The Open Infectious Diseases Journal




ISSN: 1874-2793 ― Volume 11, 2019
SYSTEMATIC REVIEW

Vitamin D and HTLV Infection: A Systematic Review



E Netto1, *, M Gomes-Neto2, C Brites3
1 Sarah Network of Rehabilitation Hospitals, Salvador, Bahia, Bahia, Brazil.
2 Physical Therapy Department, Federal University of Bahia, Brazil
3 Laboratório de Pesquisas em Infectologia, Hospital Universitário Edgard Santos, Federal University of Bahia, Bahia, Brazil.

Abstract

Background:

Vitamin D has been associated with the pathogenesis of infectious diseases.

Objective:

To perform a systematic review on the association of vitamin D and outcomes of HTLV (Human T-cell lymphotropic virus) infection.

Methods:

We searched PubMed, LILACs, Scielo, Embase and Cochrane Library for studies addressing vitamin D and HTLV infection. We included studies published in English since 1980. Studies associated with HIV, bone metabolism and not related to HTLV- associated myelopathy/ tropical spastic paraparesis (HAM/TSP) or adult T cell leukemia/lymphoma (ATL) were excluded.

Results:

Twenty-three studies were selected and sixteen studies were included in the review (eight experimental studies, three case reports, three cases series, one cross-sectional study and one review). Fourteen studies were focused on ATL, and two on HAM/TSP. The available data show that in vitro exposure to 1,25(OH)2D inhibits proliferation of HTLV-infected lymphocytes in patients with ATL or HAM/TSP. It has been observed that hypercalcemia, the main cause of death in patients with ATL, is not associated with serum levels of 1,25(OH)2D or parathyroid hormone-related protein, but leukemia inhibitory factor/D factor seems to be an important factor for hypercalcemia pathogenesis. It was also demonstrated an association between the VDR ApaI gene polymorphism and a decreased risk of HAM/TSP in HTLV positive individuals.

Conclusion:

Despite the small number and heterogeneity of the studies, this systematic review suggests that vitamin D play a role in the pathogenesis of HTLV-associated diseases.

Key words: 25(OH)D, Vitamin D, HTLV, Calcitriol, Adult T-cell lymphoma/leukemia, antigen-presenting cells (APC).


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 11
First Page: 35
Last Page: 42
Publisher Id: TOIDJ-11-35
DOI: 10.2174/1874279301911010035

Article History:

Received Date: 30/12/2018
Revision Received Date: 07/05/2019
Acceptance Date: 22/May/2019
Electronic publication date: 31/07/2019
Collection year: 2019

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© 2019 Netto et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Sarah Network of Rehabilitation Hospitals. Avenida Tancredo Neves, 2782, Caminho das Árvores, Salvador – BA, Zip Code: 41820-900; Tel: +55 (71) 98788.8525; +55 (71) 3351.2357; Email: elaine.netto@hotmail.com





1. INTRODUCTION

There is an increasing interest in the non-bony functions of vitamin D [1Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-81.
[http://dx.doi.org/10.1056/NEJMra070553] [PMID: 17634462]
, 2Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med 2011; 364(3): 248-54.
[http://dx.doi.org/10.1056/NEJMcp1009570] [PMID: 21247315]
]. The cholecalciferol, 25(OH)D3, is converted into its active form in the kidney, 1,25-dihydroxycholecalciferol (1,25(OH)2D), by the enzyme 1-α-hydroxylase. Recently, it has been demonstrated that immune cells express the vitamin D receptor (VDR) [1Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-81.
[http://dx.doi.org/10.1056/NEJMra070553] [PMID: 17634462]
-4Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc 2011; 86(1): 50-60.
[http://dx.doi.org/10.4065/mcp.2010.0567] [PMID: 21193656]
]. 1,25(OH)2D is capable of suppressing T cells activity and genes involved in cell proliferation and differentiation, downregulates the release of proinflammatory cytokines such as interferon- gamma (IFN- γ), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2) and interleukin 12 (IL- 12), and shift T cells response from Th1 to Th2-like [5Skrobot A, Demkow U, Wachowska M. Immunomodulatory Role of Vitamin D: A Review. Adv Exp Med Biol 2018; 1108: 13-23.
[http://dx.doi.org/10.1007/5584_2018_246] [PMID: 30143987]
-9Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc 2012; 71(1): 50-61.
[http://dx.doi.org/10.1017/S0029665111001650] [PMID: 21849106]
].

