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Review

Health Promoting Properties of Vitamins C and D Against HIV Disease Progression, a Narrative Review

by
Garyfallos Markou
1,
Ellie Panoutsopoulou
1,
Evangelia Stavrakoudi
1,
Charalampos Mylonas
2,
Sofia Ioannou
2,
Maria Chini
2 and
Alexandros Tsoupras
1,*
1
Hephaestus Laboratory, School of Chemistry, Faculty of Sciences, Democritus University of Thrace, Kavala University Campus, St. Lukas, 65404 Kavala, Greece
2
Department of Internal Medicine and Infectious Diseases Unit, “Korgialenio-Benakio” Red Cross General Hospital of Athens, 11526 Athens, Greece
*
Author to whom correspondence should be addressed.
Immuno 2024, 4(4), 601-619; https://doi.org/10.3390/immuno4040035
Submission received: 3 November 2024 / Revised: 4 December 2024 / Accepted: 5 December 2024 / Published: 7 December 2024
Versions Notes

Abstract

:
Human immunodeficiency virus (HIV) has troubled humankind for many years. The rate of new HIV cases is decreasing steadily, mostly because of safer sexual practices and scientific advances in medicine. However, the number of HIV-related trials has significantly increased, as the search for a definite cure for HIV is still fruitless. Our current treatment options involve antiretroviral therapy (ART) with various drug combinations that lower the patients’ viral load in order for the immune system to reconstitute itself. This way, adherent patients achieve a life expectancy similar to the general population. Besides the established treatment protocols, the focus has currently shifted towards secondary pharmaceutical regimen programs that enhance a patient’s immune system and response to opportunistic infections. Vitamins C and D are easily obtainable even in the developing world and are known to improve an individual’s daily life, with vitamin D enhancing the human immune response and vitamin C having an assisting role in both the immune response and as an important antioxidant. Recently, many studies assessing the effect of these vitamins on the progression of HIV have been performed. We aimed to collect and review these studies in order to determine the necessity of the supplementation of these vitamins in HIV-infected patients, which might complement the existing ART. To this day, the scientific community is conflicted, and more studies must be conducted before a definite conclusion about these vitamins’ effects on HIV patients can be reached.

1. Introduction

The final stage of an HIV (human immunodeficiency virus) infection is acquired immunodeficiency syndrome (AIDS). HIV is known to gradually deplete T-helper cells (or else termed CD4+ T cells), which play an important role in our body’s adaptive immunity for combating infections. Initially, the HIV infection is either asymptomatic or resembles a common self-resolving viral infection. Then, the patient usually remains symptom-free until the immune system is affected severely enough for infections to occur. It can take years for the disease to manifest clinically, leading to AIDS and finally death [1]. As of 2023, the UNAIDS (United Nations Program on HIV and AIDS) reported that approximately 39.9 million people lived with HIV, 1.3 million people became newly infected, and around 630,000 people died from AIDS-related illnesses in that year [2]. Unfortunately, there is still no definite cure for HIV, and the search is ongoing [3].
Antiretroviral therapy (ART) is a series of medications specifically targeting the variable steps of the virus’ life cycle. The notable decrease in HIV-related deaths is mostly attributed to the usage of ART, an option not always available in the developing world, where as few as 20% of the patients are receiving treatment [4]. Unfortunately, despite regulations concerning behavioral risks and attempts to increase people’s awareness, out of approximately 39.9 million people living with HIV at the end of 2023, there was an estimate of 65% of them belonging in the WHO African Region [5].
HIV/AIDS was discovered in the United States among the male homosexual population after a series of opportunistic infections that occurred in 1981 [6]. The infectious agent was identified to be transferred primarily by intercourse, blood-related activities (like needle sharing by intravenous drug users, and through blood transfusions), or even during breastfeeding, where the afflicted mother passes the virus to the child via the produced milk [7].
Proper nutrition plays a vital role in treating illnesses and maintaining one’s health, since a constant supply of retinoids and carotenoids stimulates the production and activation of macrophages [8]. Supplements were historically introduced in ancient civilizations in the form of nutritional foods and herbal remedies, as for example by Hippokrates [9]. Eventually, the distinction between food supplements and nutraceuticals was made, and the term “nutraceuticals” was established in 1989 by the Foundation for Innovation in Medicine in New York in order to describe foods or elements of food obtained from plants or animals with significant medical or health benefits [10].
Vitamins are among the most profitable and widely used supplements, with the US supplying 35% of its population [11] with multivitamin supplements and 52% of adults with simple dietary supplements, as reported by the National Health and Nutrition Examination Study (NHANES) between 1999 and 2000.
Vitamin C (also called ascorbic acid) is a major reducing agent, participating in hydroxylation reactions. By doing so, it contributes to mitigating the effects of various oxidizing stress reactions that occur during metabolic pathways. While ascorbic acid was isolated in 1928, its structure remained a mystery until 1933 [12]. Finally, it was synthetically synthesized in 1934 [13]. Vitamin C comprises a redox cofactor and is produced by various plant and animal species. Primates, like humans, cannot produce it due to the absence of L-Gulono-γ-lactone oxidase (GULO) [14]. Based on the data gathered by the third National Health and Nutrition Examination Study (NHANES III), 10% of the included population had serious vitamin C deficiency, whereas 20% of males and 15% of females, respectively, suffered from marginal vitamin C deficiency [12].
Vitamin D is a fat-soluble vitamin. In humans, the main route of obtaining vitamin D is through dermal synthesis after ultraviolet-B radiation (UVB) from sunlight exposure. This route accounts for 90% of vitamin D replenishment, whereas the remaining 10% derives from foods naturally rich in vitamin D (such as oily fish, egg yolks, shiitake mushrooms, etc.). There are various forms of vitamin D, with cholecalciferol (vitamin D3) deriving from animals and ergocalciferol (vitamin D2) from plants. Vitamins D2 and D3 are biologically inactive, requiring further enzymatic conversion from the liver and kidneys in order to achieve their biological action. Vitamin D is essential for maintaining adequate calcium and phosphate levels in blood, regulating calcium homeostasis, bone metabolism, and the promotion of enterocyte differentiation. Severe vitamin D deficiency results in rickets in infants or children and in osteomalacia in adults. Subclinical vitamin D deficiency is highly prevalent in the general population and can be linked to reduced bone mineral density and a higher incidence of falls and fractures. Thus, vitamin D supplements are widely used in order to prevent osteoporotic fractures [15]. On the other end of the spectrum, vitamin D intoxication typically emerges after inappropriate supplementation. It cannot occur through overproduction by prolonged sunlight exposure, owing to the photo-conversion of excess pre-vitamin D3 and vitamin D3 to their inactive metabolites [16].
Besides its aforementioned roles, vitamin D also has an immunomodulatory role, affecting both the innate and adaptive immune responses. People with HIV are commonly found to be vitamin D deficient. There is evidence to support that this deficiency can result not only in an elevated risk of symptomatic pulmonary tuberculosis (TB) but also in poor HIV treatment outcomes. It must be mentioned that, from a global perspective, TB is one of the leading causes of death for people with HIV and also accounts for a third of AIDS-related deaths [17,18].
In this paper, we reviewed the results of numerous studies concerning the supplementation of vitamins C and D in HIV patients, although it should be mentioned that vitamin supplements should act in conjunction with the prescribed treatment and not replace it.

