HIV/AIDS — Immune Function and Nutrition
By Dale Ames Kline, MS, RD, CNSD, LD
Today’s Dietitian
Vol. 8 No. 4 P. 13

Medical nutrition therapy is an essential component in treating HIV/AIDS. Over the past 20 years, research has clearly shown the relationship of nutrition to immune function, opportunistic infections, progression of the disease, and, most importantly, quality of life. In developed countries, the devastating progression of AIDS is mitigated in part by effective treatment, supported by a generally high level of nutritional health. Those individuals receiving highly active antiretroviral therapy (HAART), common in the United States, have fewer opportunistic infections, increased quality of life, and live longer.1 This makes proper nutrition even more important.

To fully appreciate the role of nutrition in treating HIV/AIDS, we must first understand how the virus alters the immune system and evades destruction. We also need to know how the nutritional status of the host impacts the virus and how the nutritional environment of the host is forever altered. With these understandings, the critical role of nutrition in the treatment of HIV/AIDS becomes more clear.

The HIV Virus
HIV is classified as a retrovirus. It is distinguished by the presence of reverse transcriptase, an enzyme that allows the RNA of the virus to make its own DNA by using genetic material from the host cell. Only cells that have the CD4 glycoprotein receptor on the cell membrane can become infected. These include cells of the immune system, such as CD4+ T lymphocytes (T helper cells), macrophages and monocytes, some B cells, and dendritic cells of the germinal centers (part of the nervous system). Viral replication has been detected in all regions of the central nervous system, making it a likely virus target and accounting for the neurological symptoms seen in AIDS.

To spread itself, the HIV virus binds to the CD4 receptor on the surface of a cell, then penetrates into the cell where it either begins replicating or remains inactive—“latent” or nonreplicating. Actively replicating cells “hijack” the host cell’s DNA, producing a large number of viral particles, or virons, that travel through the blood to infect more immune cells, including CD4+ T helper cells.

At any given time, the number of actively replicating HIV cells is much smaller than the number of HIV-infected latent cells, which poses a problem for the immune system.1 This is especially problematic because HIV-infected latent cells appear normal from the outside, so immune cells do not attack them. This creates a reservoir of incubating HIV cells within the body that is able to grow undetected and undisturbed.

Declining Immune Function
Once the HIV virus inside T cells has finished replicating, the cell is destroyed, releasing the new virus into the bloodstream. Each new viral particle finds a cell to infect. While T cells are being destroyed by the HIV virus, new ones are created to replace the destroyed cells. However, over time, the number of CD4+ T helper cells declines, as more cells are destroyed than are replaced.

The loss of lymphocytes is the most damaging aspect of the HIV virus because these cells regulate all aspects of immunity. They can recognize specific antigens based on the markers on the outside of the cell. CD4+ T helper cells stimulate T and B cells to respond to antigens, “turning on” the immune response and activating macrophages as well as stimulating cytotoxic T cells, which can kill infected self cells and tumor cells, activate macrophages, and detect and kill foreign cells.

Immune functions of CD4+ T lymphocytes include the following:

• regulate many aspects of immune response;

• can differentiate self cells from foreign antigens;

• reduce immune response to self cells, preventing autoimmune disease;

• control activity of antibody-producing cells;

• stimulate antibodies that prevent viruses, including HIV, from replicating;

• increase clearance of HIV virus by promoting uptake into phagocytic cells;

• increase binding of virus to cytotoxic T cells to neutralize HIV virus;

• control activity of cell-mediated immune cells;

• recognize HIV virus as foreign antigen;

• kill virus-infected cells; and

• prevent release of new viral particles.

Macrophages are the cells that identify antigens and present that information to CD4+ T helper cells so they can stimulate an immune response. Losing T helper cells and macrophages, with their central role in the immune response, severely impairs the immune system’s response to an antigen, causing immune system abnormalities. A hallmark of AIDS is the quantitative and qualitative defect of CD4+ T helper cells. The normal ratio of CD4+ to CD8+ T cells is 2:1—in AIDS, that is reversed to 1:2 or even lower.