The adaptive immune response elicits the antigen-specific immune response and mediates its effect across T and B lymphocytes [10Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med 2000; 343(1): 37-49.
[http://dx.doi.org/10.1056/NEJM200007063430107] [PMID: 10882 768]
]. Vitamin D has an indirect effect on the immune activity of lymphocytes mediated by antigen-presenting cells (APC) paracrine action or promotes a direct effect mediated by VDR [11Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiol Rev 1998; 78(4): 1193-231.
[http://dx.doi.org/10.1152/physrev.1998.78.4.1193] [PMID: 9790574]
]. Some studies have observed that 1,25 (OH)2D suppresses T lymphocyte proliferation by reducing IL-2 transcription. TCD4 + (T helper - Th) lymphocytes recognize the peptides presented by APC. Depending on the type of cytokines secreted by CD4 + T lymphocytes, they can be classified into Th1, Th2, Th17, Th22 and Treg. In vitro studies demonstrated that 1,25 (OH)2 D inhibits the secretion of IFN-γ by Th1 cells [12Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 1995; 125(6)(Suppl.): 1704S-8S.
[PMID: 7782931]
]. Some studies have also observed that vitamin D stimulates the development of Th2 cells by increasing IL-4 synthesis, but this is a still controversial topic [13Edfeldt K, Liu PT, Chun R, et al. T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci USA 2010; 107(52): 22593-8.
[http://dx.doi.org/10.1073/pnas.1011624108] [PMID: 21149724]
]. Treatment of T-cells in vitro with 1,25(OH)2D suppresses Th17 development [14Colin EM, Asmawidjaja PS, van Hamburg JP, et al. 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis Rheum 2010; 62(1): 132-42.
[http://dx.doi.org/10.1002/art.25043] [PMID: 20039421]
] and inhibits IL-17 production via a post-transcriptional mechanism [15Chang SH, Chung Y, Dong C. Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem 2010; 285(50): 38751-5.
[http://dx.doi.org/10.1074/jbc.C110.185777] [PMID: 20974859]
]. TCD8 + lymphocytes (cytotoxic T cells) recognize the peptides presented by nucleated cells. They have higher levels of VDR expression compared to other immune cells. Vitamin D reduces the proliferation of TCD8 + lymphocytes. Some studies have observed the action of vitamin D on the expression of cytokines secreted by TCD8 + lymphocytes, such as IL-6, IL-12, TNF-α, IL-5 and TGF-β (transforming growth factor β) [16Willheim M, Thien R, Schrattbauer K, et al. Regulatory effects of 1α,25-dihydroxyvitamin D3 on the cytokine production of human peripheral blood lymphocytes. J Clin Endocrinol Metab 1999; 84(10): 3739-44.
[PMID: 10523023]
].

Many studies have linked vitamin D levels to infectious diseases pathogenesis, including infection by, HIV [17Mansueto P, Seidita A, Vitale G, et al. Vitamin D Deficiency in HIV Infection: Not Only a Bone Disorder. BioMed Res Int 2015; 2015735615
[http://dx.doi.org/10.1155/2015/735615] [PMID: 26000302]
-25Hsieh E, Yin MT. Continued Interest and Controversy: Vitamin D in HIV. Curr HIV/AIDS Rep 2018; 15(3): 199-211.
[http://dx.doi.org/10.1007/s11904-018-0401-4] [PMID: 29713871]
]. The main risk factors related to HIV-associated hypovitaminosis D are exposure to specific antiretrovirals, chronic inflammation and immune activity associated with HIV infection [20Eckard AR, Judd SE, Ziegler TR, et al. Risk factors for vitamin D deficiency and relationship with cardiac biomarkers, inflammation and immune restoration in HIV-infected youth. Antivir Ther (Lond) 2012; 17(6): 1069-78.
[http://dx.doi.org/10.3851/IMP2318] [PMID: 22894927]
-22Pinzone MR, Di Rosa M, Malaguarnera M, et al. Vitamin D deficiency in HIV infection: an underestimated and undertreated epidemic. Eur Rev Med Pharmacol Sci 2013; 17(9): 1218-32.
[PMID: 23690192]
]. Some studies show a faster and more severe progression of HIV infection, lower TCD4 + count, higher mortality risk and greater susceptibility to Mycobacterium tuberculosis in individuals with hypovitaminosis D [17Mansueto P, Seidita A, Vitale G, et al. Vitamin D Deficiency in HIV Infection: Not Only a Bone Disorder. BioMed Res Int 2015; 2015735615
[http://dx.doi.org/10.1155/2015/735615] [PMID: 26000302]
, 21Bearden A, Abad C, Gangnon R, Sosman JM, Binkley N, Safdar N. Cross-sectional study of vitamin D levels, immunologic and virologic outcomes in HIV-infected adults. J Clin Endocrinol Metab 2013; 98(4): 1726-33.
[http://dx.doi.org/10.1210/jc.2012-4031] [PMID: 23457406]
, 22Pinzone MR, Di Rosa M, Malaguarnera M, et al. Vitamin D deficiency in HIV infection: an underestimated and undertreated epidemic. Eur Rev Med Pharmacol Sci 2013; 17(9): 1218-32.
[PMID: 23690192]
, 24Hidron AI, Hill B, Guest JL, Rimland D. Risk factors for vitamin D deficiency among veterans with and without HIV infection. PLoS One 2015; 10(4)e0124168
[http://dx.doi.org/10.1371/journal.pone.0124168] [PMID: 25898185]
, 26Shepherd L, Souberbielle JC, Bastard JP, et al. Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIV-infected persons. J Infect Dis 2014; 210(2): 234-43.
[http://dx.doi.org/10.1093/infdis/jiu074] [PMID: 24493824]
, 27Jiménez-Sousa MA, Martínez I, Medrano LM, Fernández-Rodríguez A, Resino S. Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease. Front Immunol 2018; 9(9): 458.
[http://dx.doi.org/10.3389/fimmu.2018.00458] [PMID: 29593721]
]. Insufficient production of 1,25(OH)2D in patients with HIV can induce proinflammatory cytokine generation and action [20Eckard AR, Judd SE, Ziegler TR, et al. Risk factors for vitamin D deficiency and relationship with cardiac biomarkers, inflammation and immune restoration in HIV-infected youth. Antivir Ther (Lond) 2012; 17(6): 1069-78.
[http://dx.doi.org/10.3851/IMP2318] [PMID: 22894927]
]. High levels of proinflammatory cytokines, especially TNF-α, (which is found in persistent immune activation in HIV infection) may induce a defect in hydroxylation of 25 (OH) D3 and on its activity, by blocking the stimulatory effect of parathyroid hormone (PTH) on the action of renal 1-α-hydroxylase enzyme, which reduces conversion from the inactive form to the active form of vitamin D (1,25 (OH)2D) [23Aguillar-Jiménez W, Zapata W, Rugeles MT. Participación de la vitamina D em la patogénesis de la infección por el virus de la inmunodeficiencia humana tipo 1. Infecto 2013; 17(3): 146-52.
[http://dx.doi.org/10.1016/S0123-9392(13)70721-5]
, 28Haug CJ, Aukrust P, Haug E, Mørkrid L, Müller F, Frøland SS. Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab 1998; 83(11): 3832-8.
[http://dx.doi.org/10.1210/jcem.83.11.5270] [PMID: 9814454]
-30Barbosa N, Costa L, Pinto M, Rosinha P, Rosinha I, Couto M. Vitamin D and HIV Infection: A Systematic Review. J Immunodefic Disord 2014; 3(1): 1-11.]. Antiretrovirals (e.g. protease inhibitors and non-nucleoside reverse transcriptase inhibitors), are also risk factors for hypovitaminosis D in these patients because they interfere with vitamin D metabolism. Vitamin D deficiency did not influence the distribution of T and B lymphocytes in HIV-positive patients, but vitamin D supplementation is related to the reduction of immune activity and T-cell depletion, acting as an adjuvant to antiretroviral therapy [24Hidron AI, Hill B, Guest JL, Rimland D. Risk factors for vitamin D deficiency among veterans with and without HIV infection. PLoS One 2015; 10(4)e0124168
[http://dx.doi.org/10.1371/journal.pone.0124168] [PMID: 25898185]
].

