The Role of Thiamine in HIV Infection

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International Journal of Infectious Diseases 17 (2013) e221–e227

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International Journal of Infectious Diseases

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Review

The role of thiamine in HIV infection

´ ˜

Khanh vinh quoˆc Lu’o’ng *, Lan Thi Hoa`ng Nguyeˆn

Vietnamese American Medical Research Foundation, 14971 Brookhurst St., Westminster, CA 92683, USA

A R T I C L E I N F O S U M M A R Y

Article history: Patients infected with HIV have a high prevalence of thiamine deﬁciency. Genetic studies have provided

Received 5 November 2012

the opportunity to determine which proteins link thiamine to HIV pathology, i.e., renin–angiotensin

Received in revised form 21 November 2012

system, poly(ADP-ribosyl) polymerase 1, Sp1 promoter gene, transcription factor p53, apoptotic factor

Accepted 24 November 2012

caspase 3, and glycogen synthetase kinase 3b. Thiamine also affects HIV through non-genomic factors,

Corresponding Editor: Eskild Petersen,

i.e., matrix metalloproteinase, vascular endothelial growth factor, heme oxygenase 1, the prostaglandins,

Skejby, Denmark

cyclooxygenase 2, reactive oxygen species, and nitric oxide. In conclusion, thiamine may beneﬁt HIV

patients, but further investigation of the role of thiamine in HIV infection is needed.

HIV

Human immunodeﬁciency virus

Vitamin B1

Transketolase

1. Introduction survival rates and decreased the number of elongated G2-arrested

cells. Prosultiamine, a disulﬁde thiamine derivative, induced

Nutritional status has been related to disease development in caspase-dependent apoptosis against human T-lymphotropic virus

patients infected with HIV. The dietary intake of vitamin C, type 1 (HTLV-1) cells and signiﬁcantly decreased the HTLV-1

thiamin, and niacin has been associated with a signiﬁcantly slower proviral copy numbers to approximately 30–50% of their

progression to AIDS in homosexual men infected with HIV type 1. pretreatment levels in patients with HTLV-1-associated myelopa-

Daily multivitamin use has been associated with a reduced risk of thy/tropical spastic paruresis. A trans-disulﬁde of thiamine

AIDS and a signiﬁcantly reduced risk of low CD4 counts at baseline disulﬁde suppresses HIV-1 replication by preventing the nuclear

in HIV-positive homosexual men. Taking multivitamin supple- translocation of both HIV-1 Tat and nuclear factor kappaB (NF-

ments during pregnancy improves weight gain and postnatal child kB). Thiamine disulﬁde markedly inhibited the production of

growth, and reduces the risk of hypertension and adverse progeny HIV-1 in acutely and chronically HIV-1-infected cells.

3–6

pregnancy outcomes in HIV-infected women. Thiamine and These results suggest a relationship between thiamine and HIV.

vitamin B6 supplements at more than twice the recommended Therefore, we review the role of thiamine in HIV infection.

dietary allowance have been associated with improved survival in

HIV-infected patients. Severe thiamine deﬁciencies, such as 2. Genetic factors related to thiamine in HIV

Wernicke encephalopathy and beriberi disease, are also observed

8–11

in HIV patients. Thiamine deﬁciency has been found in a large The primary function of the renin–angiotensin system (RAS) is

12–14

percentage of HIV-positive patients. Long-term side effects, to maintain ﬂuid homeostasis and regulate blood pressure.

such as thiamine deﬁciency and lactic acidosis, have been found in Angiotensin-converting enzyme (ACE), a key enzyme in the RAS,

HIV-infected patients using nucleoside reverse transcriptase converts angiotensin I to the potent vasoconstrictor angiotensin

inhibitors (NRTIs). Thiamine supplementation has been effective II. Serum ACE levels have been found to be signiﬁcantly elevated

15–19

in treating NRTI-induced lactic acidosis. Furthermore, treating in AIDS patients, patients in the intermediate stage of HIV