2. Methods

The bibliography was gathered through searches on Scopus, Science Direct and PubMed using each of the following keywords: (Vitamin C OR Ascorbic Acid OR Vitamin D OR calcitriol OR vitamin D3 OR deficiency OR vitaminoids OR supplements OR vitamin*) with the term AND with each one of the following keywords (HIV infection OR HIV OR AIDS OR immunodeficiency OR infection OR acute infection OR persistent infection OR chronic infection OR HIV patients OR HIV complications OR antiretrovirals OR antiviral OR antiretroviral therapy OR highly active antiretroviral therapy OR HAART OR ART OR CD4 OR transmissions OR concomitant infections OR HIV manifestations) along with using the term AND for each one of the following keywords as well (inflammation OR oxidative stress OR thrombosis OR antioxidant OR anti-inflammatory OR clinical trial OR administration OR supplementation OR cytokine OR interferon OR interleukin OR growth factor OR tumor necrosis factor OR INF OR IL OR TNF OR VEGF OR IGF).
An extensive search was made with a time frame of 2015 and after, so as to include new and upcoming results and information on the utilization of these vitamins in HIV and HIV-infected patients. By using other exclusion criteria, any duplicate articles from the above search were deleted, and also only articles in which we have full access were selected for this review. Furthermore, in order to include an article in our review, we first evaluated the titles, then the abstracts and keywords, and then the whole paper. Papers were turned down if they failed to satisfy the English language writing standard, if they were deemed not to be research articles, or if they were not within the time limit set. However, due to a research gap, especially in clinical settings and in clinical trials, the time frame of the searched articles was further extended for consulting specific articles and reviews published before 2015 with highly fitting information for the theoretical parts of this review (i.e., for the introduction and for definitions and classifications in each section), always in the case that they have not been previously thoroughly reviewed, and in order to find more information for this subject, we consulted articles and reviews. By applying this methodology, the references mentioned in the reference list were the ones finally used for this review paper.

3. HIV-AIDS

The HIV virus resides in the CD4-positive cells and proliferates by using their resources, thus placing the cells in the situation of early apoptosis due to a lack of nutrients. If not destroyed, the cells’ normal functions are affected, resulting in irregular signaling by the immune system and producing the virus’s RNA and protein components [1]. The natural history of the HIV infection can be categorized in three stages: acute infection (within 15 to 30 days after first exposure, usually resembling a mild viral-like infection, but many are asymptomatic), chronic infection (if left untreated, HIV progresses to an asymptomatic stage lasting for numerous years, even though CD4 cells are gradually depleted; as their number decreases, there is an increased chance of infections), and acquired immunodeficiency syndrome—AIDS (occurs when the CD4 cells fall below 200 cells/mm3; people with AIDS are at a higher risk of life-threatening infections and/or cancer) [3].
As for the ways of HIV transmittance, it can be contracted through an infected mother (during pregnancy, childbirth, and breastfeeding), unprotected sexual contact with an infected individual (anal secretions, semen, vaginal fluids, and blood containing the virus), shared contaminated needles, working environment (risk to healthcare workers by accidental needlestick injuries or contact with an infected individual’s bodily fluids), and medical procedures (blood transfusions and organ transplants) [3].
With a lack of a definite cure, the invention of antiretroviral medications has given infected people a shred of hope. With the introduction of ART, an HIV infection nowadays is considered a chronic condition, instead of a deadly illness [3,17]. Regardless of all the substantial advances in medicine, there is still a lack of access to such medical treatments for many infected people, especially in the developing world, leaving them to eventually develop AIDS [17].
The HIV treatment regimen, depending on the stage of infection, is specifically designed for the infected individuals [3,19]. It always involves ART, which is usually a three-drug treatment regimen aimed at preventing the replication of the virus and lessening the damage to the immune system. In AIDS patients, an important measure is the treatment of opportunistic infections [3] (one of the most prevalent of them worldwide being tuberculosis (TB) [17]). Also, chemoprophylactic therapy, depending on the patient’s CD4 count, can prevent some opportunistic infections, like toxoplasmosis and Pneumocystis jirovecii pneumonia. For patients not on ART with AIDS, symptomatic management (usual symptoms in untreated patients are fatigue, weight loss, fever, and neurological problems) and supportive care (nutritional, emotional, and psychological support) are other useful measures [3]. In treated patients, attention has focused on cardiovascular and other comorbidities [20].
In conclusion, the research for a definite cure for HIV is ongoing [3]. This lack of definite treatment leads us to rely on the use of ART in order to evade not only opportunistic infections but also the secondary transmission of the virus to other individuals. The latter is achieved by lowering the patient’s viral load, thus eliminating the possibility of them transferring the virus to others sexually [21]. However, it is essential to always pay attention to patient adherence to the antiretroviral regimen so as to maintain these effects [19].