HTLV infection causes HTLV- associated myelopathy/ tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia/lymphoma (ATL), but the development of these conditions requires other associated factors. Although the risk factors associated with HTLV-1 infection outcomes are still unclear, they include high HTLV proviral load, host genetic factors (HLA haplotypes: presence of DRB1 * 0101, B * 54, absence of * 02, C * 08); viral variants (cosmopolitan HTLV-1 viral subtype); duration of infection, age and feminine gender [31Gessain A, Cassar O. Epidemiological Aspects and World Distribution of HTLV-1 Infection. Front Microbiol 2012; 3(388): 388.
[http://dx.doi.org/10.3389/fmicb.2012.00388] [PMID: 23162541]
-33Carod-Artal FJ. [Immunopathogenesis and treatment of the myelopathy associated to the HTLV-I virus]. Rev Neurol 2009; 48(3): 147-55.
[PMID: 19206063]
]. The role of the immune response in HTLV pathogenesis is not fully understood, but the efficacy of the individual immune response defines the control or limitation of viral persistence and, ultimately, the outcome of HTLV-associated diseases [34Matsuura E, Yamano Y, Jacobson S. Neuroimmunity of HTLV-I Infection. J Neuroimmune Pharmacol 2010; 5(3): 310-25.
[http://dx.doi.org/10.1007/s11481-010-9216-9] [PMID: 20437106]
-37Quaresma JAS, Yoshikawa GT, Koyama RVL, Dias GA, Fujihara S, Fuzii HT. HTLV-1, Immune Response and Autoimmunity. Viruses 2015; 8(1): 1-10.
[http://dx.doi.org/10.3390/v8010005] [PMID: 26712781]
]. HTLV can immortalize human lymphocytes, specially TCD4 + lymphocytes in ATL [38Oliveira PD, Farre L, Bittencourt AL. Adult T-cell leukemia/lymphoma. Rev Assoc Med Bras (1992) 2016; 62(7): 691-700.
[http://dx.doi.org/10.1590/1806-9282.62.07.691] [PMID: 27925051]
].

Due to the potential effect of vitamin D on HTLV pathogenesis, and the paucity of information in this field, we performed a systematic review on the available evidence of vitamin D effects on HTLV-associated diseases. To the best of our knowledge, this is the first review on the association between vitamin D and HTLV infection.