25,26

Schizosaccharomyces pombe expressing HIV-1 viral protein R with a infection, and patients with Pneumocystis carinii pneumonia.

low concentration of hydrogen peroxide and 0.1 mmol/l thiamine Captopril, an ACE inhibitor, may offer long-term renal survival

signiﬁcantly increased both the human cell proliferation and beneﬁts in HIV-associated nephropathy in animals and humans if

27–29

the treatment is initiated prior to severe renal inefﬁciency. An

ACE inhibitor has also been shown to improve the mean velocity of

circumferential ﬁber shortening and peak systolic left-ventricular

* Corresponding author. Tel.: +1 714 839 5898; fax: +1 714 839 5989.

E-mail address: [email protected] (K.v.q. Lu’o’ng). wall stress in HIV-infected children. HIV-positive patients who

e222 K.V.Q. Lu’o’ng, L.T.H. Nguyeˆn / International Journal of Infectious Diseases 17 (2013) e221–e227

abuse cocaine have abnormalities in diastolic heart function and neuroinﬂammatory processes that promote neurodegeneration by

platelet activation that are potentially reversible with ACE inhibiting glial proliferation and/or promoting glial cell dysfunc-

31 54

inhibitor therapy. Moreover, T-cell stimulation by HIV-1 tion. Vpr protein and transcript have been shown to be present in

gp160-derived peptide p18 (presented by HLA class I molecules the brains of HIV-infected patients. Moreover, soluble Vpr caused

in a cell-free system) has been found to require proteolytic neuronal apoptosis, cytochrome c extravasation, p53 induction,

cleavage, which is blocked by captopril. An interaction between activation of caspase 9, and a depressive effect on the whole-cell

thiamine and the RAS has been observed. Thiamine deﬁciency currents in the neurons. In contrast, an increased number of

signiﬁcantly depresses plasma and urinary aldosterone responses thiamine transporters are observed in cells that overexpress

to sodium deprivation in rats. Thiamine attenuates hypertension thiamine transport genes (mTHTR-1) and in cells that are exposed

and metabolic abnormalities in spontaneously hypertensive rats to conditions that induce DNA damage or p53 activation.

(SHRs). Thiamine repletion downregulates the expression of Thiamine diphosphate inhibits p53 binding, and thiamine inhibits

angiotensinogen (80%), ACE (77%), and angiotensin type 1 intracellular p53 activity. Thiamine treatment signiﬁcantly

receptor (72%) mRNAs in SHRs. These observations suggest that decreases p53 expression in the cultured retinal neurons from

thiamine affects ACE activity in HIV-infected patients. diabetic rats. These observations suggest that the pro-apoptotic

Poly(ADP-ribosyl) polymerase 1 (PARP-1) is a nuclear protein transcription factor p53 is activated by cellular damage in HIV

present in mammalian cells and has been observed to regulate infection and that thiamine ameliorates these effects.

various biological activities. PARP-1 plays an important role in Caspases are cysteinyl aspartate-speciﬁc proteases that play a

tissue injury in conditions associated with oxidative stress and critical role in the regulatory and execution phases of apoptosis.

inﬂammation. In HIV-infected cells, increased PARP-1 activity and The overexpression of caspase 3 has been observed in the brains of

accentuated fragmentation of cellular DNA are associated with pediatric patients with HIV-1 encephalitis. The induction of

HIV-1 replication. In the brains of autopsied AIDS patients, apoptosis by HIV-1 envelope proteins gp120/160 in cultured

immune-staining for PARP was found to be more intense in the endothelial cells is mediated by caspase 3 and cleavage of focal

36 61,62

gray and white matter of patients with HIV encephalitis. PARP-1 adhesion kinase in primary human CD4+ T cells. HIV gp41-

is required for efﬁcient HIV-1 integration; PARP-1 knockout induced apoptosis is mediated by caspase 3-dependent mitochon-

ﬁbroblasts were found to be nearly completely protected from drial depolarization, which is inhibited by the HIV protease