Recognizing Self Cells and Foreign Antigens
Lymphocytes can differentiate between self cells and foreign antigens and distinguish which antigens to target. Every cell has a protein marker, genetically determined by the major histocompatibility complex (MHC) on its surface. These MHC markers have important functions in the immune response. Class I MHC markers identify cells as “self” so immune cells will leave them alone. MHC markers also determine which antigens an individual will respond to and how strong the response will be. This accounts for the variance among individuals in their response to viruses, bacteria, and allergens.

Cytotoxic T cells use the class I MHC markers to identify self cells that have been infected by viruses or have mutated. A cytotoxic T cell binds to the class I MHC marker, looking for signs of infection or mutation. If found, it destroys the infected cell. This is what happens to actively replicating HIV-infected cells.

T cells cannot recognize antigens; they must be “educated” to learn what receptor will be needed to bind that specific antigen so it can be destroyed. Class II MHC markers are used by cells that are responsible for presenting antigens to the helper T cells: macrophages, B cells, and dendritic cells. These cells are known as antigen-presenting cells (APC) because they have a small fragment of the antigen on their MHC receptor, which they present to the T helper cell or macrophage so it knows the antigen needs to be attacked.

Once a lymphocyte or macrophage recognizes the cell by the antigen fragment or the MHC marker on the cell surface, it decides either that the antigen is self (needs no response) or foreign (must be attacked). APC must first present an HIV antigen fragment to the CD4+ T lymphocyte for it to recognize the HIV virus so it can be destroyed, whether circulating in the blood or replicating in cells.

This is one way the system breaks down in HIV/AIDS. The HIV virus leaves no antigen fragments on the outside of the cell, so it can evade detection by the immune system.

Another way it escapes detection and destruction by the immune system is by mutating. When the HIV virus replicates itself, there are errors in the transcription and mutations occur. Every time the HIV virus mutates, it becomes unrecognizeable, and the immune system must again go through the recognition process described above. That takes time, which allows the new strain of virus to replicate freely. The immune system is constantly trying to catch up. Over time, some HIV virus strains become entirely resistant to immune system detection, as well as to medications.

Destruction of HIV Virus
Macrophages, neutrophils, and other granulocytes can specifically identify bacteria, virus, and debris particles they must destroy but cannot differentiate between foreign antigens, noting only that the invader is nonself and must be destroyed by phagocytosis.

During phagocytosis, the foreign antigen is bound to the surface of a macrophage or neutrophil, sometimes assisted by C3 complement. The phagocytic cell then engulfs the antigen and brings it into the cell, forming a phagosome—a sort of walled-off compartment. Destruction of the antigen takes place chemically inside the phagosome. Lysosomal enzymes, free radicals, hydrogen peroxide (in combination with ascorbic acid and copper ions), and lactoferrin are all involved in destroying the antigen. Oxygen produces lethal free radicals, including nitric oxide, that kill foreign antigens during phagocytosis. Excess hydrogen peroxide is removed from the cell by enzymes to prevent damage to the phagocytic cell. The remains of the antigen are digested by the phagocyte.

While engulfing antigens, bactericidal chemicals and free radicals leak out of the phagocyte and damage nearby cells and tissue of the host organism. After the antigen is killed, portions of it are displayed on the outer surface of the macrophage, bound to a receptor, where they can now be recognized by T cells. This is how T cells learn to recognize invaders, which begins the specific immune response.

Free Radicals and Antioxidants
It is important to note that stimulation of the immune system does cause an increase in free radical production as a result of phagocytosis. Antioxidants neutralize the free radicals. Constant stimulation of the immune system can upset the balance between free radicals and antioxidants.

Immune cells produce superoxide radicals and mobilize other reactive oxygen species (ROS) to destroy bacteria, viruses, and other foreign matter. On the surface of phagocytes is a dormant enzyme that produces O2• (superoxide radical) once phagocytosis occurs. The phagocyte consumes a lot of oxygen in a “respiratory burst” that precedes the O2• production.