4. Benefits of Vitamin D on HIV Patients

4.1. Benefits of Vitamin D

The term “vitamin D” was first introduced in 1922 [22], suggesting the existence of a vitamin, which promotes calcium deposition. In 1634, the word “rickets” was used for the first time [16]. Eventually, a connection between cod liver oil, sun exposure, and rickets became apparent, leading to the broad use of the term vitamin D.
Vitamin D is a fat-soluble vitamin and a collective term for vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). It can be obtained from several foods (such as cod liver oil, egg yolks, salmon, etc.), while the majority (around 90%) is acquired by dermal synthesis after UVB radiation. Cholecalciferol is sourced through animals, while ergocalciferol is sourced through plants. Vitamin D2 is obtained exclusively through consumption, since it cannot be synthesized by the body itself [16,23,24]. After UVB radiation, a cholesterol-like precursor (7-dehydrocholesterol) in cells, located in the epidermal part of the skin, is converted to pre-vitamin D. This pre-vitamin D then isomerizes into vitamin D3.
However, vitamins D2 and D3 are biologically inactive, signifying their need for extended enzymatic conversion in order to transform to their active forms. The conversion process begins in the liver, where 7-dehydrocholesterol undergoes 25-hydroxylation and transforms to 25(OH)D, also known as calcidiol, which is the main circulating form of vitamin D. It has a half-life of 2–3 weeks. Afterwards, 1-alpha-hydroxylation converts it to 1,25(OH)2D (calcitriol) in the kidneys, and it is now in its most active form, with a half-life of 4–6 h. The parathyroid hormone (PTH), along with other mediators (including hypophosphatemia and growth hormone), are the ones mediating this conversion process [16,23,24].
Each vitamin D intermediate has a specific effect on the human body’s biochemistry. A major way in which sufficient levels of calcitriol can benefit one’s health is through the inhibition of nuclear factor-κB, a transcription factor that increases the oxidative stress caused by inflammation or injury [25,26]. The factor, also known as NF-κB, also contributes to the maturation of preosteoclasts to osteoclasts, which in turn regulate calcium and phosphorus levels in the blood by resorbing bone tissue containing these minerals. Thus, a sufficient intake of these nutrients should be maintained to avoid bone demineralization [27]. It should be noted that ROS (reactive oxidative species) activate NF-κB, directly leading to the expression and replication of HIV [28]. Thus, vitamin D levels and efficacy are important in HIV patients, and several trials have been conducted to evaluate their effects during HIV infection with or without ART (Table 1).

4.2. Medicinal Action of Vitamin D on HIV Patients

In HIV-positive individuals, it is possible for both the virus itself and the antiretroviral medicines to induce hypovitaminosis D [24,43]. Severe vitamin D deficiency may be responsible for rickets in children and osteomalacia in adults, though no longer common in developed countries [16,24]. However, subclinical vitamin D deficiency is much more dominant and is affiliated with osteoporosis and elevated occurrences of falls or fractures [16]. It is significant to establish that even a slight insufficiency in vitamin D levels puts HIV-positive adults at a significant risk of osteoporosis [24]. Bone mineral density (BMD) acts as an indicator of bone health and the risk of fractures. Vitamin D supplementation is prescribed by clinicians in order to improve bone health [44]. Bone fractures are a major concern in HIV patients on ART because of their lower bone mineral density compared to the general population. Considering the effects and importance of vitamin D on bone mineralization and recovery, the infected individual can benefit from an adequate intake [45].
HIV-infected patients experience a significant amount of adverse chronic conditions such as disturbed bone health [43,46], cardiovascular diseases (CVD), and kidney disease. As mentioned, reduced BMD is a grave concern, particularly in young people. Since vitamin D is significant to the calcium and phosphorus metabolism, it can protect HIV-positive children and young adults from various health issues, and more specifically bone disorders. Nonetheless, numerous randomized clinical trials (RCTs) have been held in order to evaluate the effect of vitamin D supplementation in young HIV-positive individuals. Unfortunately, the results have been inconsistent [43].
Even though patients with HIV are known to suffer from secondary hyperparathyroidism, the results of trials for the effect of vitamin D on hyperparathyroidism in HIV-positive children and young adults have been unclear. At the moment, there is a lack of scientific evidence for vitamin D supplementation strategies for HIV-positive children and young adults [43].
Furthermore, ART and HIV-induced chronic inflammation have been suggested to contribute to vitamin D deficiency. A plethora of studies have indicated that a great percentage of the HIV-infected population is vitamin D deficient, even before starting ART. In contrast, other studies have reported a similar or higher rate of infected people not experiencing this deficit compared to non-infected individuals. It is concluded that there is not necessarily a causative relationship, but, nevertheless, HIV patients have a high risk of developing and being adversely affected by vitamin D deficiency [47]. BMI also appears to be important in 25(OH)D deficiency studies, as overweight people commonly lead sedentary lives, with insufficient sun exposure. Adipose tissue is a major reservoir of produced calcidiol in the body, and its cells possess receptors for the vitamin, which in turn partakes in the development of inflammation [29].
Multiple clinical trials have tested the effect of vitamin D3 on HIV patients’ outcomes (Table 1). Sudfeld et al. [18] ran trials on Tanzanian adults who contracted HIV and had recently started ART. It was found that, even though their serum 25(OH)D was greatly raised, the mortality rate of the HIV-infected individuals was not affected by vitamin D supplementation. However, there was an association with a decrease in the cases of sputum-positive tuberculosis, with smaller bacterial loads. TB infection is often studied along with HIV, because it stands as the main cause of death for patients infected with the virus and accounts for one third of AIDS-related deaths worldwide. Furthermore, survival rates were improved in the HIV/TB and advanced HIV disease subgroups that started ART in these disease stages. This study comes in contrast to a number of other studies on this matter, which claim that a deficiency of 25(OH)D allows the further progression of AIDS and increases the rate of death of affected individuals, suggesting that vitamin D deficiency should also be addressed, as it seems that vitamin D can contribute against HIV replication along with ART [29].
Vitamin D positively influences the function of the immune system through various paths. In brief, it participates in the regulation of inflammatory cytokines, hindering viral replication, activation of T cells, propagation of B cells, faster immune reconstitution, interferon gamma (IFN-γ)-mediated activity of macrophages, stimulation of phagolysosome fusion, regulation of the peptide cathelicidin, which aids macrophages to eliminate mycobacteria, and modulation of the adaptive immune response [18,29].
HIV-positive subjects were observed to have compromised antibacterial responses to infections such as Mycobacterium tuberculosis. Low serum 25(OH)D may worsen the patients’ immune system even further, leading to the appearance of serious opportunistic infections. To combat this, an increase in serum 25(OH)D, even a minor one, may be induced so that the monocyte intracrine vitamin D system gets stimulated [30]. It has been suggested that the aid of vitamin D to the immune system is actually based on the conversion of 25(OH)D to 1,25(OH)2D, through the CYP27B1 gene. Considering that the IFN-γ receptor is functional, the resulting 1,25(OH)2D activates the vitamin D receptor (VDR) signaling, triggering an antimicrobial response that includes the vitamin D-dependent induction of autophagy, phagolysosomal fusion, and up-regulation of the antimicrobial peptides cathelicidin and DEFB4. Thus, the monitoring of the serum concentration of the substrate is indeed vital, whereas serum calcitriol levels are presumably not as important an indicator for the antibacterial response [48,49].