37,38

HIV-1 infection. Established small interference RNA (siRNA) inhibitor nelﬁnavir but not by other HIV protease inhibitors or

against PARP-1 was found to signiﬁcantly suppress HIV-1 inhibitors of calpain and cathepsin. A potent and selective HIV-1

0 0 0

replication, as well as the activation of the integrated HIV-1 long reverse transcriptase inhibitor, 3 -azido-2 ,3 -deoxythymidine

terminal repeat (LTR) promoter. Thiamine has a cytoprotective (AZT) is widely used in antiretroviral therapy. AZT inhibits

effect on cultured neonatal rat cardiomyocytes under hypoxic visna/maedi virus-induced apoptosis and diminishes the activity

40 64

insult; it also inhibits PARP cleavage and DNA fragmentation. of caspases 3, 8, and 9; however, breast cancer cells that are

Benfotiamine, a fat-soluble thiamine analog, also prevents transfected with the thiamine transporter SLC19A3 gene show an

bacterial endotoxin-induced inﬂammation and PARP cleavage in increase in apoptosis when they are exposed to doxorubicin and

mouse macrophage cell lines. Adenosine thiamine triphosphate radiation, and the caspase 3-dependent pathway partially med-

(ATTP), a new thiamine derivative, has been identiﬁed in small iates this effect. The thiamine deﬁciency caused by thiamine

amounts in the mouse brain, heart, skeletal muscle, liver, and antagonists leads to caspase 3 apoptosis in the neuronal

42 43 66

kidneys, and has been shown to inhibit PARP-1 activity. differentiated PC-12 cells of rats. Thiamine has a cytoprotective

Vpr is an HIV-1 virion protein that plays a role in enhancing effect on cultured neonatal rat cardiomyocytes against hypoxia-

HIV-1 replication in vivo. Vpr interacts with transcription factor induced apoptosis; it also inhibits caspase 3 activation.

Sp1 when Sp1 is bound to the Sp1 motifs within the HIV-1 LTR, and Benfotiamine accelerates healing in the ischemic diabetic limbs

Vpr transactivation through Sp1 is critical for the immediate early of mice by potentiating angiogenesis and preventing the induction

44 67

transcription of HIV-1. An interaction between NF-kB and Sp1 is of pro-apoptotic caspase 3. Sulbutiamine, a highly lipid-soluble

required for inducible HIV-1 gene expression and may activate synthetic analog of thiamine, attenuates trophic factor depriva-

speciﬁc viral and cellular genes. Sp1 and Sp3 regulate the basal tion-induced cell death in transformed retinal ganglion cells (RGC-

transcription of the ABOBEC3G gene, which is expressed in 5) and decreases the expression of cleaved caspase 3. These

peripheral blood lymphocytes and has activity against HIV-1 ﬁndings suggest that thiamine may inﬂuence HIV infection by

and other retroviruses. Mutation of the Sp1 sequence impairs inhibiting the activity of the apoptotic factor caspase 3.

both multimerization and the membrane-binding activities of HIV- Glycogen synthetase kinase 3b (GSK3b) is a protein kinase that

1 Gag. Thiamine uptake in the human intestine occurs via a is involved in many physiological processes, e.g., metabolism, gene

specialized carrier-mediated mechanism, and the human thiamine expression, and apoptosis. The HIV-1 Tat-mediated activation of

transporters (THTRs) are expressed in the intestine and are GSK3b contributes to Tat-mediated neurotoxicity and antag-

48,49 70

regulated via Sp1 promoter elements. onizes the NF-kB survival pathway in neurons. GSK3b-speciﬁc

The p53 gene and protein play critical roles in regulating the inhibitors, such as AR-A014418 and B6B30, prevent direct

normal cell cycle, cell cycle arrest, and apoptosis. p53 expression neurotoxicity in primary human neurons exposed to HIV.

