{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T17:11:49Z","timestamp":1782234709256,"version":"3.54.5"},"reference-count":47,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T00:00:00Z","timestamp":1602547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Conflicting results on the involvement of vitamin D deficiency in inflammatory and immune response in HIV+ subjects are reported. We aimed to characterize the possible influence of vitamin D status on changes in expression of tissue transglutaminase gene (TGM2) and other genes involved in inflammatory response and autophagy in peripheral blood mononuclear cells (PBMC) from HIV+ subjects. HIV+ subjects (n = 57) under antiretroviral therapy (ART) and healthy controls (n = 40) were enrolled. mRNA levels of 1-alpha-hydroxylase (CYP27B1), tumor necrosis factor-\u03b1 (TNF-\u03b1), interferon-\u03b3 (IFN-\u03b3), TGM2, microtubule-associated protein 1A\/1B-light chain 3 (LC3), autophagy-related 5 homolog (ATG5), and Beclin 1 (BECN1) were quantified by real-time PCR. In HIV+ subjects, 25(OH)D3 plasma levels were negatively correlated with time since HIV diagnosis. In PBMC from HIV+ subjects, increases in gene expression of TNF-\u03b1 and IFN-\u03b3 in comparison to controls were observed. The highest increase in TNF-\u03b1 transcripts was observed in HIV+ subjects with deficient 25(OH)D3 levels. Autophagy-related genes LC3, ATG5, and BECN1 were down-regulated in HIV+ subjects. Moreover, TGM2 transcripts were up-regulated in PBMC from HIV+ subjects with 25(OH)D3 deficiency. Changes observed in PBMC from HIV+ subjects appeared to be dependent on vitamin D status. The present results suggest that vitamin D deficiency is associated with changes in the expression of markers of inflammation and autophagy, resulting in immune cell dysfunction.<\/jats:p>","DOI":"10.3390\/ijms21207558","type":"journal-article","created":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T08:59:22Z","timestamp":1602665962000},"page":"7558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Vitamin D Status Modulates Inflammatory Response in HIV+ Subjects: Evidence for Involvement of Autophagy and TG2 Expression in PBMC"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8852-7023","authenticated-orcid":false,"given":"Monica","family":"Curr\u00f2","sequence":"first","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9072-1148","authenticated-orcid":false,"given":"Giuseppa","family":"Visalli","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9640-8742","authenticated-orcid":false,"given":"Giovanni Francesco","family":"Pellican\u00f2","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Department of Human Pathology of Adult and Childhood \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Ferlazzo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giovanna","family":"Costanzo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"D\u2019Andrea","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8593-9495","authenticated-orcid":false,"given":"Daniela","family":"Caccamo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Nunnari","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Ientile","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1097\/QAD.0b013e328337b161","article-title":"High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients","volume":"24","author":"Mueller","year":"2010","journal-title":"AIDS"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1097\/QAI.0b013e31822e57e9","article-title":"Prevalence of hypovitaminosis D and factors associated with vitamin D deficiency and morbidity among HIV-infected patients enrolled in a large Italian cohort","volume":"58","author":"Vescini","year":"2011","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1093\/cid\/ciq158","article-title":"Study to Understand the Natural History of, H.I.V.; Investigators, A.i.t.E.o.E.T. Low vitamin D among HIV-infected adults: Prevalence of and risk factors for low vitamin D Levels in a cohort of HIV-infected adults and comparison to prevalence among adults in the US general population","volume":"52","author":"Dao","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"425","DOI":"10.3851\/IMP1502","article-title":"Association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D","volume":"15","author":"Brown","year":"2010","journal-title":"Antivir. