HIV and Malnutrition: Effects on Immune System

KEY POINTS

Nutrition and Immunity: You Are What You Eat
Necropsy studies on malnourished patients have also shown profound depletion of the thymolymphatic system and severe depression of cell-mediated immunity. It has been proved that good nutrition increases resistance to infection and disease, improves energy, and thus makes a person stronger and more productive. Clin Sci Lond ; Leptin regulation of the immune response and the immunodeficiency of malnutrition. Micronutrients and HIV-1 disease progression. Of the micronutrients, zinc; selenium; iron; copper; vitamins A, C, E, and B-6; and folic acid have important influences on immune responses. Children with acrodermatitis enteropathica, a congenital defect of zinc absorption, have thymic atrophy, lymphopenia, reduced lymphocyte response to mitogens, reduced DTH, and reduced immunoglobulin responses

Trends in Immunology

Journal of Immunology Research

Examples of micronutrients are vitamins, and minerals such as calcium, iron, zinc, copper, selenium, and iodine. Assessment of nutritional status is a complex subject beyond the scope of this article, but it can be divided into three elements: As malnutrition has such a profound effect on functional performance, many nutritionists would also add that assessment of function such as muscle strength, cognitive ability, quality of life should be included.

Separate syndromes of severe malnutrition are recognized: Severe malnutrition is a result of two dominant processes: In both of these situations, peripheral oedema may supervene but its pathogenesis is not understood and it is not clear if the presence of oedema has any implications for host defence.

This is a serious problem in the literature. There is a very large body of literature that attempts to define immunological dysfunction in malnourished patients, which we will deal with here, though probably the best evidence comes from intervention studies see below.

Studies reporting the findings in cohorts of children with severe malnutrition are difficult to integrate, as the studied groups are often incompletely described and when described well, clearly far from homogenous. There are difficulties in the definition of malnutrition, the identification of cause, and the comprehensive description of concurrent infections, which are often hidden yet are critical confounders. With more complex testing procedures, problems also exist with the definition of normal ranges for age-matched and infection-matched controls.

Future studies will need to describe very carefully the groups studied with particular attention to infectious diseases, and have control data clearly identified to reduce bias and aid interpretation. Our work in Lusaka addresses children and adults with malnutrition, HIV, and a broad spectrum of infectious diseases and gastrointestinal pathologies. In one recent study, we were not able to confidently identify a single case of primary malnutrition in a cohort of 84 severely malnourished children, as all had presented with history of either lengthy diarrhoeal disease, or pulmonary disease or were found to be HIV infected.

The most compelling evidence that malnutrition is associated with immunodeficiency comes from the descriptions of the infections in severe malnutrition.

However, it must be remembered that infections are as much a cause of malnutrition as a consequence, and errors can be made ascribing cause and effect. Infection itself is known to have a negative effect on immunocompetence. Regarding infections in the severely malnourished, two additional facts must be considered. First, infection plays a very major role in the clinical presentation of severe malnutrition. Second, infection is often silent, as the febrile response to infection is often inadequate.

Many authors have aimed to study primary malnutrition, yet this is difficult. However, T-lymphocyte populations were normal and lymphocyte proliferation in response to phytohaemagglutinin and concanavalin A was if anything increased These findings and others listed below leave us with considerable uncertainty as to whether it is the malnutrition per se that leads to the immune defects we describe, and in later sections we ask whether nutritional treatment can restore immune function.

Before examining the impact of malnutrition on elements of the immune system, it is important to first recognize that susceptibility to infection and associated mortality depends on other host factors also. Various aspects of barrier function become deranged in malnutrition, for example gastric acid secretion is reduced, leading to increased susceptibility to intestinal infection There is agreement that malnutrition worsens prognosis in AIDS patients 15 , and in Lusaka we have confirmed that low body mass index is an independent predictor of death in the short term in patients with AIDS-related diarrhoea Macronutrient support can improve survival in severely malnourished AIDS patients However, it is not clear if this is an effect on immunological function.

Substantiation of malnutrition-related immunodeficiency is assembled from three distinct evidence bases. Selected evidence, from studies of malnourished human subjects, for and against a malnutrition-associated immunodeficiency is presented in Table 1. Where possible, data have been collected from longitudinal nutrition intervention studies. Where this has not been possible, observational studies have been cited.