Antioxidants protect the body from the damaging effects of free radicals. There are two types of antioxidants: antioxidant enzymes and nonenzymatic dietary antioxidants.

Superoxide dismutase (SOD) is an enzyme able to convert superoxide radicals into the less toxic hydrogen peroxide. SOD requires mineral cofactors to function: zinc and either manganese or copper. Other enzymes—catalase and glutathione peroxidase—then convert the hydrogen peroxide into oxygen and water. Catalase is a heme-requiring enzyme; glutathione peroxidase is a selenium-containing enzyme that requires glutamine or glutamate to produce glutathione.

The ability of these enzymes to work depends on the availability of the minerals needed as cofactors: manganese, selenium, zinc, copper, and iron. The body will bind and sequester these metals to protein carriers, such as transferrin and ceruloplasmin, to make them unavailable for conversion to ROS. (Iron and copper have a dual role in the production and destruction of ROS. While both are necessary for protective enzymes, they can, in the presence of hydrogen peroxide, cause the production of the toxic hydroxyl radical.)

Nonenzymatic antioxidants are the other line of defense against ROS and include vitamins E and C, carotenes, glutathione, uric acid, taurine, and phytochemicals. All these antioxidants are found in food; they work by intercepting and stabilizing the ROS. This is known as scavenging.

Vitamin E is the most important antioxidant within lipid membranes, preventing cell membrane damage by scavenging the peroxyl radical.

Vitamin C is the most abundant water-soluble antioxidant with a vast array of ROS it can protect against. In addition, it prevents the conversion of nitrites to the carcinogenic nitrosamines and can regenerate vitamin E once it gets used up scavenging free radicals.

Carotenes, especially beta-carotene, are potent scavengers of peroxyl and hydroxyl radicals. They can also protect lipid membranes. Chart 1 lists the nutrients necessary to prevent oxidative stress.

Glutathione is an important antioxidant, scavenging free radicals, removing hydrogen and lipid peroxides, and preventing the oxidation of various substances in the body.2 Many other functions of glutathione involve nutrient metabolism, the regulation of gene expression, DNA and protein synthesis, cell proliferation, cytokine production, and immune response.2 A protein deficiency will cause a glutathione deficiency, as it is synthesized from the amino acids cysteine, glutamate, and glycine, with cysteine usually the rate-limiting amino acid.2 Methionine can be used as a precursor to cysteine, while glutamine is effective as a precursor for glutamate.

In people with HIV/AIDS, decreased levels of antioxidants and increased oxidative stress have been documented.3 As oxidative stress increases, so does viral replication, which increases the destruction of CD4+ T cells and the disease’s progression.4

Oxidative Stress and Immunity
One of the most provocative concepts regarding oxidative stress and immunity is the relationship between nutritional status, antioxidant status, and the virulence of certain viruses.

Beck showed that animals fed selenium- or vitamin E-deficient diets, when exposed to a virus that induces cardiomyopathy, got sick earlier and more severely than animals on a nutritionally adequate diet.5 The researcher believed that increased oxidative damage decreased immune function. Not only that, but the selenium- and/or vitamin E-deficient animals got sick on a virus that was not virulent to nutritionally adequate animals. In other words, a normally benign virus changed to a virulent one when the diet was inadequate in two important antioxidants.

This was borne out in another experiment. Beck injected a virus into two groups of mice.5 One group was fed a nutritionally adequate diet and the other was selenium- and/or vitamin E-deficient. The mice fed an adequate diet did not get sick, but the nutritionally deficient group did. When the researchers took the virus from the sick mice and injected it into the healthy mice (remember, the healthy mice were already injected with the same virus), this time they got sick.

The researchers concluded that the immune response of the host with the nutritionally deficient diet is impaired due to increased oxidative stress—not enough antioxidants to prevent damage from ROS. A decrease in immune response may allow a more virulent strain of virus to emerge. Another possibility is that ROS damage to viral RNA leads to increased mutations of the virus, making it more virulent. Once the viral mutation occurs, even the nutritionally adequate mice are susceptible to the virus.

