Micronutrient Synergy in the Control of HIV Infection and AIDS

above positive findings could save millions of lives.


Nutritional deficiencies in HIV and AIDS
The relationship between nutrition, infection and immunity is well established since the early 1940's (Scrimshaw 2003, Webb andVillamor 2007). It is for instance well recognized that nutritional deficiency can lower immunity and predispose individuals to microbial infection. Conversely, nutritional supplementation can improve immune function and prevent/confer resistance to infection. As the latent period between HIV infection and AIDS manifestation has been estimated at 8-10 years (Morgan et al 2002), nutritional cofactors, besides HIV, have been implicated in AIDS development (Beach et al., 1992, Baum et al., 1995, Jariwalla et al., 2008a. Furthermore, nutrient supplementation in asymptomatic HIV-infected individuals was shown to delay the onset of AIDS (Abrams et al., 1993, Tang et al., 1993, supporting involvement of nutritional status as a contributory factor in AIDS development. It is universally known since the emergence of the AIDS epidemic in the early 1980's that nutritional deficiencies are prevalent in persons with HIV infection and AIDS (Gray 1984, Beach et al., 1992, Jariwalla 1995; see also Table 1). These deficits include: (i) specific micronutrient abnormalities such as reduced blood levels of the common ACE vitamins, minerals, trace elements including selenium, amino acids such as cysteine, and the tri-peptide glutathione, which displays a global systemic deficiency; (ii) macronutrient abnormalities such as protein calorie malnutrition, which has been linked to a wasting disease, characteristic of AIDS. Malnutrition has also been linked to the spread of AIDS and TB in developing countries and with reduced survival (Paton et al., 2006, Turchenko et al., 2008 MICRONUTRIENT ABNORMALITIES

Vitamins
Trace Elements

Impact of nutritional deficiencies
Micronutrient deficiencies in particular vitamin and mineral deficiencies can promote and strengthen microbial growth by weakening the immune system of the host, making it prone to acquiring new infections (Scrimshaw 2003, Webb andVillamor 2007; see Fig 1).

Essential role of micronutrients in cell physiology and immunity
Micronutrients are essential for sustaining all cellular functions including metabolic reactions in the cytosol and biochemical functions within cellular organelles (Fig 2). Vitamins and minerals are needed in smaller amounts than proteins, fats and sugars but without them, cells cannot convert food into biological energy and build different body structures. Micronutrients are also critical for optimum functioning of the immune system including cell-mediated immunity, antibody production (humoral immunity) and optimum thymus function (Fig. 3). The pathological basis of AIDS is a dysfunctional immune system clinically indicated by abnormally low levels of white blood cells. Micronutrients are essential for blood formation, including white blood cells. Of particular importance are: vitamin B-3, vitamin B-5, vitamin B-6, vitamin B-12, vitamin C, folic acid and iron. Any textbook of biology or biochemistry documents these scientific facts. Moreover, no less than nine Nobel Prizes in Medicine have been awarded to date on the discovery of the health benefits of vitamins, relevant to their role in cellular physiology and impact on the immune system (Nobel Prize Committee website, Nobelprize.org).