2. METHODOLOGY

This systematic review was performed by assessing the available data on the association between vitamin D and HTLV infection. Qualitative analysis was completed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [39Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015; 350: g7647.
[http://dx.doi.org/10.1136/bmj.g7647] [PMID: 25555855]
]

We searched PubMed, LILACs, Scielo, Embase and Cochrane Library from 1980 to February 2017. We used the keywords “VITAMIN D”, “25(OH)D”, “CALCITRIOL”, “ADULT T-CELL LYMPHOMA/LEUKEMIA” AND “HTLV” to identify related articles. We only included studies addressing vitamin D and the outcome of interest (HTLV infection), when associated with diseases such as ATL, HAM/TSP or with immune response. Only articles written in English have been included. Studies focused on HIV, bone metabolism or which had no relationship to HTLV -associated diseases were excluded. Three authors independently extracted data from the selected articles to evaluate if they fit the study questions, regarding population, outcomes, and rates of missing data.

3. RESULTS

Twenty-three studies were selected and sixteen studies were included in the review. Seven studies were excluded (one was related to HIV, two were focused on bone metabolism and four did not include HTLV-related diseases). Eight out of the sixteen included studies were experimental, five were case reports, one case series, one cross-sectional, and one review. Fourteen studies were focused on ATL, and two on HAM/TSP, as summarized in Fig. (1).

Table 1 describes the main characteristics and results of selected studies.

3.1. Effects of Vitamin D on HTLV-associated Diseases (HAM/TSP)

The literature review identified two articles reporting an association between vitamin D and HAM/TSP [40Saito M, Eiraku N, Usuku K, et al. ApaI polymorphism of vitamin D receptor gene is associated with susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis in HTLV-1 infected individuals. J Neurol Sci 2005; 232(1-2): 29-35.
[http://dx.doi.org/10.1016/j.jns.2005.01.005] [PMID: 15850579]
, 41Yamada H, Nakao Y, Fujita T. Inhibition of cellular proliferation in human T lyophotropic virus type I (HTLV-I)-infected T cells from patients with HAM by steroid hormones and cyclosporin A. Kobe J Med Sci 1991; 37(2): 57-79.
[PMID: 1921263]
]. Saito et al. conducted a study to investigate whether VDR polymorphism is associated with HAM/TSP development. They evaluated the frequency of four VDR single nucleotide polymorphisms in a group of 207 patients with HAM/TSP and 224 HTLV asymptomatic carriers. It was identified a significant association between VDR ApaI AA genotype polymorphism and a reduced risk of HAM/TSP in HTLV-infected women . However, there was no association between ApaI genotypes and HTLV proviral load, cerebrospinal fluid neopterin levels, or HTLV antibody titers in patients with HAM/TSP or in asymptomatic carriers [40Saito M, Eiraku N, Usuku K, et al. ApaI polymorphism of vitamin D receptor gene is associated with susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis in HTLV-1 infected individuals. J Neurol Sci 2005; 232(1-2): 29-35.
[http://dx.doi.org/10.1016/j.jns.2005.01.005] [PMID: 15850579]
]. Yamada et al. investigated the inhibitory effects of steroid hormones (dexamethasone and 1,25(OH)2D) and cyclosporin A on the synthesis of de novo DNA in four HTLV cell lines from patients with HAM/TSP. T cell lines showed high rates of expression of IL-2-receptor (IL-2R) and HLA-DR antigen. Twenty-four hours after incubation with either steroid hormones or cyclosporine A, an increase in the inhibitory effect on cellular proliferation was observed, except in the fourth lineage, which was insensitive to those drugs. Although cells presented a high level of IL-2R expression, no IL-2 production was detectable. This study suggested that the inhibition of cellular proliferation by the tested drugs in three HAM/TSP T-cell lines was not caused by the inhibition of HTLV p40 gene. They found that it was caused by the inhibition of c-myc products and other transcriptional factors, which are important proto-oncogenes that promote nuclear regulation in cellular proliferation of several T- cell leukemias [41Yamada H, Nakao Y, Fujita T. Inhibition of cellular proliferation in human T lyophotropic virus type I (HTLV-I)-infected T cells from patients with HAM by steroid hormones and cyclosporin A. Kobe J Med Sci 1991; 37(2): 57-79.
[PMID: 1921263]
].