4.3. Advantages of Vitamin D on HIV Patients

For this section, vitamin D will be addressed as the collective sum of both D2 and D3, with the latter being synthesized inside the human body, making it more accessible [31]. The advantages of vitamin D mainly revolve around the tissue, skin, and bone maintenance, growth, and regeneration, as well as numerous metabolic processes. Acne can also be tackled with the adequate consumption of vitamin D, since it acts as a regulating factor to the bacterially induced Th17 differentiation, which occurs because of the inflammation caused by the immune system’s reaction to Propionibacterium acnes (P. acnes) [50,51]. Furthermore, it has been repeatedly reported that the presence of calciferols reduces the development of certain skin and organ cancer types [51], by inducing apoptosis in cancer cells and repressing the expression of the anti-apoptotic proteins Bel-2 and Bel-XL, or even promoting the expression of pro-apoptotic proteins such as BAX, BAD, and BAK [52].
It has been found that a sufficient daily intake of vitamin D can decrease the risk factor of CVDs or even alleviate some of the symptoms [53,54]. Moreover, vitamin D plays a vital role in the regulation of the immune system by the binding of 1,25(OH)D (converted 25(OH)D by up-regulating VDR and CYP27B1) to VDR, leading to the modulation of monocyte and macrophage activity [53]. Another property of vitamin D, regarding the immune system, is that it can regulate the differentiation rate of immune system cells, such as monocytes, and promote the development of T cells [55]. T cell induction is modulated by dendritic cells, whose tolerogenicity can be enhanced by agents such as vitamin D receptor agonists [56]. In addition to its boosting capabilities towards the T cell system, vitamin D has been recently found responsible for enhancing the elimination process of pathogens by affecting macrophages directly alongside the presence of VDR [55]. The T cell phenotype can be modulated by the bioactive vitamin D metabolite 1,25-dihydroxyvitamin D3 and so work as another regulator in the immune system [57].
Sufficient supplementation of vitamin D has been found to increase CD4+ cell count recovery in HIV patients, regardless of which antiretroviral therapy they received; however, the increase in 25(OH)D levels between zidovudine- and efavirenz-receiving patients differed, with efavirenz patients showing a more positive correlation to the increase in CD4+ [31]. There is also tenofovir disoproxil fumarate (TDF), which is another retroviral agent administered in highly active antiretroviral therapy (HAART)-treated AIDS patients, but this compound may produce negative results if vitamin D is not received in moderation. That is because vitamin D deficiency in this instance can lead to TDF nephrotoxicity, hypertension, and hyper-lipidaemia [55,58]. Another example of CD4+ cell count recovery maintenance is with adult individuals with AIDS, specifically the ones having HAART, and an insufficiency of vitamin D decreased their recovery rate [59].
It must be noted that vitamin D decreases the general mortality rate of both symptomatic and asymptomatic HIV-infected patients by inhibiting the development of the infection, as it was found in a study on Tanzanian women, who received multivitamin supplementation. To be more precise, women in the trial that did have a low vitamin D status showed signs of severe anemia, unlike the ones who received the supplements [32].
Considering a EuroSIDA study based on the vitamin D deficiency of AIDS-affected patients that also receive ART, it was reported that the mortality rate was increased because of risk factors such as inflammation and coagulation activation, which can be partially tackled with proper nutrition and vitamin intake. To go further into detail, it has been found that vitamin D supplementation decreased the amounts of cytokine TNF-α and increased the anti-inflammatory cytokine IL-10 in patients with severe cardiovascular conditions [33].
Taking into account that platelet activating factor (PAF) and other inflammatory cytokines and chemokines like TNFα, IL-1, VEGF, etc., are involved in the progression of inflammation-related manifestations and comorbidities due to HIV infection [60,61,62], while vitamin D and its analogues have shown anti-inflammatory benefits against such thrombo-inflammatory mediators and also against their inflammatory signalling, both in vitro and in vivo in clinical studies [63], it seems that the co-administration of vitamin D along with ART, which also affects such inflammatory signalling [60,64,65,66], may provide further ani-inflammatory benefits against these pathways and HIV-related inflammatory manifestations as well. Nevertheless, this needs further study, both in vitro and in the in vivo clinical setting.

5. Benefits of Vitamin C on HIV Patients

5.1. Benefits of Vitamin C

Ascorbic acid is a lipophobic, antioxidant compound that is composed of six carbons, and its stereochemical form resembles that of glucose, and its L-isomer form is the active one [12,67]. The most important roles for which ascorbic acid is praised by the scientific community are its stimulating factor on the immune system and its antioxidant properties, while it also is a crucial cofactor for various metabolic pathways and participates essentially in the synthesis of collagen [67,68].
Humans and other primates are unable to produce ascorbic acid within their bodies because of a defect in the enzyme L-gulono-1,4-lactone oxidase (GULO) that has been altered. Scientists attempted to replicate the biosynthesis of ascorbic acid by enabling a heterologous expression of the gene for GULO with the construction of a first-generational adenoviral vector cDNA that was expressed in rodents. Nevertheless, it has been found that the overexpression of the specific gene can lead to the inhibition of cell growth. The study also reported that GULO is covalently linked to the FAD molecule [69].
The term “antioxidant” stands for compounds that prevent or block oxidation reactions, especially on unsaturated fatty acids. Oxidative stress is a situation where the human body has accumulated excessive amounts of oxygen radicals due to various metabolic processes or processes concerning the oxidation of cellular macromolecules, such as lipids, proteins, and nucleic acids, and is unable to prevent the radicals from causing oxidative damage to cells [12]. As an antioxidant compound, ascorbic acid is a reducing agent and an electron donor. It reduces oxidized molecules like metals, such as iron and copper, though this will lead to the production of more oxidant molecules, like superoxide and hydrogen peroxide. Depending on the number of lost electrons, ascorbic acid is turned into ascorbate radical or dehydroascorbic acid. Ascorbate radical is the form in which one electron is lost, and, unlike other radicals that have a very short lifespan, this radical can exist for seconds and even minutes, depending on the presence of electron acceptors, like oxygen, and catalytic metals, like iron [70,71]. Furthermore, the effectiveness of ascorbic acid lies in its ability to counteract and quench aqueous oxygen radicals and nitrogen species [12,72].
Vitamin C can be collected naturally by the consumption of citrus fruits like oranges and clementines, kiwi, broccoli, and, most importantly, peppers, which have been observed to contain 80% of the necessary daily vitamin intake [73]. It has also been reported that ascorbic acid was found in sausages [74].
Another matter to be addressed is the bio-accessibility of vitamin C in supplements, since it has been found that there are more factors to the synthesis of the supplement or natural substances that affect its absorption rate, such as secondary ingredients. Also, even if supplements contain a higher concentration of vitamin C, their bio-accessibility is less than in natural products, which is the primary argument for the consumption of supplements over actual food. Finally, vitamin C deficiency has been recorded to lead to scurvy, alongside numerous cardiovascular diseases, weakness, and fatigue [75], and sometimes even tissue damage, delayed wound healing, and various hemorrhages [76].

