-laden, and synthetic ones). Or free radicals can be produced internally by immune cells themselves, which either use free radicals to dissolve foreign invaders or actually shoot "bullets" of free radicals at foreign invaders or malfunctioning cells in order to destroy them.

Not all free radicals are created alike, however. Some are far more greedy (and destructive) than others. Some of the worst are superoxides (.O2), peroxides (.H2O2), perhydroxyls (.OOH) and hydroxyl radical (OH-). [Technically, the hydroxyl radical is not a free radical since it has two electron pairs in outer orbital Nonetheless, it is extremely reactive.] These are produced as oxygen (O2) is converted into water (H2O). There are many other types of radicals, some less reactive than these (like the radical vitamin E produces, the tocopheryl radical).

Some free radicals target a cell's outer lipid (or fat) membrane, causing damage to the cell. This is called lipid peroxidation. A similar process occurs when butter fat or other oils turn rancid. The membrane of the molecule, which allows nutrients to enter and wastes to be excreted among other functions, is composed of neatly aligned fatty acids. During the peroxidation by free radicals, this alignment is damaged by the neighboring fatty acids hooking up with each other (cross-linking) which stiffens the membrane. This prevents the normally flexible membrane from doing its job.

Other free radicals target the genetic material (the DNA-wrapped chromosomes; such damage-inducing agents are known as clastogenic factors). This can cause mutation and recent research has linked such damage with aging and cancers. This can destroy the cell, which is desirable if the cell is infected. The oxidative respiratory burst that the body uses to attack infections is intended to cause damage (for example, the purpling or darkening that occurs around an infected cut). This is supposed to shut down after the infection is eliminated so the damage does not persist. When the infection is not completely eliminated, there's trouble. (Winyard, 1993; Fuchs, 1993).

As has been mentioned, this immune response to infection results in inflammation--an example of which you can see as the redness, swelling and heat around an open cut (not to mention it hurts!) Such reactions also occur within the body during the inflammatory phase of an immune response. A distinct feature of HIV infection is that inflammation becomes exaggerated, generalized and dysfunctional--parts of your immune system become locked in overdrive while other parts diminish. This process can become even more exaggerated by co-infections which create even further immune activation, increasing the inflammatory aspects of the immune system as immune cells generate more free radicals in order to help fend off the foreign invader (infection).

When the body reacts to an infection, many powerful anti-bacterial or infected cell-killing defenses are brought into play. One particular cellular response is phagocytosis (literally from Latin, cell eating), in which different cells like macrophages, neutrophils or natural killer cells consume foreign material (pathogens) and break it down. Antigens are substances that causes the immune system to respond. [Antigens originally referred to substances that caused the body to react by forming antibodies However, the immune system does more than that, like identifying and killing infected cells The definition of antigen has been broadened since everyone uses it to refer to any substance that activates any part of the immune system More accurately, one should use the term immunogen See the Immunology Primer in TIP for a more detailed background and discussion of immune function.] During this process, a variety of chemical reactions occur, including the respiratory burst As this name suggests, a certain amount of breathing (or respiration) is going on. The neutrophil or macrophage that is phagocytosing (eating) a cell, or bacterium, etc., will also start consuming a lot more oxygen than it does when it is resting. This oxygen is then sent through a cascade of reactions that are intended to be toxic to a special marker of the invader (or antigen).

Also, HIV proteins are themselves severely inflammatory and destructive to cells. One purified HIV protein called gp120 has been added to laboratory dishes with human cells and dramatically increased (up to 40 fold) the release of inflammatory by-products and free radicals. Wahl, 1989). Another protein of HIV, called tat, has been found to severely disrupt and deplete a critical enzyme system called manganese SOD inside the mitochondria (powerhouse) of human cells. (McCord, 1993). This enzyme is responsible for protecting the cell against free radical accumulation by regenerating the major protector against free radicals inside of all cells called glutathione, a peptide composed of three amino acids. (Peptides are smaller sub-units of proteins, all of which are composed of molecules called amino acids strung together).

While the mechanisms by which HIV depletes the body of many antioxidants are still mysterious, it is extremely well documented that the loss of glutathione (GSH) is the earliest and most critical. Without sufficient free radical protecting quantities of GSH inside of cells, many cellular genes which are free-radical-sensitive become increasingly over-expressed That is to say that these genes get turned on too frequently and too severely by the increasing presence of more and more free radicals. This loss of antioxidants may help to perpetuate the ongoing acute phase response (see above).

Early HIV infection is controlled by the immune response. However, very slowly, due to the loss of critical sulfur amino acids (see Section IX on glutathione), the inflammatory immune dysregulation and free-radicals build, disrupting fat metabolism (our body's ability to process and manufacture certain fat-based nutrients and other products). The levels of these inflammatory immune messengers (cytokines) have now been measured along the digestive tract in early HIV infection, and were found to be increased. Several researchers feel that their presence at the site of nutrient absorption compromises our ability to utilize critical fat-soluble nutrients (vitamins A, E, beta-carotene and other carotenes, co-enzyme Q10, fatty acids, etc.)

As HIV infection proceeds, this entire process of oxidative imbalance (the presence of too many free radicals and too few protective antioxidants) keeps getting worse, assuring viral activation. Virus which has already been integrated inside cells can be asleep (latent) or replicating at a very low level until it is stimulated by free-radicals, further immune hyperactivation and disease progression. This process may be slowed down or reversed with antioxidant supplementation.

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