3.2. Effects of Vitamin D on Adult T Cell Leukemia/Lymphoma (ATL)

Fourteen selected studies were related to ATL [42Koizumi T, Nakao Y, Kawanishi M, Maeda S, Sugiyama T, Fujita T. Suppression of c-myc mRNA expression by steroid hormones in HTLV-I-infected T-cell line, KH-2. Int J Cancer 1989; 44(4): 701-6.
[http://dx.doi.org/10.1002/ijc.2910440425] [PMID: 2793241]
-44Elstner E, Lee YY, Hashiya M, et al. 1 α,25-Dihydroxy-20-epi-vitamin D3: an extraordinarily potent inhibitor of leukemic cell growth in vitro. Blood 1994; 84(6): 1960-7.
[PMID: 8080998]
, 46Nakao Y, Koizumi T, Matsui T, et al. Effect of 1 α,25-dihydroxyvitamin D3 on proliferation of activated T-cells and established human lymphotropic virus type I-positive T-cell lines. J Natl Cancer Inst 1987; 78(6): 1079-86.
[PMID: 2884343]
-54Dodd RC, Winkler CF, Williams ME, Bunn PA, Gray TK. Calcitriol levels in hypercalcemic patients with adult T-cell lymphoma. Arch Intern Med 1986; 146(10): 1971-2.
[http://dx.doi.org/10.1001/archinte.1986.00360220125022] [PMID: 2876692]
, 56Umemiya-Okada T, Natazuka T, Matsui T, Ito M, Taniguchi T, Nakao Y. Expression and regulation of the leukemia inhibitory factor/D factor gene in human T-cell leukemia virus type 1 infected T-cell lines. Cancer Res 1992; 52(24): 6961-5.
[PMID: 1458488]
, 57Masutani H, Ueda S, Yodoi J. The thioredoxin system in retroviral infection and apoptosis. Cell Death Differ 2005; 12(Suppl. 1): 991-8.
[http://dx.doi.org/10.1038/sj.cdd.4401625] [PMID: 15818395]
]. Nakao et al. showed that the in vitro exposure to 1,25(OH)2D was able to inhibit the cell proliferation and de novo DNA synthesis of certain HTLV-1-positive T-cell lines. It was also observed that a potent 1,25(OH)2D analog modulates the induction of differentiation and inhibition of clonal proliferation in leukemic cells, but does not interfere in normal myeloid clonal growth [46Nakao Y, Koizumi T, Matsui T, et al. Effect of 1 α,25-dihydroxyvitamin D3 on proliferation of activated T-cells and established human lymphotropic virus type I-positive T-cell lines. J Natl Cancer Inst 1987; 78(6): 1079-86.
[PMID: 2884343]
].

Koizumi et al. evaluated the effects of 1,25(OH)2D on the regulation of mRNA involved in the proliferation of HTLV-infected T cells. Both 1,25(OH)2D and dexamethasone inhibit cellular proliferation and c-myc expression in HTLV-1-infected T-cell line. However, the rate of inhibition in c-myc mRNA expression was much higher in 1,25(OH)2D-treated cells [42Koizumi T, Nakao Y, Kawanishi M, Maeda S, Sugiyama T, Fujita T. Suppression of c-myc mRNA expression by steroid hormones in HTLV-I-infected T-cell line, KH-2. Int J Cancer 1989; 44(4): 701-6.
[http://dx.doi.org/10.1002/ijc.2910440425] [PMID: 2793241]
].

Inoue et al. observed that 22-oxa-1,25(OH)2D, a non-calcemic analog of 1,25(OH)2D, and 1,25(OH)2D, are able to suppress both cell proliferation and PTHrP gene expression via binding to overexpressed VDR in HTLV infected T cells [43Inoue D, Matsumoto T, Ogata E, Ikeda K. 22-Oxacalcitriol, a noncalcemic analogue of calcitriol, suppresses both cell proliferation and parathyroid hormone-related peptide gene expression in human T cell lymphotrophic virus, type I-infected T cells. J Biol Chem 1993; 268(22): 16730-6.
[PMID: 8393873]
]. Elstner et al. found that another potent analog of 1,25(OH)2D, the 1,25(OH)2-20-epi-D3, has antiproliferative and differentiating effects on leukemic cells [44Elstner E, Lee YY, Hashiya M, et al. 1 α,25-Dihydroxy-20-epi-vitamin D3: an extraordinarily potent inhibitor of leukemic cell growth in vitro. Blood 1994; 84(6): 1960-7.
[PMID: 8080998]
].

The production of 1,25(OH)2D and parathyroid hormone-related protein (PTHrP) by HTLV-infected lymphocytes was considered as a potential cause of the syndrome of humoral hypercalcemia of malignancy (HHM) frequently found in ATL patients (Fig. 2) [45Shu ST, Dirksen WP, Weibaecher KN, Rosol TJ. Mechanisms of Humoral Hypercalcemia of Malignancy in Leukemia/Lymphoma.T Cell-Leukemia 2011; 181-206.]. However, this was not confirmed by several studies that failed in showing increased levels of PTHrP or 1,25(OH)2D in ATL patients [47Reichel H, Koeffler HP, Norman AW. 25-Hydroxyvitamin D3 metabolism by human T-lymphotropic virus-transformed lymphocytes. J Clin Endocrinol Metab 1987; 65(3): 519-26.
[http://dx.doi.org/10.1210/jcem-65-3-519] [PMID: 2887583]
-52Johnston SR, Hammond PJ. Elevated serum parathyroid hormone related protein and 1,25-dihydroxycholecalciferol in hypercalcaemia associated with adult T-cell leukaemia-lymphoma. Postgrad Med J 1992; 68(803): 753-5.
[http://dx.doi.org/10.1136/pgmj.68.803.753] [PMID: 1480540]
]. ATL T-lymphocytes produced an osteoclast-activating-factor-like product that promoted osteoclast proliferation and hypercalcemia [52Johnston SR, Hammond PJ. Elevated serum parathyroid hormone related protein and 1,25-dihydroxycholecalciferol in hypercalcaemia associated with adult T-cell leukaemia-lymphoma. Postgrad Med J 1992; 68(803): 753-5.
[http://dx.doi.org/10.1136/pgmj.68.803.753] [PMID: 1480540]
]. Dodd et al. observed that some patients with hypercalcemia and ATL had normal or suppressed levels of 1,25(OH)2D [54Dodd RC, Winkler CF, Williams ME, Bunn PA, Gray TK. Calcitriol levels in hypercalcemic patients with adult T-cell lymphoma. Arch Intern Med 1986; 146(10): 1971-2.
[http://dx.doi.org/10.1001/archinte.1986.00360220125022] [PMID: 2876692]
].