In an excellent review of this work, Beck shows that there are genomic changes in the viruses taken from nutritionally deficient mice that account for the change in the virulence of the virus.6

Beck wanted to find out whether their study of the coxackievirus was true for other viruses and decided to study the influenza virus. Every year in the United States, more than 100,000 individuals are hospitalized with influenza and more than 20,000 die from the disease. Beck and colleagues gave an influenza virus to selenium-deficient and selenium-sufficient mice.7 Normally, the virus causes pneumonitis. However, the selenium-deficient mice had more severe lung pathology that lasted longer than the selenium-sufficient mice. The lung pathology was caused by a proinflammatory immune response and was due to a mutation of the virus in the selenium-deficient mice. The study’s authors propose that RNA viruses are highly susceptible to oxidative damage if the host is antioxidant-deficient, and that can lead to a more virulent strain of the virus.

Nutrition and HIV/AIDS
What constitutes adequate nutrition in patients with HIV/AIDS? We saw that the virus causes a constant stimulation of the immune system that alters nutritional status and nutrient needs. What are the nutritional implications of this?

• HAART. Opportunistic infections usually occur when the CD4+ T helper counts go below 200 per cubic millimeter and is a sign that the HIV infection has progressed to AIDS. With a CD4+ T helper count below 200 per cubic millimeter, the immune system is vulnerable to opportunistic infections, the hallmark of AIDS.1

HAART, a combination of antiretroviral drugs, can maintain the CD4+ count above 200 per cubic millimeter, preventing progression of the disease. However, HAART can cause lipodystrophy, a metabolic syndrome characterized by loss of fat in the extremities, accumulation of visceral and abdominal fat, breast hypertrophy, and the emergence of interscapular fat pad (which is much less common). Metabolic changes include hypertriglyceridemia, insulin resistance, increased serum cholesterol, and lactic acidosis. Other problems identified include hepatic steatosis, osteopenia, and osteoporosis.

In other words, in individuals receiving HAART, the nutritional problems seen in HIV/AIDS (such as severe weight loss, malnutrition, wasting, and complications from opportunistic infections) have been replaced with concerns about chronic diseases such as heart disease, osteoporosis, and changes in body composition.8

• Increased nutrients to maintain immune function. Nutrients provide the support necessary for the immune system to mount an immune response. Every component of the immune system appears susceptible to nutritional deficiencies, including nonspecific responses such as phagocytosis and killing activity, as well as cell-mediated and humoral (antibody) immune functions.

With the continual activation of the immune system, there is an increased demand for nutrients, especially those associated with cellular production. Deficiencies of protein; vitamins B1, B2, B6, B12, E, and folate; and minerals zinc, selenium, copper, and iron impair immune function.

Baum and associates have been interested in investigating the relationship of nutritional status to disease progression.9 To do that, they examined the effects of immune parameters and nutrients known to affect immune function on the survival of male and female drug users who are HIV-positive. Over 3.5 years, 21 of the 125 participants died of HIV-related causes. The study found that impaired nutritional status—defined as low prealbumin, vitamin A, B12, zinc, and selenium—over time was significantly associated with mortality. The only independent predictor of survival was selenium, even when controlling for baseline CD4+ count below 200, CD4+ count over time, overall poor nutritional status, and deficiencies of vitamins A and B12 and zinc.10

The authors of this study speculate that selenium is important in the progression of the disease because it is involved in gene regulation and viral expression. The HIV virus replicates more slowly with adequate selenium than when selenium is deficient. Viral load will affect the disease’s progression.

Other studies have shown that multivitamin and mineral supplementation can slow HIV disease progression. Abrams showed that multivitamin and mineral supplementation was associated with a 30% reduced risk of progression to AIDS and a 40% reduced risk of low CD4+ counts.11

Pregnant women in Tanzania given a multivitamin and mineral supplement that included vitamins A, B, C, and E and beta-carotene had significantly higher CD4+ and CD8+ counts as well as significantly lower viral loads.12 The vitamin/mineral supplementation was able to delay the initiation of antiretroviral therapy, delay the progression of the disease, and reduce mortality.