Role of micronutrients in suppression of virus infection
Additionally, experimental studies have shown that specific micronutrients can suppress virus infection at various steps in the viral life cycle that include blocking (a) virus entry, (b) virus multiplication, (c) virus activation in latently infected cells and (d) virus spread (Fig 4). Prevent viral entry into cells (Vitamin C, EGCG) Stop viral multiplication (Vitamin C, N-Acetylcysteine) Prevent activation of "silent" viruses (Vitamin C) Limit spread of infections (Lysine, Vitamin C) In the case of HIV, micronutrients have been shown to block virus expression at all stages of virus-host interactions, which include acute infection, chronic expression and activation from latently infected cells (Fig 5). The specific micronutrients demonstrated to affect different phases of virus infection are listed in Table 2. Most of them are reducing agents with antioxidant properties. They include: vitamins C and E, amino acid thiols such as cysteine or its derivative N-acetyl cysteine (NAC), disulfides such as alpha-lipoic acid, tripeptides such as glutathione and its derivative glutathione monoester, polyphenols such as epigallo-catecheine gallate (EGCG from green tea) and the trace element selenium. Among them, ascorbic acid (vitamin C or ascorbate) is the most versatile, capable of blocking HIV replication in all phases of HIV infection namely, acute, chronic and latent infection (Harakeh et al., 1990;Harakeh andJariwalla, 1991, 1995). Cysteine and glutathione monoester inhibit chronic HIV expression (Mihm et al., 1991;Kalebic et al., 1991) whereas NAC and selenium are effective in inhibiting HIV activation in latently-infected cells (Roederer et al., 1990, Harakeh andJariwalla 1991;Sappey et al., 1994). It has been reported that alpha-lipoic acid can block acute infection (Bauer et al., 1991) and flavonoids including the polyphenol EGCG inhibit HIV at an early stage, blocking interaction of the virus with host-cells receptor (Mahmood et al., 1993, Fassina et al., 2002. More recently, green tea extract enriched in such polyphenols (80% by weight) was shown to suppress HIV production in chronically and latently infected cells (Jariwalla et al., 2010

Our approach to controlling virus infection with nutrient synergy
Although specific, single nutrients have been shown to suppress HIV in previous studies, little attention has been directed at blocking virus expression with nutrient combinations. To investigate this, we have utilized the principle of nutrient synergy i.e. use of nutrients in combination at low to moderate (physiological) levels for prevention and control of disease (Rath and Niedzwiecki 1996, Rath et al., 2005, Jariwalla et al., 2008a). The principle underlying nutrient synergy is that nutrients work in the body in harmonious synergy, not isolation, and they allow for maximal benefits when used in combination at physiological doses. In nutrient synergy 1 + 1 is more than 2 (Fig 6). We have applied this principle to both experimental studies of HIV infection as well as the in vivo evaluation of a defined multimicronutrient supplement in AIDS patients in a community wide setting. All nutrients work in our bodies in harmonious synergy, not in isolation. Nutrient Synergy allows for achieving maximum health benefits and keeping cellular processes in balance using smaller quantities of nutrients. Use of single vitamins in very high-doses or a randomly selected nutrient combination is not recommended as an optimal approach to health.

Experimental studies in HIV infection
Studies conducted by us of micronutrient combinations in laboratory cultures of HIV infected cells have provided further support for nutritional efficacy in viral immunodeficiency disease (Jariwalla et al., 2010). In these studies, we compared the ability of micronutrient combinations to single nutrients in the suppression of HIV replication in both chronically and latently infected cells. H9-HTLV IIIB is a model, chronically-infected T lymphocytic cell line that constitutively produces HIV cytopathic virus in the cell culture supernatant , Harakeh et al., 1990, Harakeh and Jariwalla 1991. Exposure of these cells to low/moderate concentrations of single micronutrients such as ascorbic acid, green tea extract and the amino acids such lysine produced only small inhibitory effects on virus production. In contrast, exposure of cells to combinations of micronutrients conferred significantly greater HIV suppression compared to single nutrients, indicating a synergistic effect. A nutritional mixture (NM), consisting of vitamin C, green tea extract, amino acids (lysine, proline, arginine), NAC and selenium also gave enhanced suppression of HIV production in this cell line compared to single nutrients (Jariwalla et al., 2010; see also Table 2). A similar inhibitory effect on cytokine-stimulated virus expression was obtained in latently infected T cells, indicating that micronutrients cooperate to suppress virus expression in both chronically and latently-stimulated cells (Jariwalla et al., 2010; Table 2).