5.2. Medicinal Action of Vitamin C on HIV Patients

It is well established that vitamin C, or ascorbic acid, concentration should be maintained at the appropriate level to combat disease, as it is part of many enzymatic processes in the human body. As was the case with vitamin D, people living with HIV (PWH) are deficient in vitamin C compared to the healthy population, possibly due to the oxidative stress caused by the virus. Another factor leading to this might be a renal leak, meaning an abnormally increased disposal of the vitamin through urination. This occurs especially often in PWH; it is associated with ART and is also not related to nutritional habits [77,78].
It is evident that HIV and the ART used to fight it both increase oxidative stress in humans. Notably, HAART has been observed to increase blood ROS. Unfortunately, this oxidation does not seem to be affected by supplementing vitamin C. Supplementation does not correlate with better outcomes for PWH or those also suffering from TB. However, correct nutrition rich in micronutrients can generally benefit one’s health and quality of life, so it should not be omitted even with these findings in mind [79,80].
A positive effect that should be further investigated was highlighted by Merenstein et al. [73], who discovered that HAART adherence in HIV+ women was higher during periods of vitamin C use compared to periods without. What is more, vitamin C has been shown to significantly help against HIV-induced oxidative stress when used in combination with vitamin E. This combined action is due to the fact that vitamin C participates in the regeneration of vitamin E during the process of eliminating radicals [28].

5.3. Advantages of Vitamin C on HIV Patients

It has been claimed that daily consumption of the required vitamin C amounts reduces the risk of atherosclerosis [12]. Vitamin C does not only protect the cells from oxidation damage but also blocks the inhibition effects of TNF-α (tumor necrosis factor-α)-induced apoptosis of endothelial cells, which promotes the development of atherosclerosis [81].
Chronic inflammation is one of the features of long-term HIV patients, with gut breaching being one of the main sources of its chronic activation. To be more precise, microbial products infiltrate the gut epithelium and thus stimulate a continued activation of the immune system. This mechanism requires the absence of crucial Th17 cells, due to early infection or apoptosis, that regulate the activation rate along the gut epithelium. These cells do not proliferate like others, and, even with ART treatment, they do not regenerate. It is important to mention that irregularities in Type I interferon release rate are also affecting the chronic inflammation of patients, so as to provide a suitable environment to infect more cells and develop [82].
The human body tackles unwanted inflammation and increased oxidative stress by utilizing vitamin C levels in plasma, and it was found that HIV’s plasma ascorbate was reduced in HIV patients, even with an adequate consumption being provided to the subjects [72]. Obese HIV patients are also prone to developing metabolic irregularities regarding HIV infection and antiviral medicine, since the absorption of nutrients is disturbed by poor dietary choices caused by inadequate nutritional education or cultural preferences [83].
Vitamin C consumption has also been associated with the improvement of HAART to HIV-positive women. HAART adherence was improved in the group of women that received vitamin C; nevertheless, there was no link between ascorbic acid intake and the proliferation or diminishment of CD4+ T cells or the viral load [73]. A batch of clinical trials showed that micronutrient supplementation, which contained ascorbic acid, did enhance the survival rate of infected individuals, but the study does mention that the results concern Bangkok in Thailand, and more trials should be conducted under different settings [84]. Interestingly, another study based on clinical records regarding the supplementation of both vitamin C and E on HIV-infected Zambian adults showed that the reduction in lipid peroxidation was increased while there was a minor decrease in the viral load within a period of 3 months. This study aimed to point out the importance and significant contribution of multivitamin supplements, like vitamins A, E, and C, in decreasing the mortality rate of the infected [85]. It should be mentioned that it is possible for the multivitamin supplements to increase the survival rate of the infected because they enhance the daily lives of the patients, which would otherwise be challenging due to their illness.
Another counteractive property of ascorbic acid in HIV development is the inhibition of the retrovirus’s replication in a non-cytotoxic concentration. This can be attributed to vitamin C’s neutralized calcium salt preventing HIV replication in chronically infected cells by reducing extracellular RT (reverse transcriptase) [74,86]. Nevertheless, ascorbic acid’s anti-HIV effects are reversible; thus, to achieve suppression of the virus, the patient must be receiving an adequate amount of vitamin C continuously [74]. The Linus Pauling Institute reported in 1984 that numerous AIDS patients receiving high doses of vitamin C showed clinical improvement. This suggests positive clinical outcomes against chronic viral infections when co-administered [87].
Taking into account that inflammatory chemokines and cytokines like PAF, TNFα, IL-1, VEGF, etc., are involved in the development of inflammation-related manifestations and comorbidities due to HIV infection [60,61,62], and vitamin C has also shown antithrombotic and anti-inflammatory benefits against such thrombo-inflammatory mediators and also against their inflammatory signalling [88], it seems that the co-administration of vitamin C along with ART, which also affects such inflammatory signalling [60,64,65,66], may also provide both anti-inflammatory and antioxidant health-promoting effects against these pathways and the HIV-related inflammatory complications as well. Nevertheless, this also requires further study, both in vitro and in the in vivo clinical setting. Table 2 shows the clinical trials on the effects of vitamin C during HIV infection conducted to date.