• Increase in free radical production and oxidative stress. It has been consistently documented that the antioxidant nutrients are low in those with HIV/AIDS, even when given a supplement.13,14 Supplementing with the antioxidant nutrients to Daily Recommended Intake will increase serum levels. Supplementing with increased amounts of the nutrients may not be necessary and is unproven.15 In fact, it has been shown that supplemental vitamin A may be harmful and negatively impact longevity in AIDS.14

In addition, glutathione is decreased in the body of people with HIV/AIDS, leading to a decreased T cell count and impaired functioning of T cells. Supplementing with glutathione itself or its precursors may be necessary to fully restore immune function, especially when undergoing antiretroviral therapy.16

• Weight and body composition. Unintentional weight loss is associated with morbidity and mortality in people with HIV. Opportunistic infections and tumors are responsible for a large majority of the severe weight loss seen in AIDS.1

For individuals on HAART, it is more common to see a gradual loss of lean body mass accompanied by cachexia and increased resting energy expenditure.17 After studying 172 men with HIV who were treated with HAART, Roubenoff concludes that severe weight loss is rare but loss of lean body mass is due to an increase in catabolic cytokines, not inadequate intake.

Cytokines, produced when the immune system is activated, initiate the acute phase response (APR), which redistributes resources to maximize immune function, with the end result of metabolic catabolism. The APR is characterized by fever, skeletal muscle catabolism, inflammation, liver synthesis of acute phase proteins (including C-reactive protein), alterations in hormone production, increases in neutrophils, and changes in serum levels of trace elements and antioxidants. In an APR, the level of C-reactive protein is increased above 1.5 milligrams per deciliter and can stay elevated as long as there is sufficient activation of the immune system. It has been speculated that over time, this can lead to losses in lean body mass and cachexia, leading to decreased food intake.

When working with patients with HIV/AIDS, it is important to consider body composition. Even though patients are not losing weight, are they losing muscle? If they gain weight, is the weight fat or muscle? Body composition changes have ramifications for other treatments, such as preventing atherosclerosis and cerebralvascular disease.

As you can see, the underlying infection with HIV begins a long process of alterations in immune function and nutritional status. No two people react the same to the virus and treatment. Beginning nutrition intervention early in the infection, before the disease has progressed, can increase quality of life, slow the disease’s progression, save resources, and save lives.

— Dale Ames Kline, MS, RD, CNSD, LD, is president of Nutrition Dimension, Inc. A
former hospital chief clinical dietitian and nutrition educator in the Women, Infants & Children program, she has written and edited continuing education home study courses
since 1984.

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Nutrients Involved in Antioxidant Enzymes
• Superoxide dismutase: zinc and either manganese or copper
• Glutathione peroxidase: glutathione and selenium
• Catalase: heme (iron)

Nonenzymatic Antioxidants
• Vitamin E
• Vitamin C
• Carotenes
• Glutathione (produced from substrates cysteine, glutamate, and glycine)
• Taurine
• Phytochemicals

Examination
1. Which of the following cells can become infected with the HIV virus?
a. Phagocytes and T lymphocytes
b. T lymphocytes and macrophages
c. Red blood cells and macrophages
d. Phagocytes and macrophages

2. Destruction of T helper cells by the HIV virus damages which of the following immune functions?
a. Distinguishing self cells from foreign antigens
b. Antibodies blocking the HIV virus from replicating
c. Clearance of HIV virus from the blood
d. Killing of virus-infected cells
e. All of the above

3. The HIV virus escapes detection by the immune system through which of the following?
a. Disguises the receptors on the outside of the cell
b. Hiding inside the cell and not displaying any antigen fragments on the outside of the cell
c. By mutating so the immune system cannot recognize it
d. a and b
e. b and c

4. Which of the following nutrients are necessary for phagocytosis to kill virus-infected cells?
a. Iron, copper, and vitamin C
b. Zinc, copper, and selenium
c. Iron, vitamin C, and selenium
d. Copper, vitamin C, and zinc

5. Free radical production increases with an HIV infection for which of the following reasons?
a. The HIV virus produces free radicals when it replicates.
b. Production of new immune cells to replace those destroyed
c. Constant stimulation of phagocytosis to fight the infection
d. Free radicals are involved in the recognition of foreign antigens.