and activation have been associated with faster disease progres- Exposure to pyrithiamine, an anti-thiamine compound, also

sion in HIV-infected patients. Thakur et al. provided evidence increases the b-amyloid protein accumulation and GSK3 activity

that the cell-killing effect of the HIV-1 viral protein Tat is mediated in the brain. Benfotiamine was shown to improve cognitive

by activating the p53 pathway. In one experiment, p53 was fused function, reduce amyloid deposition, and suppress GSK3 activity in

with HIV Tat protein; the fusion product can cross cell membranes an animal model of Alzheimer’s disease. These ﬁndings suggest

and inﬂuences HepG2 cell apoptosis. The HIV-1-mediated that thiamine may inﬂuence HIV by suppressing GSK3 activity.

increase in p53 gene expression is associated with the virus-

mediated induction of type I interferon in human primary CD4 + T 3. The non-genetic role of thiamine in HIV

cells. Tat contributes to neuronal degeneration by activating

a pathway that involves the p53 and p73 transcription factors Matrix metalloproteinases (MMPs) are proteolytic enzymes

in neuroAIDS. Activation of the p53-mediated pathways in that are responsible for extracellular matrix remodeling and for

the glia of HIV-associated dementia patients contributes to the regulating of leukocyte migration through the extracellular matrix,

K.V.Q. Lu’o’ng, L.T.H. Nguyeˆn / International Journal of Infectious Diseases 17 (2013) e221–e227 e223

which is an important step in inﬂammatory processes and dialysis in uremic rats, treatment with benfotiamine decreased

infectious diseases. MMPs are produced by many cell types peritoneal ﬁbrosis, markers of inﬂammation, neovascularization,

103

including lymphocytes, granulocytes, astrocytes, and activated and VEGF staining. Furthermore, benfotiamine has also been

macrophages. There is an increased concentration of MMPs 1, 3, 7, shown to improve the functional recovery of infarcted hearts and

8, 9, 25, and 26 in the saliva and gingival tissue of HIV-infected reduce the phosphorylation/activation of the VEGF receptor 2/Akt

74,75 104

patients. Gingival mast cells have also been shown to strongly signaling pathways in a mouse macrophage cell line.

express MMP-1 and MMP-8 in HIV-infected patients. MMP-9 Heme oxygenase-1 (HO-1) is a stress protein that may confer

was found to be overexpressed in the glomeruli of a patient with cytoprotection by enhancing the catabolism of the pro-oxidant

HIV-associated nephropathy. Maternal HIV-1 infection sup- heme to the radical scavenging bile pigments biliverdin and

105

presses MMP-1 expression in the endothelial cells of uninfected bilirubin. Seu et al. reported that increased numbers of HO-1

newborns and may contribute to the impaired cardiac function promoter region GT(n) repeats correlated with higher levels of

observed in these newborns. Increased levels of serum MMP-1 soluble CD4 during highly active antiretroviral therapy, as well as a

and MMP-7 are correlated with micro-structural brain alterations higher mean viral load off-therapy in African-Americans but not

and brain atrophy. Elevated cerebrospinal ﬂuid levels of MMP-2, Caucasians. These authors also demonstrated that HO-1 GT(n)

MMP-7, and MMP-9 are correlated with HIV dementia. In a rat microsatellite polymorphism is associated with HO-1 expression

model of human HIV-related encephalopathy, MMP-2 and MMP-9 levels. Ritonavir, an HIV protease inhibitor, has been shown to

were upregulated by the HIV envelope gp120. Increased levels of promote apoptotic cell death. Ritonavir enhances HO-1 mRNA

106

MMP-2 were found in plasma from patients with AIDS-related levels and protein expression in DLD-1 colon carcinoma cells.

Kaposi’s sarcoma. No MMP-9 activity was detected after Hemin, a critical component of hemoglobin, ameliorates HIV-1

antiretroviral therapy in the HIV-infected subjects. Treatment infection via induction of HO-1; treatment of monocytes with

107,108

with both zidovudine and indinavir was found to inhibit the hemin was found to substantially inhibit HIV replication.

expression of MMP-2 in astrocytes, but these anti-HIV drugs Similarly, thiamine deﬁciency produces region-speciﬁc neuronal

85,86

decreased the expression of MMP-9 in both astrocytes and loss and HO-1 induction in microglia. Thiamine administration

84 85,86

microglia. MMP-9 is also upregulated in the TD mouse brain. inhibits further neuronal loss and the induction of HO-1-positive

109

Thiamine prevents diabetes-induced cardiac ﬁbrosis and decreases microglia, but other microglial changes persist.