5.4. Disadvantages of Vitamin C on HIV Patients

Fat-soluble vitamins (A, D, E, K, and B12) are known to be stored in the body, causing problems with excessive accumulation. Water-soluble vitamins, such as vitamin C, on the other hand, can rarely accumulate in the body, since they are secreted by the kidneys. This vitamin cannot be synthesized by humans due to the absence of GULO, whereas a number of plants and animals can [14]. As a result, the only way for humans to acquire the required daily intake of this vitamin is through the consumption of the organisms that produce it, or through supplements [69].
Vitamin C’s heat sensitivity is responsible for its decrease in nutritional value when boiling or cooking takes place. Moreover, the vitamin’s total body storage is 1500 mg, and deficiency ensues when dropped to 350 mg. For the first 8–12 weeks, the clinical symptoms are mainly fatigue, depression, mood changes, anorexia, etc. Followed by teeth loss, hyperkeratosis, hair abnormalities, and ecchymosis. The standard treatment for vitamin C deficiency is direct replacement of the vitamin, which is continued up until the symptoms have completely subsided. The complete recovery of the patient is expected within 3 months of vitamin C supplementation [23].

6. Conclusions and Future Perspectives

The present treatment for the fatal, when left untreated, disease caused by HIV is ART. However, concomitant vitamin D and C supplementation may provide additional benefits that improve patients’ health overall. The beneficial activity of vitamin D on HIV-infected individuals receiving HAART is to be highlighted. Vitamin D has shown anti-inflammatory effects, which can protect against dangerous and cancerous chronic inflammation. It is supported by evidence that HIV-positive individuals may experience hypovitaminosis D and bone health deterioration. To add to this, obese patients are bound to have an affected vitamin D status and metabolism due to the lipophilic nature of this vitamin. An insufficient diet and decreased sun exposure are of no help, since they eventually lead to a susceptibility to the development of an impaired glucose metabolism. Finally, over-supplementation can lead to intoxication, while sun overexposure raises the risk of skin cancer. Maintaining healthy habits can greatly ameliorate the disease’s impact on a patient’s health.
Moving on to vitamin C, it is the most generally used lipophobic antioxidant, with various applications for healthy, asymptomatic, and symptomatic HIV-infected individuals. The antioxidant effects of vitamin C affect mainly oxidized lipids and other oxidized metabolic products. Unlike vitamin D, vitamin C can only be obtained from external sources like foods and supplements and even from an AA (ascorbic acid)-rich diet to prevent or battle opportunistic diseases. It does not directly fight an active infection but mainly provides a fertile ground for maintaining bodily functions and recovery. There has been evidence of patients showing more promising results after receiving HAART enhancement with the presence of adequate amounts of AA. Lastly, vitamin C deficiency can lead to fatigue and mental illnesses, such as depression. The standard treatment is direct replenishment of the vitamin, and it is only ceased when all the symptoms completely subside.
In a nutshell, multivitamin supplements are considered to be beneficial for HIV-infected individuals to improve their daily lives. Most studies have aimed to emphasize the importance of conducting more trials and research on the matter in different settings, with the factors responsible for the patient adherence to ART also being considered. Furthermore, at the time of this paper being written, no evidence of HIV patients taking both vitamin supplements concurrently was available. Thus, more research with co-administration of both vitamins C and D in HIV patients for potential benefits in a clinical setting should also be considered. As a result, even more findings on a global scale will be extracted, and perhaps even more plausible evidence or innovative ways of battling this disease will be introduced.

Author Contributions

Conceptualization, A.T.; methodology, A.T.; software, all authors; validation, A.T.; investigation, all authors; writing—original draft preparation, G.M., E.P., E.S., and A.T.; writing—review and editing, A.T., C.M., S.I., and M.C.; visualization, A.T.; supervision, A.T.; project administration, A.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

The authors would like to thank the Department of Chemistry of the Democritus University of Thrace for its continuous support.

Conflicts of Interest

The authors declare no conflicts of interest.