The data represent well the breadth and depth of published findings, though the list of citations is not comprehensive. It is clear that there is much circumstantial evidence in support of malnutrition-associated immunodeficiency, but some evidence against it, and much uncertainty regarding cause and effect. Given the maelstrom of immune defects, it is tempting to consider these many elements of immune dysfunction as evidence of dysregulation rather than immunodeficiency; however, the disturbed processes remain to be uncovered.

In addition, against classical immune dysregulation, there is no evidence of allergic disease in the severely malnourished and rarely is there a suggestion of autoimmune pathology.

Early data from our work in Lusaka suggest that DC function, which has not previously been addressed, may also be important, and may underlie some of the dysregulation described above. One child, a girl aged 20 months presented with a 3-month history of diarrhoea and a 5-day history of sores in the mouth, fever and cough. She was emaciated, and had pedal oedema.

She made a rapid recovery from her malnutrition and her diarrhoea ceased during her admission. Laboratory examination of her DCs on admission and then on recovery Figure 1 identified a low DC count initially, which had risen at the time of her discharge.

In concert with this finding was the discovery that she had an unusual phenotype to her cultured DC population. Evidence of depletion of dendritic cell DC number s and dysfunction of DCs in the child whose case is described in the text. DCs have little or no staining for these markers.

C and D histograms of cultured DCs at rest blue shading and after stimulation with lipopolysaccharide open histogram delineated by black line which is expected to stimulate DCs; isotype control is shown as green histogram.

Standard nutritional rehabilitation for severe malnutrition now begins with blind antibiotic therapy, though in the past this was not routine. We have selected studies in which primary malnutrition was treated with nutritional therapy alone, though in many studies we cannot be certain that antibiotics were not given. Studies confirm that the initial finding of thymolymphatic atrophy resolves with renutrition 53 , and in parallel, T-lymphocyte function as examined by cell proliferation and the tuberculin test improves 28 , 45 , Clinical trials of nutritional rehabilitation and immune function are few.

Although there are many trials of nutrition interventions and their effect on infectious disease, trials that show a successful improvement in nutritional status and a subsequent effect on measures of immunological function are very few.

In one of the studies in anorexia nervosa referred to above, nutritional rehabilitation returned the increased mitogen responsiveness towards normal Cytokine perturbations also returned to normal after re-feeding 13 , but in both of these instances it is not possible to dissect out the influence of macro- and micronutrients.

In a trial in which Kenyan school children were randomized to several different food supplementation foods meat-based, milk-based, vegetable oil-based or none , antibody titres to Helicobacter pylori , rotavirus, tetanus toxoid and malaria merozoite surface proteins showed very little change The effect of nutritional therapy on malaria has been unclear ever since the Murray team found in the s that undernutrition protected against morbidity and mortality This unexpected finding was borne out by studies in protein-deprived animals.

Subsequent work has not really supported this contention, and a recent WHO analysis has, characteristically, attempted to quantify the proportion of malaria attributable to malnutrition This more comfortable reading suggests that micronutrient deficiency plays a more significant role in immunity to malaria than macronutrient deficiency.

It is well established that survival in AIDS is determined to a considerable degree by nutritional status both macronutrient and micronutrient , and if this is through an effect on immune function one would expect to see improvements in CD4 count if weight gain can be achieved.

Despite a careful search of several databases, no evidence for an effect of treatment using macronutrients on immune function in AIDS could be found see also Macallan For example, parenteral nutrition improved nutritional status body composition compared to controls, but no assessment was made of immune function There is no evidence that lipid supplementation is of benefit 56 , If there is a relationship between body composition and immune function, it might be mediated by leptin Leptin, produced by adipose tissue, acts as a satiety signal: The leptin receptor has structural similarities to the IL-6 family of cytokines and leptin signalling is inhibited by SOCS-3 that regulates other cytokines.

Macrophages from leptin-deficient mice are constitutionally activated and over-react in response to LPS, but their killing of Escherichia coli is impaired.