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"19826","DOI":"10.7448\/IAS.17.4.19826","article-title":"Hypovitaminosis D in HIV-infected patients in Lisbon: A link with antiretroviral treatment","volume":"17","author":"Boura","year":"2014","journal-title":"J. Int. AIDS Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/1742-6405-7-40","article-title":"Decrease of vitamin D concentration in patients with HIV infection on a non nucleoside reverse transcriptase inhibitor-containing regimen","volume":"7","author":"Florence","year":"2010","journal-title":"AIDS Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1093\/cid\/civ455","article-title":"Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study","volume":"61","author":"Taiwo","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1093\/infdis\/jir188","article-title":"Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202","volume":"203","author":"McComsey","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1097\/00002030-200303070-00006","article-title":"HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D","volume":"17","author":"Cozzolino","year":"2003","journal-title":"AIDS"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Legeai, C., Vigouroux, C., Souberbielle, J.C., Bouchaud, O., Boufassa, F., Bastard, J.P., Carlier, R., Capeau, J., Goujard, C., and Meyer, L. (2013). Associations between 25-hydroxyvitamin D and immunologic, metabolic, inflammatory markers in treatment-naive HIV-infected persons: The ANRS CO9 \u226aCOPANA\u226b cohort study. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074868"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1089\/aid.2012.0120","article-title":"Serum 25-hydroxyvitamin d levels and C-reactive protein in persons with human immunodeficiency virus infection","volume":"29","author":"Poudel","year":"2013","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1097\/QAD.0b013e328347f6f7","article-title":"Vitamin D and clinical disease progression in HIV infection: Results from the EuroSIDA study","volume":"25","author":"Viard","year":"2011","journal-title":"AIDS"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"881","DOI":"10.2310\/JIM.0b013e31821b8755","article-title":"Vitamin D and the immune system","volume":"59","author":"Aranow","year":"2011","journal-title":"J. Investig. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.rdc.2012.03.013","article-title":"Vitamin D: Extraskeletal health","volume":"38","author":"Holick","year":"2012","journal-title":"Rheum. Dis. Clin. North. Am."},{"key":"ref_15","unstructured":"Bishop, E., Ismailova, A., Dimeloe, S.K., Hewison, M., and White, J.H. (2020). Vitamin D and immune regulation: Antibacterial, antiviral, anti-inflammatory. JBMR Plus."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"40","DOI":"10.23876\/j.krcp.19.093","article-title":"Correlation between CD4 count and glomerular filtration rate or urine protein:Creatinine ratio in human immunodeficiency virus-infected children","volume":"39","author":"Aliyannissa","year":"2020","journal-title":"Kidney Res. Clin. Pract."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.4161\/cc.9.11.11754","article-title":"Intracellular accumulation of cell cycle regulatory proteins and nucleolin re-localization are associated with pre-lethal ultrastructural lesions in circulating T lymphocytes: The HIV-induced cell cycle dysregulation revisited","volume":"9","author":"Visalli","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_18","first-page":"307","article-title":"Autophagy in HIV-induced T cell death","volume":"335","author":"Espert","year":"2009","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1172\/JCI26185","article-title":"Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4","volume":"116","author":"Espert","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/joim.12596","article-title":"Role of autophagy in HIV infection and pathogenesis","volume":"281","author":"Nardacci","year":"2017","journal-title":"J. Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sassi, F., Tamone, C., and D\u2019Amelio, P. (2018). Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients, 10.","DOI":"10.3390\/nu10111656"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.4161\/auto.21154","article-title":"Autophagy induction by vitamin D inhibits both Mycobacterium tuberculosis and human immunodeficiency virus type 1","volume":"8","author":"Campbell","year":"2012","journal-title":"Autophagy"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00726-016-2334-9","article-title":"Is monocyte- and macrophage-derived tissue transglutaminase involved in inflammatory processes?","volume":"49","author":"Chrobok","year":"2017","journal-title":"Amino Acids"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Caccamo, D., Ferlazzo, N., Curro, M., Ricca, S., and Ientile, R. (2018). Transglutaminase 2 Up-Regulation Is Associated with Inflammatory Response in PBMC from Healthy Subjects with Hypovitaminosis D. Med. Sci., 6.","DOI":"10.3390\/medsci6040103"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7497","DOI":"10.1002\/jcp.26603","article-title":"Transglutaminase activity regulates differentiation, migration and fusion of osteoclasts via affecting actin dynamics","volume":"233","author":"Sun","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Paolella, G., Nanayakkara, M., Sposito, S., Lepretti, M., Auricchio, S., Esposito, C., Barone, M.V., Martucciello, S., and Caputo, I. (2020). Constitutive Differential Features of Type 2 Transglutaminase in Cells Derived from Celiac Patients and from Healthy Subjects. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041231"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0022-1759(02)00077-7","article-title":"\"Tissue\" transglutaminase in AIDS","volume":"265","author":"Amendola","year":"2002","journal-title":"J. Immunol. Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.cca.2020.04.041","article-title":"Vitamin D status influences transcriptional levels of RANKL and inflammatory biomarkers which are associated with activation of PBMC","volume":"507","author":"Ferlazzo","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7708","DOI":"10.1038\/s41598-018-26064-6","article-title":"Vitamin D levels correlate with lymphocyte subsets in elderly patients with age-related diseases","volume":"8","author":"Mao","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1210\/jc.2011-0385","article-title":"Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline","volume":"96","author":"Holick","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.gene.2014.04.035","article-title":"Vitamin-D pathway genes and HIV-1 disease progression in injection drug users","volume":"545","author":"Laplana","year":"2014","journal-title":"Gene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"487","DOI":"10.2174\/157016210793499330","article-title":"Immunophenotype of vitamin D receptor polymorphism associated to risk of HIV-1 infection and rate of disease progression","volume":"8","author":"Torres","year":"2010","journal-title":"Curr. HIV Res."},{"key":"ref_33","first-page":"59","article-title":"Vitamin D deficiency in HIV: A shadow on long-term management?","volume":"16","author":"Orkin","year":"2014","journal-title":"AIDS Rev."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Zicari, S., Sessa, L., Cotugno, N., Ruggiero, A., Morrocchi, E., Concato, C., Rocca, S., Zangari, P., Manno, E.C., and Palma, P. (2019). Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART. Viruses, 11.","DOI":"10.3390\/v11030200"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1097\/QAD.0000000000001782","article-title":"Vitamin D status and immune function reconstitution in HIV-infected men initiating therapy","volume":"32","author":"Abraham","year":"2018","journal-title":"AIDS"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5968","DOI":"10.4049\/jimmunol.1003332","article-title":"Vitamin D and the regulation of placental inflammation","volume":"186","author":"Liu","year":"2011","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1093\/hmg\/ddt529","article-title":"The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells","volume":"23","author":"Shahijanian","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.bonr.2018.02.004","article-title":"Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review","volume":"8","author":"Bikle","year":"2018","journal-title":"Bone Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.imbio.2017.10.039","article-title":"Serum interleukin-6 levels are increased in HIV-infected patients that develop autoimmune disease during long-term follow-up","volume":"223","author":"Trovato","year":"2018","journal-title":"Immunobiology"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Manion, M., Hullsiek, K.H., Wilson, E.M.P., Rhame, F., Kojic, E., Gibson, D., Hammer, J., Patel, P., Brooks, J.T., and Baker, J.V. (2017). Vitamin D deficiency is associated with IL-6 levels and monocyte activation in HIV-infected persons. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175517"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1093\/infdis\/jiu074","article-title":"Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIV-infected persons","volume":"210","author":"Shepherd","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1146\/annurev-med-042909-093756","article-title":"HIV infection, inflammation, immunosenescence, and aging","volume":"62","author":"Deeks","year":"2011","journal-title":"Annu. Rev. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/S0140-6736(13)61809-7","article-title":"The end of AIDS: HIV infection as a chronic disease","volume":"382","author":"Deeks","year":"2013","journal-title":"Lancet"},{"key":"ref_44","first-page":"325","article-title":"Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection","volume":"11","author":"Wu","year":"2011","journal-title":"Discov. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"25596","DOI":"10.1074\/jbc.M801716200","article-title":"Vitamin D3 induces autophagy of human myeloid leukemia cells","volume":"283","author":"Wang","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.3389\/fimmu.2019.01907","article-title":"In vivo Differentiation of Human Monocytes","volume":"10","author":"Coillard","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5539","DOI":"10.1073\/pnas.0700732104","article-title":"Alteration in the gene expression pattern of primary monocytes after adhesion to endothelial cells","volume":"104","author":"Lindecke","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/20\/7558\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:20:40Z","timestamp":1760178040000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/20\/7558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,13]]},"references-count":47,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ijms21207558"],"URL":"https:\/\/doi.org\/10.3390\/ijms21207558","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,13]]}}}