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Table 1. Clinical trials of vitamin D in HIV patients.
Table 1. Clinical trials of vitamin D in HIV patients.
Hypothesis—InterventionStudy Design-/Parameters ExaminedMain FindingsYear of StudyRef.
Aim: assess the efficacy of vitamin D3 supplementation for pulmonary TB 1 and mortality prevention among HIV-infected adults initiating ART.Randomized, parallel-group, placebo-controlled, double-blind trial on HIV+ Tanzanian adults recently starting ART (vitamin D 50,000 IU weekly, followed by 2000 IU daily after one month of ART).
  • Their serum 25(OH)D was greatly raised.
  • The mortality rate or incidence of pulmonary TB was not affected by vitamin D3 supplementation.
  • Decrease in cases of sputum-positive tuberculosis and smaller bacterial loads.
2020[18]
Aim: 25(OH)D deficiency’s risk factors and associated outcomes.Randomized cART 2 trial, 1571 cART-naive adults in US.
  • Low 25(OH)D was associated with high BMI 3, lower viral load and increased risk of HIV progression and even death.
2014[29]
Aim: examine the possible importance of vitamin D for antibacterial responses in HIV+ patients.Total of 44 HIV-positive individuals with compromised antibacterial responses to infections received vitamin D3 supplementation (two groups: 4000 IU and 7000 IU, daily).
  • Low serum 25(OH)D may worsen their already compromised response and even further lead to the appearance of serious opportunistic infections.
  • To combat this, an increase in serum 25(OH)D, even minor, may be induced so that the monocyte intracrine vitamin D3 system gets stimulated.
2015[30]
Aim: success or failure to achieve 25(OH)D ≥ 30 ng/mL by the end of the trial.Total of 97 HIV patients (regardless of which ART they received), received vitamin D3 supplementation (5 weeks: 50,000 IU, 19 weeks: 8000 IU).
  • Sufficient supplementation of vitamin D3 → increased CD4+ cell count recovery.
  • Zidovudine and efavirenz-receiving patients → different increases in 25(OH)D levels.
  • Efavirenz-receiving patients → positive correlation with the increase in 25(OH)D levels.
  • Zidovudine-receiving patients → lower post-repletion 25(OH)D levels.
2015[31]
Vitamin D decreases the general mortality rate of symptomatic and asymptomatic HIV-infected patients.Total of 884 Tanzanian women who received multivitamin supplementation (assessment of vitD levels).
  • Women with a low vitamin D status: signs of severe anemia, unlike the ones receiving the supplements.
  • Inhibiting the infection’s development: sufficient vitamin D intake decreases general mortality rate.
2010[32]
Aim: Investigating the correlation between 25(OH)D and HIV disease progression.EuroSIDA study based on the vitamin D levels of 16,599 HIV-1-infected people.
  • Proper nutrition and vitamin intake can partially tackle the mortality rate increase.
  • Vitamin D supplementation decreased the cytokine TNF-α levels and increased the anti-inflammatory cytokine IL-10 in patients with severe cardiovascular conditions.
2011[33]
A biological mechanism exists that explains the faster HIV disease progression and increased mortality rates when blood vitamin D levels are low, and supplementation could improve T cell immunity function.Pilot, open-label, three-arm prospective phase 1 study on patients with low plasma vitamin D, 17 with HIV+ (11 on HAART and 6 treatment-naive), 11 healthy controls, received vitamin D3 supplements (200,000 IU on a single dose).
  • Plasma vitamin D levels were increased to the required range.
  • In HIV+ HAART+ patients, the expression of (MIP)-1β chemokine protein increased along with the proteins’ levels in plasma.
  • Plasma cathelicidin was enhanced.
  • Vitamin D supplementation modulates the T-cell functions associated with immunity in HIV-infected patients and may be used in addition to HAART therapy.
2015[34]
Daily vitamin D3 and phenylbutyrate supplementation could boost immune function, restore adequate nutrition, and hinder viral replication.A 16-week double-blind, placebo-controlled, randomized trial in Ethiopia, ART-naïve HIV+ patients’ viral load recording (supplementation included 5000 IU daily).
  • Supplementation safely and rapidly corrected vitD3 deficiency but failed to demonstrate positive effects on HIV viral load, T cell counts, BMI, or MUAC.
  • Administration of vitD3 + PBA daily for 16 weeks was safe and well-tolerated, and the number of clinical adverse effects was not different between the groups.
2019[35]
  • 7000 IU/d daily for 12 months can increase 25(OH)D levels in PHIV and BHIV children and young adults.
  • Supplementation could modulate HIV immune status.
Double-blind trial of 58 subjects; safety markers related to 25(OH)D immune status were assessed at baseline, 3, 6, and 12 months.
  • Daily 7000 IU vitD3 for 12 months: safe in HIV-infected subjects and effective in increasing 25(OH)D.
  • Supplementation improved some clinically important HIV immune markers in subjects on HAART.
2015[36]
Aim: evaluate the variables involved in vitamin D metabolism and risk factors associated with hypovitaminosis in HIV patients.Weekly 50,000 IU vitamin D tests of 1,25(OH)2D, PTH, total Ca, ionic Ca, glucose, urea, creatinine, osteocalcin, propeptide of procollagen type 1 (P1NP), renal function, and urine conducted on 73 patients.
  • Vitamin D levels slightly increased and small increase in T CD4+ lymphocytes.
  • Efavirenz can negatively influence vitD levels; supplementation is necessary to improve CD4+ T cells.
  • Dose of 50,000 IU of vitamin D was sufficient to normalize the vitamin deficiency.
  • Positive results on the inflammatory process, gradual increase in skeletal calcium for rheumatoid arthritis patients.
  • Supplementation can help smokers receiving reverse transcriptase inhibitors.
2021[37]
Aim: assess the prevalence of vitamin D deficiency among 101 PHIV-infected Thai adolescents receiving ART. Information regarding sunlight exposure was collected.Cross-sectional study of vitamin D levels and BMD 4, serum (25(OH)D), PTH, calcium, and BMD determination on 101 HIV-infected Thai adolescents.
  • A total of 50% of participants had vitamin D insufficiency, and 25% of them had vitamin D deficiency, but the numbers were similar to those of the healthy population.
  • No association between low vitamin D level and BMD, deficiency and BMI, bone mineral density, CD4 cell count, HIV RNA, WHO stage, EFV use, or sun exposure.
  • EFV treatment and vitD deficiency relation: CYP450 5 enzyme’s pathway interference.
2014[38]
Bone accrual could be enhanced by supplementation with vitamin D and calcium.In a 24-month randomized, placebo-controlled, multicenter clinical trial at 4 NYC hospitals, 59 participants, received daily 100,000 IU oral cholecalciferol and 1 g Ca daily or double placebo intake.
  • Baseline mean serum 25(OH)D concentrations increased.
  • A significant effect of treatment on bone mass accrual was not detected.
  • Possible failure to sustain adequate concentrations of 25(OH)D found → unclear cause.
  • There was an insignificantly larger increase in TBBMC and SBMC in participants who underwent puberty during the trial.
2012[39]
The objective was to test the safety and efficacy of two oral daily doses of D3 over 12 weeks in children and adults with HIV in Botswana.A 12-week pilot, prospective randomized double-blind 12-week pilot trial, 60 participants were aged 5 to 50.9 years, HIV infected, on first-line ART, and in a usual state of good health, 4000 or 7000 IU D3 daily, excluded were subjects with some HIV-unrelated chronic conditions.
  • Weight status improved in children and adolescents, while height status improved in those receiving 7000 IU/d after 12 weeks.
  • High-dose vitamin D supplementation is safe in the African setting.