MMP-2 activity in the hearts of diabetic rats. Moreover, thiamine Prostaglandins (PGs) play a role in inﬂammatory processes.

and benfotiamine correct the increase in MMP-2 activity that Cyclooxygenase (COX) participates in the conversion of arachi-

results from high glucose levels in human retinal pericytes, while donic acid into PGs. Increased levels of the brain markers of

increasing TIMP-1. Fursultiamine, a vitamin B1 derivative, was neuroinﬂammation and arachidonic acid metabolism are reported

110

found to enhance the chondro-protective effects of glucosamine in the brains of HIV-1-infected transgenic rats. In vitro, co-

hydrochloride and chondroitin sulfate and reduce MMP-1 levels in cultures of HIV-infected macrophages and brain endothelium have

89 111

rabbit experimental osteoarthritis. shown upregulation of COX-2 expression. Extracellular HIV Tat

Angiogenesis is a complex process that involves coordinated was found to induce COX-2 mRNA and protein expression, as well

endothelial cell activation, proliferation, migration, and tube as PGE2 synthesis in astrocytoma cell lines and primary human

112

formation, as well as capillary sprouting. In addition, angiogenesis astrocytes. COX-2 inhibitors attenuated HIV Tat-induced

113

requires the participation of numerous intracellular signaling alterations in occluding expression at the blood–brain barrier,

pathways. Vascular endothelial growth factor (VEGF) is a key prevented the apoptotic death typically produced by HIV-1 gp120

114

mediator of angiogenesis. The HIV Tat protein plays a key role in in the neo-cortex, and reduced the level of PGE2, thereby

115

vascular cell activation and is a heparin-binding angiogenic growth reversing T cell anergy. Moreover, the expression of COX-2

factor. Tat induces the growth of Kaposi’s sarcoma spindle cells mRNA and PGE2 are selectively increased in vulnerable regions

and is angiogenic in vivo and in transgenic mice. Tat speciﬁcally during the symptomatic stages of TD encephalopathy in animal

116

binds and activates the Flk-1/kinase insert-domain receptor (Flk-1/ models. Upregulation of 15-hydroxyprostaglandin dehydroge-

KDR) and a VEGF-A tyrosine kinase receptor. Tat-induced nase (15-PGDH) expression was observed in breast cancer cell lines

angiogenesis is blocked by the agents blocking the Flk-1/KDR transfected with THTR2, and downregulation was observed after

91 117

receptor. VEGF-mimetic HIV-1 Tat is connected to increased suppression of THTR2 with siRNA vectors. The overexpression of

118

microvessel density in AIDS-related diffuse large B cell and 15-PGDH inhibited interleukin 1b-induced COX-2 expression.

Burkitt’s lymphomas. The AIDS Kaposi’s sarcoma cell lines Benfotiamine inhibited the expression of COX-2 in endotoxin-

119

express higher levels of VEGF than either human umbilical vein induced uveitis in rats. Benfotiamine also blocked the expres-

endothelial cells or human aortic smooth muscle cells. The VEGF sion of COX-2 and its PGE2 product in murine macrophages in a

plasma levels increase in AIDS patients with Kaposi’s sarcoma lipopolysaccharide (LPS)-induced cytotoxicity model.

compared to HIV-1-infected persons without Kaposi’s sarco- Reactive oxygen species (ROS) are produced by activated

94,95

ma. In HIV-associated central nervous system (CNS) diseases, phagocytes as a part of their microbicidal activities. Depressed

the VEGF levels increase in the serum but not in the CSF. VEGF is a neutrophil superoxide production has been demonstrated in HIV-1