Leptin-deficient mice also have lymphopenia and impaired delayed-type hypersensitivity DTH. However, this has not been shown in humans, and the link between macronutrient depletion and the immune dysfunction remains tentative. It has been clear that vitamin A has important anti-infective properties since when it was shown that it reduced case fatality from measles.

Large studies in Ghana, Indonesia and elsewhere have confirmed that vitamin A has important effects in reducing adverse outcome from infectious disease in underdeveloped countries, particularly diarrhoea and measles There are also two relevant clinical trials of the effect of vitamin A supplementation on malaria.

Vitamin A supplementation may reduce placental infection However, the outstanding question is: In laboratory animals, vitamin A polarizes the immune response towards Th2 64 , 65 , acting through retinoic acid, its principal oxidative metabolite.

Retinoic acid also boosts the antitetanus antibody response However, evidence of an immune booster effect in humans is much less clear. This evidence has recently been thoroughly reviewed To summarize this evidence 67 , there is evidence that intestinal epithelial integrity is improved by vitamin A 68 , but not of improved antimicrobial properties in breast milk, and no evidence of improved barrier function in the vagina.

There is some evidence of a beneficial effect in raising CD4 counts in HIV-infected children but not in adults. Neither is there conclusive evidence of effects on cytokine production or lymphocyte function, but antibody responses to tetanus toxoid may be enhanced if the vitamin A is given before the vaccine When contrasted with the highly significant effects of vitamin A in reducing childhood morbidity and mortality, particularly from measles and diarrhoea, the very uncertain evidence of effects on immune competence is striking.

It seems likely on the basis of current evidence that epithelial or barrier integrity is an important part of the effect of vitamin A. Furthermore, addition of a vitamin A supplement to a supplement of vitamins B, C, and E given to HIV-infected pregnant women detracted from the benefit attributable to the supplement 69 so the effects of vitamin A, even if mediated by augmented cell-mediated immunity, are complex and can be disadvantageous.

There is abundant clinical evidence that zinc is a critically important nutrient for the proper functioning of the immune system. Zinc is effective in prevention of diarrhoea: Similar benefits were also found for pneumonia and malaria, though fewer trials are available for analysis.

Thus, it appears that zinc supplementation is clinically effective in reducing morbidity and mortality due to diarrhoeal disease and malaria in children. But is this an effect on immunity or host defence or something else? There are two lines of evidence that suggest that zinc deficiency adversely affects immune function and that supplementation improves it.

First, in humans there are data from the s which, though not conclusive, support this contention. Children with acrodermatitis enteropathica, a congenital defect of zinc absorption, have thymic atrophy, lymphopenia, reduced lymphocyte response to mitogens, reduced DTH, and reduced immunoglobulin responses Many other reports of immune defects in zinc-deficient patients are difficult to interpret because of comorbid processes e.

In terms of innate immunity, Paneth cells, which synthesize antimicrobial molecules for innate defence of the small intestine in humans, are also dependent on zinc 76 , Challenging zinc-deficient animals with low doses of Trypanosoma cruzi or intestinal nematodes resulted in death The deficiency state was associated with reduced numbers of lymphocytes due to impaired lymphopoiesis, but the production of antibody by each cell was not impaired.

Furthermore, while zinc deficiency had marked effects on lymphoid cells, there was no effect on myeloid cells, and this lead Fraker et al.

This is that maintenance of lymphocyte populations is very expensive in terms of zinc and other nutrients, and that in the face of nutritional stress innate defence is maintained at the expense of adaptive immune responses.

The Fraker theory is very attractive and deserves much further work. If true, the ramifications for management of infectious disease in malnourished patients could be considerable. However, there is evidence that NK cell function and phagocytosis by macrophages are also impaired in zinc deficiency, and this may be a consequence of reduced oxidative burst capacity, for example in trypanosomiasis Zinc supplementation of mice during Plasmodium berghei infection reduced markers of oxidative stress 81 , but the significance of this is not clear.

Early data suggest that zinc is important for maintenance of antimicrobial peptide delivery in the small intestine 77 , The most definitive evidence that zinc deficiency is critical for immune function in humans comes from experimental zinc deficiency induced by dietary restriction in human volunteers NK cell activity was also reduced in the volunteers on a zinc-deficient diet.