Fig. (1)
Flowchart on the review procedures.


Fig. (2)
Humoral hypercalcemia of malignancy (HHM) in ATL is caused by increased osteoclastic bone resorption. Cancer cells secrete bone regulatory factors, including parathyroid hormone-related protein (PTHrP), macrophage inflammatory protein-1 alpha (MIP-1α), calcitriol (1,25(OH)2D), and receptor activator of nuclear kappa-B ligand (RANKL) to increase osteoclast activity. The resorbing bone secretes bone-derived growth factors that increase ATL cell growth. In osteoblasts, the RANKL/OPG expression ratio increases when cells are co-cultured with T-cell leukemia lines. Antibodies against HTLV-1 Gp46 can inhibit osteoprotegerin (OPG) and contributes to the pathogenesis of hypercalcemia.


Leukemia inhibitory factor/D factor (LIF) is a cytokine that affects the growth and differentiation of cell types, including hematopoietic, hepatic, adipogenic, renal, neuronal, osteoblastic and embryonic cells. Gearing et al. reported that LIF produced by osteoblastic cells stimulates bone resorption by the promotion of osteoclastic formation [55Gearing DP. Leukemia inhibitory factor: does the cap fit? Ann N Y Acad Sci 1991; 628: 9-18.
[http://dx.doi.org/10.1111/j.1749-6632.1991.tb17218.x] [PMID: 1906256]
]. LIF is secreted by activated T-cells and monocytes as a part of immune response. Umemiya-Okada et al. studied the expression of LIF gene in HTLV infected T-cell lines and observed that the expression of LIF was suppressed by 1,25(OH)2D and by dexamethasone. It has been reported that HTLV infected T cells have phenotypic similarity to activated T cells, which raised the hypothesis that LIF may also contribute to the hypercalcemia and/or the immunological abnormalities of ATL [56Umemiya-Okada T, Natazuka T, Matsui T, Ito M, Taniguchi T, Nakao Y. Expression and regulation of the leukemia inhibitory factor/D factor gene in human T-cell leukemia virus type 1 infected T-cell lines. Cancer Res 1992; 52(24): 6961-5.
[PMID: 1458488]
].

Human thioredoxin (TRX) was first identified in HTLV-cell lines and has been associated with the pathophysiology of retroviral infections. TRX system has an antiapoptotic effect. Cell death induced by oxidative stress seems to be apoptosis as long as the intracellular reducing status is maintained by the TRX system [57Masutani H, Ueda S, Yodoi J. The thioredoxin system in retroviral infection and apoptosis. Cell Death Differ 2005; 12(Suppl. 1): 991-8.
[http://dx.doi.org/10.1038/sj.cdd.4401625] [PMID: 15818395]
]. Thioredoxin 2 (TRX-2) is an important regulator protein of cytochrome c release and mitochondrial apoptosis. Overexpression of TRX-2 confers an increase in mitochondrial membrane potential and resistance to etoposide-induced cell death. Vitamin D treatment upregulatesTBP-2 expression leading to growth arrest. Many tumors show downregulation of TBP-2 mRNA expression, indicating a close association between mRNA expression reduction and tumorigenesis. A growth suppressor thioredoxin binding protein-2 /vitamin D3 upregulated protein 1 (VDUP1) has its expression suppressed in HTLV-cell lines. The interaction between TBP-2/VDUP1 and TRX was documented in vitro and in vivo and apparently acts as a negative regulator of TRX. Loss of TBP-2 expression was found to be an important pathway of some HTLV cell line transformation [57Masutani H, Ueda S, Yodoi J. The thioredoxin system in retroviral infection and apoptosis. Cell Death Differ 2005; 12(Suppl. 1): 991-8.
[http://dx.doi.org/10.1038/sj.cdd.4401625] [PMID: 15818395]
].

4. DISCUSSION

This systematic review is the first one, to the best of our knowledge, to assess the role of vitamin D in HTLV infection. Despite the low number of published works on this topic, an association was observed between vitamin D and HTLV- associated diseases.

