Reactive oxygen species (ROS) are highly reactive byproducts of cellular respiration. As second messengers, they play an important role in cell signaling and in gene regulation (e.g., cytokine, growth factor, and hormone action and secretion; ion transport; transcription; neuromodulation; and apoptosis) [1
]. ROS are also important for the normal function of the immune system; T cells both are influenced by and influence intracellular ROS levels. In particular, ROS play a positive role in the proliferation of T cells and immunological defence [1
A variety of reactive oxygen species are produced throughout the body. One particular species of interest, superoxide (
), is generated in two ways and for different reasons [5
]: (1) as an accidental result of incomplete electron transfers in the electron transport chain and (2) in activated white blood cells with the purpose of destroying pathogens. Moreover, upon production, these
molecules are rapidly metabolized into hydrogen peroxide (H2
), a mild oxidant, which further helps to destroy some pathogens. Intermediate concentrations of H2
(and certain other ROS) result in the activation of nuclear factor κ
B), a transcription factor that upregulates several cellular processes, including cell proliferation and apoptosis [1
Despite their positive role, reactive oxygen species can be harmful. At normal ROS concentrations, cell function and structure are protected from destructive interactions with ROS by various defence mechanisms. These include the use of both enzymatic and nonenzymatic antioxidants, substances that significantly delay or prevent the oxidation of a given substrate. Non-enzymatic antioxidants obtained directly from the diet (i.e., glutathione, vitamins A, C and E, and flavenoids) decrease oxygen concentrations, remove catalytic metal ions and eliminate radicals from the system [8
]. Enzymatic antioxidants remove ROS from the system and are not consumed by the reaction. These enzymes, such as superoxide dismutases, catalase and glutathione peroxide, are naturally produced by the body [9
]; oral supplements and injections are also available [9
]. In addition, antioxidants repair oxidative damage, eliminate damaged molecules and prevent mutations from occurring [8
In the event that intracellular ROS levels increase moderately, cells respond by boosting antioxidant levels and by promoting proinflammatory gene expression [10
]. There are two main functions of the resulting translated proteins: (1) signaling proteins activate the immune system by various cytokines, growth factors and chemokines, and (2) enzymes improve a cell's response to inflammatory, growth-stimulatory and apoptotic signals [11
]. When ROS levels exceed a cell's antioxidant capacity, oxidative stress is reached; this has the potential to cause significant damage to DNA, proteins and lipids, and can induce apoptosis. In addition, conditions favourable for the pathogenesis of several diseases may be created [1
]. Such high levels of ROS are generally the result of chronic and acute inflammatory diseases or environmental stress [10
Individuals infected by the human immunodeficiency virus (HIV) exhibit heightened serum concentrations of ROS [6
] and lowered antioxidant concentrations [14
]. The resulting oxidative stress affects disease progression in several ways. First, oxidative damage to CD4+
T cells may impair the immune system's response to HIV [15
]. Second, the well-known hallmark of HIV, the depletion of CD4+
T cell concentration in the plasma, is further exacerbated by oxidative stress-induced apoptosis. Third, increased HIV transcription leading to faster disease progression results from an increased activation of NF-κ
]. It has been found that while NF-κ
B activation is not absolutely necessary for viral replication, it accelerates the process 20-fold [15
]. Moreover, it has been suggested that NF-κ
B is itself activated by HIV [16
]. It has been shown that this activation of NF-κ
B is inhibited by antioxidants (such as N-acetyl cysteine and pyrrolidine dithiocarbarnate) [7
The lowered antioxidant concentrations observed in HIV-positive individuals are associated with micronutrient deficiencies [14
] which are themselves caused by a combination of decreased nutrient intake, gastrointestinal malabsorption, increased nutritional requirements, and psychosocial factors [18
]. Observational studies and intervention trials of nutritional shortfalls in HIV-positive individuals not receiving HAART reveal that low serum concentrations of micronutrients such as thiamine, selenium, zinc, and vitamins A, B-3, B-6, B-12, C, D, and E have been independently linked to a weakened immune system and a higher risk of the following: vertical transmission [20
], faster disease progression [21
], low CD4+
T cell counts, HIV-related diseases, and mortality [22
]. Intervention trials have shown that such individuals can benefit from micronutrient supplementation [22
]. Among their other benefits, certain micronutrients have antioxidant properties: carotenoids and vitamins A, C, and E [5
]. Since elevated ROS levels have been linked to more rapid HIV progression [13
], antioxidant supplementation has been suggested [6
] and studied [22
] as a potential complement to HIV therapy.