In studies in iron-deficient humans, iron deficiency has been associated with defects in both adaptive and innate immunity, and these are reversible with iron therapy Adaptive immune defects include reduced T-cell numbers, reduced T-cell proliferation, reduced IL-2 production by T cells, reduced MIF production by macrophages, and reduced tuberculin skin reactivity.

Innate immune defects include reduced neutrophil killing, probably due to reduced myeloperoxidase activity and impaired NK cell activity. Email alerts New issue alert. Receive exclusive offers and updates from Oxford Academic. More on this topic Direct evidence that primary acquired cell-mediated immunity is less resistant than is primary thymus-dependent humoral immunity to the depressive influence of wasting protein-energy malnutrition in weanling mice.

Relevance of pre- and postnatal nutrition to development and interplay between the microbiota and metabolic and immune systems. Energy, evolution, and human diseases: Related articles in Google Scholar. Antigen host response differences between the animal-type strain and human-clinical Pythium insidiosum isolates used for serological diagnosis in Thailand. Persistence of varicella-zoster virus cell-mediated immunity after the administration of a second dose of live herpes zoster vaccine.

Citing articles via Google Scholar. Though HIV-specific humoral immune responses can be detected during primary infection, they mostly comprise low-avidity env specific IgG antibodies with little or no neutralising activity [ 12 ]. Significant neutralising titers are believed to take place after chronicity has set in.

HIV evolves various strategies to establish chronicity in human body. Initial CTL responses cause downregulation of viremia and prevent disease progression, but later it induces the selection of virus mutants capable of escaping the immune response [ 14 ]. Immune activation in HIV is supported by an experiment by Pandrea et al.

High T-cell turnover in chronic HIV infection is attributed to overlapping and nonsynchronized bursts of proliferation, differentiation, and death in response to T-cell receptor- TCR- mediated stimulation and inflammation [ 16 , 17 ].

Antiretroviral therapy ART results in a marked reduction of T-cell activation and apoptosis and helps to decrease naive T-cell consumption and restore their numbers [ 18 ].

Chronic HIV infection also causes immunological or direct virotoxic effects on gastrointestinal tract which shows blunted villi, crypt hyperplasia, and damaged epithelial barrier with increased permeability and malabsorption of bile acid and vitamin B12, microbial translocation, and enterocyte apoptosis. There is a decrease of luminal defensins and massive CD4 T-cell depletion but high concentration of infected CD4 T cells [ 19 ]. Malnutrition is considered to be the most common cause of immunodeficiency worldwide [ 20 ].

Malnutrition, immune system, and infectious diseases are interlocked in a complex negative cascade [ 1 ]. Malnutrition elicits dysfunctions in the immune system and promotes increased vulnerability of the host to infections [ 21 ]. Every type of immunological deficiency induced by malnutrition can be included under the NAIDS umbrella. Protein-energy malnutrition PEM , now known as protein-energy undernutrition, is an energy deficit due to chronic deficiency of all macronutrients [ 22 ].

In children, PEM causes widespread atrophy of lymphoid tissues, particularly T-lymphocyte areas. The thymus involutes causing a reduction in the thymus-derived lymphocyte growth and maturation factors, arrest of lymphocyte development, reduced numbers of circulating mature CD4 helper cells, and impairment of antibody production to T-dependent antigens.

Imbalance in Th1-Th2 activation occurs depending on nature of stimuli and altered regulatory pathways, including responses mediated by the nuclear factor-kB NF-kB [ 23 ], a major transcription factor involved in the development of innate and adaptive immunity. However, CD8 suppressor cells are relatively preserved.

The lymphocytes not only get reduced in blood, but also impaired show T-lymphocyte mitogenesis and diminished activity in response to mitogens [ 24 ]. According to Chandra [ 25 ], in children with PEM, there is a decrease or reversal of the T-helper-suppressor cell ratio and total numbers of T-lymphocytes decrease due to reduced numbers of these T-cell subpopulations.