The main results of this review indicate that vitamin D can contribute to the pathogenesis of HTLV infection. It was also observed that 1,25(OH)2D inhibited, in vitro, the synthesis of de novo DNA and proliferation of HTLV infected lymphocytes [41Yamada H, Nakao Y, Fujita T. Inhibition of cellular proliferation in human T lyophotropic virus type I (HTLV-I)-infected T cells from patients with HAM by steroid hormones and cyclosporin A. Kobe J Med Sci 1991; 37(2): 57-79.
[PMID: 1921263]
-43Inoue D, Matsumoto T, Ogata E, Ikeda K. 22-Oxacalcitriol, a noncalcemic analogue of calcitriol, suppresses both cell proliferation and parathyroid hormone-related peptide gene expression in human T cell lymphotrophic virus, type I-infected T cells. J Biol Chem 1993; 268(22): 16730-6.
[PMID: 8393873]
]. This action could contribute to control HTLV replication. Although initial observations suggested that the synthesis of 1,25(OH)2D and PTHrP by HTLV-infected lymphocytes in patients with ATL was associated with hypercalcemia, the main cause of death in patients with ATL, subsequent studies failed to show increased levels of 1,25(OH)2D and PTHrP [38Oliveira PD, Farre L, Bittencourt AL. Adult T-cell leukemia/lymphoma. Rev Assoc Med Bras (1992) 2016; 62(7): 691-700.
[http://dx.doi.org/10.1590/1806-9282.62.07.691] [PMID: 27925051]
, 41Yamada H, Nakao Y, Fujita T. Inhibition of cellular proliferation in human T lyophotropic virus type I (HTLV-I)-infected T cells from patients with HAM by steroid hormones and cyclosporin A. Kobe J Med Sci 1991; 37(2): 57-79.
[PMID: 1921263]
]. A prospective study of subjects admitted to a hematology unit evaluated the incidence of hypercalcemia and the association with humoral mechanisms involving PTHrP, parathyroid hormone (PTH) and 1,25(OH)2D. Hypercalcemia was detected in few subjects and was caused by primary hyperparathyroidism. No evidence was found on a humoral mechanism associated with 1,25(OH)2D, but increased levels of PTHrP (similar to those seen in humoral hypercalcemia of malignancy) were detected in some patients. The relationship between elevated circulating PTHrP, and hypercalcemia during treatment, indicates a PTHrP role in the pathogenesis of hypercalcemia [58Firkin F, Seymour JF, Watson AM, Grill V, Martin TJ. Parathyroid hormone-related protein in hypercalcaemia associated with haematological malignancy. Br J Haematol 1996; 94(3): 486-92.
[http://dx.doi.org/10.1046/j.1365-2141.1996.d01-1819.x] [PMID: 8790147]
] Such association raises the hypothesis that PTHrP production by neoplastic cells in such disorders promotes a paracrine effect to induce local bone resorption. When it is released in greater amounts (generating increased circulating levels), it can promote an additional humoral-mediated effect on the development of hypercalcemia [58Firkin F, Seymour JF, Watson AM, Grill V, Martin TJ. Parathyroid hormone-related protein in hypercalcaemia associated with haematological malignancy. Br J Haematol 1996; 94(3): 486-92.
[http://dx.doi.org/10.1046/j.1365-2141.1996.d01-1819.x] [PMID: 8790147]
, 59Firkin F, Schneider H, Grill V. Parathyroid hormone-related protein in hypercalcemia associated with hematological malignancy. Leuk Lymphoma 1998; 29(5-6): 499-506.
[http://dx.doi.org/10.3109/10428199809050909] [PMID: 9643563]
]. Data from patients with lymphoma (including patients with AIDS-associated tumors) suggest that the deregulated synthesis of a 1,25(OH)2D-like metabolite is a frequent cause of hypercalcemia and hypercalciuria [60Adams JS, Fernandez M, Gacad MA, et al. Vitamin D metabolite-mediated hypercalcemia and hypercalciuria patients with AIDS- and non-AIDS-associated lymphoma. Blood 1989; 73(1): 235-9.
[PMID: 2910361]
].

Some available evidence suggests that 1,25(OH)2D or vitamin D analogs can potently differentiate acute myeloid leukemia cells in vitro. The action of vitamin D on the inhibition of malignant cell proliferation in hematological malignancies indicates that it can be used in cancer therapy [61Cao H, Xu Y, de Necochea-Campion R, et al. Application of vitamin D and vitamin D analogs in acute myelogenous leukemia. Exp Hematol 2017; 50: 1-12.
[http://dx.doi.org/10.1016/j.exphem.2017.01.007] [PMID: 28174131]
, 62Kim M, Mirandola L, Pandey A, et al. Application of vitamin D and derivatives in hematological malignancies. Cancer Lett 2012; 319(1): 8-22.
[http://dx.doi.org/10.1016/j.canlet.2011.10.026] [PMID: 22193723]
].