  • Τhe 7000 IU/d may convey a growth in height advantage in children and adolescents.
  • Reduced vitamin D status in people with HIV treated with NNRTIs was documented in an African setting for the first time.
2015[40]
Aim: determine vitamin D3 supplementation’s impact on body composition, bone density, structure, and strength, and assess differences between those with PHIV or BHIV 6 infections.A 12-month randomized, placebo-controlled, double-blind study of vitamin D3 supplementation in children (7000 IU daily) and young adults, ages 5 to 24.9, with PHIV or BHIV infection.
  • Achieving and sustaining year-round 25(OH)D concentrations above 30 ng/mL may be necessary to have an optimal impact on bone density in people with HIV.
  • Supplementation did not result in changes in body composition or bone health as indicated by bone density and strength.
2016[41]
In this study, a vitD3 dose was considered unsafe if it resulted in elevated 25(OH)D > 160 ng/mL coupled with an elevated calcium (age- and sex-specific range).Double-blind trial, subjects infected with HIV were given vitamin D3 supplementation of 4000 IU/day or 7000 IU/day and evaluated for changes in vitD status and HIV indicators.
  • Daily high-dose vitD supplementation is safe, effective, and required to achieve optimal response, as indicated by serum 25(OH)D. No elevation of serum calcium concentrations or deterioration in HIV status may be caused.
  • Results from the present study are in agreement, with subjects on efavirenz having significantly lower 25(OH)D at baseline.
  • Efavirenz-receiving patients: better supplementation response; further study needed.
2014[42]
1 TB: tuberculosis, 2 cART: combination antiretroviral therapy, 3 BMI: body mass index, 4 BMD: bone mineral density, 5 CYP450: cytochromes P450, 6 PHIV: perinatally acquired HIV, and BHIV: behaviorally acquired HIV.
Table 2. Clinical trials of vitamin C in HIV patients.
Table 2. Clinical trials of vitamin C in HIV patients.
Hypothesis—InterventionStudy Design/Parameters ExaminedMain FindingsYear of StudyRef.
Aim: examine the impact of high-dose micronutrient supplementation.Randomized 48-week placebo-controlled trial, 481 HIV-infected individuals in Bangkok, CD4 cell counts 50 × 106–50 × 106/L, micronutrients (vitamin D3, vitamin C 400 mg, among others) or placebo intake.
  • The survival rate of infected individuals was indeed enhanced by micronutrient supplementation containing ascorbic acid.
  • No impact on the CD4 cell count or plasma viral load.
2003[84]
Aim: examine the significance of multivitamin supplements in decreasing the patients’ mortality rate.A 3-month randomized placebo-controlled, double-blind study of vitamin C (1000 mg daily) and E (800 IU daily) supplementation on 49 HIV+ adults.
  • The reduction in lipid peroxidation was increased.
  • There was a minor decrease in the viral load within the period of 3 months.
  • It is possible for the multivitamin supplements to increase the survival rate of the infected, since the patients’ daily lives are enhanced.
1995–1996[28]
Micronutrient status could be a determining factor in the advance of HIV disease.Total of 1078 pregnant women with HIV, double-blind, placebo-controlled trial in Tanzania, daily supplementation of vitamin A, multivitamins containing B, C (500 mg daily), and E, or both.
  • The progression of HIV disease in women receiving supplements was delayed, and the relative risk of death was reduced.
  • CD4+ and CD8+ cell counts were higher, and viral loads significantly lower.
  • Vitamin A: ineffective against HIV disease symptoms, reduced the multivitamin’s benefit.
  • Vitamin B, C, and E supplements, excluding vitamin A, may be used as an inexpensive treatment to delay the introduction of ART in pregnant women.
2003[89]
Aim: investigate the effects of vitamin A, multivitamins, or both supplementation on T cell counts and birth outcomes. Total of 1075 participants; randomized, double-blind, placebo-controlled trial with a 2 × 2 factorial design, HIV-1-infected women at 12–27 weeks’ gestation (supplementation included 500 mg vitamin C daily).
  • The rates of low birthweight, severe preterm birth, and small size for gestational age were decreased significantly.
  • CD4, CD8, and CD3 counts significantly increased.
  • Vitamin A had no notable effect.
  • Multivitamin supplementation provides a low-cost approach for substantially decreasing adverse pregnancy outcomes among HIV-infected women.
1998[90]
Poor micronutrient status in pregnant women could be associated with HIV-1 transmission through breastfeeding.Tanzanian HIV-infected pregnant women, 20 weeks gestation, during lactation, vitamin A or multivitamins without A supplementation (supplementation included 500 mg vitamin C daily).
  • Multivitamin (B, C, and E) supplementation of breastfeeding mothers reduced child mortality and HIV-1 transmission through breastfeeding among immunologically and nutritionally compromised women.
  • Vitamins B, C, and E supplementation to lactating, nutritionally compromised women could be beneficial; vitamin A should not be considered.
2002[91]
Indinavir was given for 2 days, plus a 7-day washout period and 7 days vitC supplementation. After 6 days of vitC, indinavir was resumed to measure its pharmacokinetics.Prospective, open-label, longitudinal, two-period time series on 7 healthy volunteers (supplementation included 1000 mg vitamin C daily). High doses of vitamin C apparently reduced steady-state indinavir plasma concentrations and can lead to subtherapeutic concentrations of antiretroviral medication, causing viral resistance and treatment regimen failure.2005[92]
Aim: to identify the modulatory roles of vitamin A and C supplementation on oxidative stress associated with HIV mono-infection and HIV-TB co-infection.Total of 90 adult patients with HIV and HIV-TB co-infection from Lagos, Groups A and C: vitamin supplementation (2600 mg of vitamin C). Determined the following: antioxidant enzyme activity, lipid peroxidation, catalase, SOD, MDA, and GSH 1.
  • HIV mono-infected subjects with no supplementation: significantly higher level of CAT.
  • Post-supplementation group: the oxidative stress indices were significantly lower.
  • HIV-TB co-infected subjects without supplementation: significantly higher levels of GSH and SOD.
  • HIV-infected group: showed factors suggesting anemia.
  • HIV-infected subjects at baseline: elevated mean total protein, AST, and ALT levels and a lower level of creatinine—possibility of hepatotoxicity.
2017[79]
1 SOD: superoxide dismutase, MDA: malondialdehyde, GSH: reduced glutathione.
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Markou, G.; Panoutsopoulou, E.; Stavrakoudi, E.; Mylonas, C.; Ioannou, S.; Chini, M.; Tsoupras, A. Health Promoting Properties of Vitamins C and D Against HIV Disease Progression, a Narrative Review. Immuno 2024, 4, 601-619. https://doi.org/10.3390/immuno4040035

AMA Style

Markou G, Panoutsopoulou E, Stavrakoudi E, Mylonas C, Ioannou S, Chini M, Tsoupras A. Health Promoting Properties of Vitamins C and D Against HIV Disease Progression, a Narrative Review. Immuno. 2024; 4(4):601-619. https://doi.org/10.3390/immuno4040035

Chicago/Turabian Style

Markou, Garyfallos, Ellie Panoutsopoulou, Evangelia Stavrakoudi, Charalampos Mylonas, Sofia Ioannou, Maria Chini, and Alexandros Tsoupras. 2024. "Health Promoting Properties of Vitamins C and D Against HIV Disease Progression, a Narrative Review" Immuno 4, no. 4: 601-619. https://doi.org/10.3390/immuno4040035

APA Style

Markou, G., Panoutsopoulou, E., Stavrakoudi, E., Mylonas, C., Ioannou, S., Chini, M., & Tsoupras, A. (2024). Health Promoting Properties of Vitamins C and D Against HIV Disease Progression, a Narrative Review. Immuno, 4(4), 601-619. https://doi.org/10.3390/immuno4040035

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