120

potent angiogenic factor in AIDS-associated Kaposi’s sarcoma- infection. Oxidative stress in erythrocytes is associated with the

derived spindle cells. Tat induces human monocyte chemotaxis progression of HIV disease; in the advanced stages, superoxide

by activating the VEGF receptor 1. The HIV-1 induction of VEGF dismutase (SOD) activity is increased, while glutathione (GSH) is

121

expression in podocytes may be a critical step in the pathogenesis decreased at advanced HIV stages. Selenium stimulation of GSH

99 122

of HIV-associated nephropathy. HIV protease inhibitors decrease activity decreases HIV-1 activation. Lipid peroxide levels have

100

VEGF expression and angiogenesis in glioblastoma cells. also been found to be signiﬁcantly higher in HIV-positive

123

Moreover, thiamine deﬁciency has been shown to result in patients. Restoration of the GSH levels reverses the HIV-1

polyneuropathy after a gastrectomy; this deﬁciency has also been protein-mediated effects on superoxide, nitric oxide (NO), and

124

associated with high levels of serum VEGF. VEGF levels typically vasorelaxation. Similarly, oxidative stress is associated with

return to normal following the intravenous administration of region-speciﬁc neuronal death, and lipid peroxidation products

thiamine, which further improves the symptoms of polyneuro- accumulate in the remaining thalamic neurons after 11 days in

101 125

pathy. In addition, increased serum levels of VEGF have been TD animal models. Cardiac oxidative stress is involved in

102

reported in patients with wet beriberi. In a model of peritoneal TD-induced heart failure rats; intracellular cardiac superoxide,

e224 K.V.Q. Lu’o’ng, L.T.H. Nguyeˆn / International Journal of Infectious Diseases 17 (2013) e221–e227

Thiamine & Benfotiamine Human Immunodeficiency Virus

Angioten sinogen PARP Acvaon Reacve oxygen species Glycogen Synthetase Kinase 3 Vascular EndothE d elial Growth Factor

Poly(AD P-ribosyl) polymerase-1 Ser 9 Tyrosine

Inac ve Acve

Angioten sin I NAD , NADPH, ATP p53 and Caspase Mitochondrial dysfuncon MAPK Angiogenesis

Endothelial Cells

Angioten sin II COX-2, iNOS, PGE2, NO, and inﬂammatory cytokines MMPs

(Mat rix metalloproteins)

Degradaon Products CELL DEATH INFLAMMATION CELL GROWTH DEGRADATION

& DIFFERENTIATION

Red Color: Acvated, Increased.

Solid Blue Color: Aenuated, Decreased.

Figure 1. The role of thiamine in HIV infection.

SOD protein, and H2O2 contents are increased, while GSH Figure 1 illustrates the beneﬁcial role of thiamine in HIV

126

peroxidase activity is decreased. Thiamine inhibits lipid infection.

peroxidation and the free-radical oxidation of oleic acid in rat

127

liver microsomes in vitro. In one study, male Wistar rats were 4. Conclusions

intoxicated with a dose of ethanol, and changes in the levels of

malondialdehyde (MDA), GSH, and vitamin E were measured to The relationship between thiamine and HIV infection is

evaluate the function of the antioxidant system of the liver; these discussed above. Thiamine may serve a beneﬁcial role in HIV

128

levels were improved in the thiamine-treated group. Thiamine infection. Genetic studies have provided the opportunity to

supplementation suppresses paraquat-induced manganese-con- determine which proteins link thiamine to HIV pathology. Thiamine

129

taining SOD and glucose-6-phosphate dehydrogenase in vitro. also affects HIV through non-genomic mechanisms. It is important

Nitric oxide synthase (NOS) synthesizes NO, which regulates a to check the thiamine levels of HIV-infected patients. Further

variety of important physiological responses, including cell investigation of the effect of thiamine on HIV infection is needed.

migration, the immune response, and apoptosis. NO affects the Conﬂict of interest: No conﬂict of interest to declare.

development and function of the CNS. HIV-1 gp120 induces

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