VDR ApaI gene polymorphism was associated with a lower risk of developing HAM/TSP but it was not associated with the clinical course or disability degree in HAM/TSP. Six major VDR polymorphisms (CDx, A1012G, FokI, BsmI, ApaI and TaqI) have been studied in infection susceptibility to enveloped viruses [63Laplana M, Royo JL, Fibla J, Vitamin D. Vitamin D Receptor polymorphisms and risk of enveloped virus infection: A meta-analysis. Gene 2018; 678: 384-94.
[http://dx.doi.org/10.1016/j.gene.2018.08.017] [PMID: 30092343]
]. In studies carried out with HIV patients, it was observed an association of VDR gene polymorphisms and HIV disease progression in injection drug users [64Laplana M, Sánchez-de-la-Torre M, Puig T, Caruz A, Fibla J. Vitamin-D pathway genes and HIV-1 disease progression in injection drug users. Gene 2014; 545(1): 163-9.
[http://dx.doi.org/10.1016/j.gene.2014.04.035] [PMID: 24768180]
, 65de la Torre MS, Torres C, Nieto G, et al. Vitamin D receptor gene haplotypes and susceptibility to HIV-1 infection in injection drug users. J Infect Dis 2008; 197(3): 405-10.
[http://dx.doi.org/10.1086/525043] [PMID: 18205531]
]. In addition, another study detected an association between specific VDR gene polymorphisms and delayed disease progression rates, as well as, in resistance to HIV infection [66Nieto G, Barber Y, Rubio MC, Rubio M, Fibla J. Association between AIDS disease progression rates and the Fok-I polymorphism of the VDR gene in a cohort of HIV-1 seropositive patients. J Steroid Biochem Mol Biol 2004; 89-90(1-5): 199-207.
[http://dx.doi.org/10.1016/j.jsbmb.2004.03.086] [PMID: 15225772]
]. It was observed an association between rates of progression to AIDS and the VDR FokI polymorphism [52Johnston SR, Hammond PJ. Elevated serum parathyroid hormone related protein and 1,25-dihydroxycholecalciferol in hypercalcaemia associated with adult T-cell leukaemia-lymphoma. Postgrad Med J 1992; 68(803): 753-5.
[http://dx.doi.org/10.1136/pgmj.68.803.753] [PMID: 1480540]
]. A meta-analysis also showed the association of FokI polymorphism with susceptibility to respiratory syncytial virus [63Laplana M, Royo JL, Fibla J, Vitamin D. Vitamin D Receptor polymorphisms and risk of enveloped virus infection: A meta-analysis. Gene 2018; 678: 384-94.
[http://dx.doi.org/10.1016/j.gene.2018.08.017] [PMID: 30092343]
].

Table 1
Characteristics and results of selected studies.


High levels of proinflammatory cytokines (especially TNF-α, which is found in persistent immune activation in HIV infection), may induce a defect in hydroxylation and 25(OH)D3 activity by blocking the PTH stimulatory effect on renal 1-α-hydroxylase enzyme, reducing conversion from the inactive form to the active form of vitamin D (1,25 (OH)2D) [23Aguillar-Jiménez W, Zapata W, Rugeles MT. Participación de la vitamina D em la patogénesis de la infección por el virus de la inmunodeficiencia humana tipo 1. Infecto 2013; 17(3): 146-52.
[http://dx.doi.org/10.1016/S0123-9392(13)70721-5]
, 30Barbosa N, Costa L, Pinto M, Rosinha P, Rosinha I, Couto M. Vitamin D and HIV Infection: A Systematic Review. J Immunodefic Disord 2014; 3(1): 1-11., 67Aguilar-Jiménez W, Zapata W, Caruz A, Rugeles MT. High transcript levels of vitamin D receptor are correlated with higher mRNA expression of human beta defensins and IL-10 in mucosa of HIV-1-exposed seronegative individuals. PLoS One 2013; 8(12)e82717
[http://dx.doi.org/10.1371/journal.pone.0082717] [PMID: 24349345]
]. In a preliminary study, we identified a high frequency of hypovitaminosis D in patients with HAM / TSP, and these patients had increased levels of TNF-α when compared to asymptomatic carriers of HTLV and controls (negative HTLV) (Netto, et al., submitted) [68Netto E, Silva A, Pedroso C, Brites C. Hypovitaminosis D is associated with higher levels of inflammatory cytokines and with HAM/TSP in HTLV-infected patients (submitted).]

Reprinted from Shu, S.; Dirksen, W.; Weibaecher, K..; Rosol, T. Mechanisms of Humoral Hypercalcemia of Malignancy in Leukemia/Lymphoma. In T Cell-Leukemia. Babusikova O., Ed.; 2011, 181-206 [45Shu ST, Dirksen WP, Weibaecher KN, Rosol TJ. Mechanisms of Humoral Hypercalcemia of Malignancy in Leukemia/Lymphoma.T Cell-Leukemia 2011; 181-206.].

5. REVIEW LIMITATIONS

The results of this analysis should be interpreted with caution, due to some limitations. Firstly, there was a wide heterogeneity among studies, which did not allow us to perform a meta-analysis. In addition, most included studies were in vitro experiments with little emphasis on the clinical aspects of diseases associated with HTLV infection. Nevertheless, the available data demonstrate a potential action of vitamin D on HTLV pathogenesis and provides a rationale for a deep investigation of the relationship between vitamin D and HTLV infection.

CONCLUSION

This review demonstrates that there is an association between vitamin D and HTLV infection. However, further studies on infected HTLV patients are needed to understand the mechanisms involved in the pathogenesis of hypercalcemia in ATL and the relationship between vitamin D and HAM/TSP development.

LIST OF ABBREVIATIONS

HIV = Human Immunodeficiency Virus;
HTLV = Human T-cell Lymphotropic Virus;
ATL = Adult T cell Leukemia/Lymphoma;
HAM/TSP = HTLV- Associated Myelopathy/ Tropical Spastic Paraparesis

CONSENT FOR PUBLICATION

Not applicable.

STANDARD OF REPORTING

PRISMA Guideline and Methodology were followed.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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