In malnourished children, changes such as dermal anergy, loss of delayed dermal hypersensitivity DDH reactions, and loss of the ability of killer lymphocytes to recognize and destroy foreign tissues were noted [ 20 ]. Necropsy studies on malnourished patients have also shown profound depletion of the thymolymphatic system and severe depression of cell-mediated immunity.

Chronic thymic atrophy with peripheral lymphoid tissue wasting along with depletion of paracortical cells and loss of germinal centres was noted. This was suggested to have led to various types of infections from which these patients actually died [ 26 ].

B-lymphocyte numbers and functions generally appear to be maintained though immunoglobulin concentrations get reduced including secretory IgA sIgA , which is responsible for mucosal immunity.

This may be due to increased bacterial adherence to nasopharyngeal and buccal epithelial cells or altered expression of membrane glycoprotein receptors [ 27 ]. It has been speculated that the existing antibody production is conserved or even increased during generalized malnutrition but new primary antibody responses to T-cell-dependent antigens and antibody affinity are impaired [ 20 ].

The failure of antibody formation is reversed within a few days of protein therapy as amino acids become available for the synthesis of immune proteins [ 28 ]. It also reduces complement formation, and interferon and lower interleukin 2 receptors [ 26 ]. In patients with severe generalized malnutrition, functional status of the immune system should be assessed by simply looking at the tonsils in young children.

In adequately nourished children they are usually huge but are virtually undetectable in children with severe PEM. Deficiencies of other nutrients also adversely affect the immune mechanisms. Deficiencies of essential amino acids can depress the synthesis of proteins responsible for production of cytokines released by lymphocytes, macrophages, and other body cells, complement proteins, kinins, clotting factors, and tissue enzymes activated during acute phase responses [ 24 ].

Arginine deficiency diminishes the production of nitric oxide, and hence, the antioxidants, allowing damaging effects of free oxygen radicals [ 24 ]. Arginine has also been shown to enhance phagocytes of alveolar macrophages, depress T suppressor cells, and stimulate T helper cells [ 29 ]. Particularly the omega-3 fatty acids, serve as the key precursors for the production of eicosanoids like prostaglandins, prostacyclins, thromboxanes, and leukotrines that play a variety of host defensive roles.

Thus their deficiency in the diet can impair cytokine synthesis [ 30 ]. Vitamin A has an important role in nucleic acid synthesis, and its deficiency is also characterized by lymphoid tissue atrophy, depressed cellular immunity, impaired IgG responses to protein antigens, and pathologic alterations of mucosal surfaces. Experimental animals with vitamin A deficiency have decreased thymus and spleen sizes, reduced natural killer cell, macrophage and lymphocyte activity, lower production of interferon, and weak response to stimulation by mitogens [ 31 ].

B-group vitamins like thiamin, riboflavin, pantothenic acid, biotin, folic acid, and cobalamin can influence humoral immunity by diminishing antibody production. Pyridoxine deficiency has also been associated with reduced cell-mediated immunity.

Folic acid and vitamin B are essential to cellular replication. Experimental deficiencies of these vitamins were shown to interfere with both replication of stimulated leukocytes and antibody formation. In anemia due to folic acid deficiency, cell-mediated immunity is depressed [ 32 ]. In vitamin C deficiency, phagocytic cells cannot produce tubulin, therefore, with impaired chemotaxis, microorganisms cannot be engulfed and destroyed [ 33 ].

Vitamin D acts as an immunoregulatory and a lymphocyte differentiation hormone [ 34 ]. In vitamin E deficiency, leukocyte especially lymphocyte killing power gets reduced. In animals it was shown to interfere with antibody formation, plaque-forming cells, and other aspects of cell-mediated immunity. At higher than recommended levels, it has been shown to enhance immune response and resistance to disease [ 35 ]. Zinc is also the fundamental component of thymic hormones and shares a similar role as vitamin A in nucleic acid synthesis.

Zinc deficiency influences both lymphocyte and phagocyte cell functions and affects more than metalloenzymes that are zinc dependent [ 36 ]. During infections, reticuloendothelial cells sequester iron from the blood and phagocytes release lactoferrin with a higher iron binding capacity than bacterial siderophores.

HIV and Malnutrition: Effects on Immune System