6. Selenium is necessary for the functioning of which of the following antioxidant enzymes?
a. Superoxide dismutase
b. Catalase
c. Gluthathione peroxidase
d. Alcohol dehydrogenase

7. When a “host” is deficient in selenium and/or vitamin E, viruses can become more virulent and cause more severe illness.
a. True
b. False

8. Which of the following are seen in patients taking highly active antiretroviral therapy?
a. Increased serum triglycerides, decreased serum glucose, weight gain, and increased lean body mass
b. Increased serum triglycerides, decreased serum cholesterol, increased serum glucose, body fat changes, and increased T helper cells
c. Decreased serum triglycerides, insulin resistance, decreased lean body mass, decreased body fat, weight loss, and immune dysfunction
d. Increased serum triglycerides, increased serum cholesterol, insulin resistance, body fat redistribution, decreased lean body mass, and decreased viral load

9. Of the following nutrients, which one is the most important to supplement in a person with HIV/AIDS, as it has been linked to survival?
a. Vitamin A
b. Selenium
c. Vitamin C
d. Zinc

10. Which of the following patients is at risk for malnutrition?
a. A newly diagnosed HIV-positive patient who is asymptomatic
b. A patient who is HIV-positive, on HAART, and has a CD4+ count of 400 per cubic millimeter
c. A patient who has AIDS with one or two opportunistic infections per year
d. A patient on HAART with lipodystrophy
e. All of the above

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References
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2. Wu G, Fang YZ, Yang S, et al. Glutathione metabolism and its implications for health. J Nutr. 2004;134(3):489-492.

3. Allard JP, Aghdassi E, Chau J, et al. Oxidative stress and plasma antioxidant micronutrients in humans with HIV infection. Am J Clin Nutr. 1998;67(1):143-147.

4. Cole SB, Langkamp-Henken B, Bender BS, et al. Oxidative stress and antioxidant capacity in smoking and nonsmoking men with HIV/acquired immunodeficienty syndrome. Nutr Clin Prac. 2005;20(6):662-667.

5. Beck MA. The influence of antioxidant nutrients on viral infection. Nutr Rev. 1998;56(1 Pt 2):S140-S146.

6. Beck MA. Nutritionally induced oxidative stress: Effect on viral disease. Am J Clin Nutr. 2000;71(6 suppl):1676S-1681S.

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10. Baum MK, Shor-Posner G, Lai S, et al. High risk of HIV-related mortality is associated with selenium deficiency. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;15(5):370-374.

11. Abrams B, Duncan D, Hertz-Picciotto I. A prospective study of dietary intake and acquired deficiency syndrome in HIV-seropositive homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol. 1993;6:949-958.

12. Fawzi WW, Msamanga GI, Spiegelman D, et al. A randomized trial of multivitamin supplements and HIV disease progression and mortality. N Engl J Med. 2004;351(1):23-32.

13. Skurnik JH, Bogden JD, Baker H. Micronutrient profiles in HIV-1-infected heterosexual adults. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;12:75-83.

14. Coyne-Meyers K, Trombley LE. A review of nutrition in human immunodeficiency virus infection in the era of highly active antiretroviral therapy. Nutr Clin Prac. 2004;19(4):340-355.

15. Nerad J, Romeyn M, Silverman E, et al. General nutrition management in patients infected with human immunodeficiency virus. Clin Infect Dis. 2003;36(suppl 2):S52-S62.

16. Aukrust P, Muller F. Glutathione redox disturbances in human immunodeficiency virus infection: Immunologic and therapeutic consequences. Nutrition. 1999;15(2):165-167.

17. Roubenoff R, Grinspoon S, Skolnik PR, et al. Role of cytokines and testosterone in regulating lean body mass and resting energy expenditure in HIV-infected men. Am J Physiol Endocrinol Metab. 2002;283(1):E138-E145.