Despite many indications that antioxidant supplementation is beneficial in HIV-positive individuals [22
], it has been suggested that antioxidant supplementation may not be universally recommended [22
]. For example, although reduced mortality has been shown in HIV-positive children receiving vitamin A supplementation [30
], the administration of vitamin A supplements to women has been implicated in increased vaginal viral shedding (no effect on risk was observed from vitamins B, C, and E) [31
], a heightened risk of mother-to-child HIV transmission [32
], and hastened progression of child mortality [30
]. In addition, high doses of vitamin C supplementation have been shown to reduce the bioavailability of the protease inhibitor, indinavir [33
]. These findings, among others, undoubtedly necessitate concern, and have led authors to question the benefits of universal vitamin A supplementation for women in HIV-endemic areas [30
]. Despite these concerns, Fawzi et al.
] maintain that prenatal supplementation of vitamins B, C, and E should be continued due to their many reported positive effects on maternal and fetal health.
In short, studies have shown a range of potential implications of antioxidant supplementation. Some have found reasons for concern, others have shown negligible effects, and still others have been positive about the potential of antioxidant supplementation as a therapy or supplemental therapy for HIV-infected individuals. Despite this range of opinions, the 2007 review by Drain et al.
] maintains that supplementation in individuals not receiving HAART is clearly beneficial; however, there are not sufficient data to indicate whether the same can be said for individuals receiving HAART.
Injection drug users form a particular group of interest due to the endemic nature of HIV infection in this population. According to the WHO, the global population of injection drug users (IDUs) consists of approximately 15.9 million people, of which 3 million are HIV-positive. The spread of the virus is particularly rampant in populations where injecting equipment is re-used and shared. Of the new HIV infections, one in ten are caused by the use of injection drugs. In Eastern Europe and Central Asia, drug use can be attributed to 80% of all HIV infections [34
]. Thus, for the potential eradication of HIV, it is critical that this population, among others, be targeted. Furthermore, oxidative stress has been implicated as a factor in faster disease progression in HIV-positive IDUs. Lower serum concentrations of vitamin A, compared with HIV-negative IDUs, have also been observed [35
A particular clinical study conducted by Jaruga et al.
] demonstrated a clear benefit for antioxidant therapy in IDUs when compared with the appropriate control group. In this study, samples were collected from a control group of 10 healthy volunteers, a group of 15 HIV-negative injection drug users (denoted HIV(-)) and a group of 30 asymptomatic HIV-positive injection drug users (denoted HIV(+)). The latter HIV-positive group was divided into two subgroups: one subgroup of 15 patients received a placebo (HIV(+)P), while the other received a daily supplement of 5000 units of vitamin A, 100 units of vitamin E and 50 mg of vitamin C (HIV(+)V). After six consecutive months of treatment, it was found that patients in groups HIV(-) and HIV(+)P had significantly lower blood plasma concentrations of vitamins A, C and E than the control group, while individuals in the HIV(+)V group had levels characteristic of the control group. In addition, while there was a lack of statistical significance, the CD4+ T cell count for HIV(+)V individuals was 100 cells/μ
L higher than for those receiving a placebo. In conclusion, the authors of the study reaffirm that the combination of infection with HIV and lifestyle factors typical of injection drug users (for example, a diet which is not rich in antioxidants) may lead to oxidative stress, a potential factor in AIDS development.
In the sections which follow, a mathematical model is developed to investigate the use of antioxidants as a treatment strategy for HIV. We use clinical data from Jaruga et al.
] to estimate parameter values for both control and HIV(+) cases, and then test in detail the results of varying the level of antioxidant supplementation in the HIV(+)V group, largely through numerical bifurcation analysis. We also include an analysis of the sensitivity of our predictions to both parameter estimates and interpatient variability.
Despite the benefits that can be obtained from antioxidant supplementation, we maintain that the need for accessible and affordable antiretrovirals in developing countries is of utmost importance and must not be neglected.