Clinical nutrition studies in AIDS patients
Based on the above scientific evidence of micronutrient effectiveness in laboratory cultures of virally-infected cells, we have incorporated the use of micronutrients in natural control of HIV infection. Our studies conducted in persons with AIDS symptoms have provided further support for micronutrient efficacy in viral immunodeficiency disease (Jariwalla et al., 2008a(Jariwalla et al., , 2009). This in vivo confirmation of micronutrient efficacy was demonstrated in AIDS patients in a community wide program conducted in South Africa between 2005 and 2008. In this community program, the Dr. Rath Foundation donated a micronutrient supplement to the South African National Civic Organization (SANCO) who distributed it among people affected by AIDS in various townships in South Africa. The micronutrient supplement contained vitamins and trace elements (except iron) that are known to modulate the immune system (listed in Fig. 3) plus selenium, essential minerals and other important nutrients such as amino acids, green tea extract, bioflavonoids, N-acetyl cysteine, inositol and coenzyme Q10. This supplement was given to subjects to be taken 3 times a day with meals. The characteristics of participants, patient selection, informed consent, administration of questionnaire grading AIDS-defining symptoms and the evaluation methodology were reported previously (Jariwalla et al., 2008a(Jariwalla et al., , 2009). The first township where a pilot nutritional program was evaluated was Khayelitsha, a township near Cape Town (Jariwalla et al., 2008a). In this pilot protocol, 56 AIDS patients completed all 3 examinations and their completed questionnaires were evaluated for www.intechopen.com changes in severity of symptoms seen after the first 3 visits (8-12) weeks from the beginning of micronutrient supplementation. Table 3 lists the AIDS-defining symptoms for Africa, other physical symptoms, pain symptoms and symptoms of well-being. Tables 4-6 show a summary of the impact on these symptoms from micronutrient supplementation. The results showed that within 10-12 weeks, the micronutrient supplement statistically significantly suppressed all AIDS-defining symptoms compared to baseline. The supplement also significantly suppressed other physical symptoms frequently seen in AIDS patients including state of well-being (Jariwalla et al., 2008a). The micronutrient supplement evaluated in Khayelitsha was also rolled out in KwaZulu Natal district (near Durban) where a very large group (522 patients) completed all 3 exams and questionnaires. Similar to Khayelitsha, the same trend in reduction of AIDS-defining symptoms, other physical AIDS-associated symptoms and pain symptoms was seen (Tables  4-6). The results were also confirmed in two other townships (Western Cape and Free State), for a total of 813 participants from all 4 townships (Tables 4-6).  Table 6. Impact of micronutrient supplementation on pain symptoms in AIDS patients in community wide program * 8-12 weeks except Free State (= 40 weeks)

Conclusion
The results we have seen are not in isolation. Beneficial effects of micronutrients and their combinations have been seen in clinical studies conducted by other researchers as summarized in Table 7. These studies have evaluated nutrients in combination and reported beneficial effects on various outcomes including improvement in viral and immune parameters, antioxidant protection from cellular damage, slowing of disease progression, reduction of AIDS-related symptoms and improvement of birth outcomes in pregnant women. The impact of nutritional support and vitamin and micronutrient supplementation in the treatment of HIV and AIDS is a seriously under-investigated area. Repeated calls have been made for more studies in this area by international health agencies. Although micronutrients are not a cure for AIDS, in the absence of an effective cure or vaccine and in the face of the toxicity and limited efficacy of ARVs, they are a safe, effective and affordable way to halt progression towards and even reduce the symptoms of the AIDS disease and to improve the quality of life of AIDS patients. The implications of micronutrient supplementation results for public health and control of infectious and immunodeficiency disease are enormous. If properly evaluated, micronutrients have the potential of being incorporated into strategies for fighting viral pandemics on a global scale. Implementation of the above positive findings could save millions of lives.

Acknowledgement
We would like to thank Lisa Smith for help with formatting/presentation of the graphics and Anupriya Pandit for tabulating data and organizing references.