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Human and Medical Genetics • Genet. Mol. Biol. 42 (2) • Apr-Jun 2019 • https://doi.org/10.1590/1678-4685-GMB-2017-0289   copy

VDR polymorphisms influence immunological response in HIV-1+ individuals undergoing antiretroviral therapy

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Vitamin D exerts an immuno-modulatory activity on several immune system cells through the vitamin D receptor (VDR). Herein, we verified that age and a therapeutic regimen containing protease inhibitors are associated with failures in antiretroviral therapies (ARVs). In addition, we assessed whether a VDR SNP (rs11568820: C allele and CC genotype) and GC (rs2228570-rs11568820) allelic combinations are associated with immunological failure (p < 0.05). Our findings suggest a possible role of VDR SNPs on immunological failure in HIV-1+ individuals undergoing regular ARVs.

Keywords:
VDR; HIV-1; ARVs; SNPs; CD4 recovery

Antiretroviral therapies (ARVs) have changed the landscape of Human Immunodeficiency Virus (HIV) treatment in the last years. ARVs act by boosting immune functions and reducing morbidity and mortality by suppressing viral replication (Palella et al., 2006Palella FJ, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT and Holmberg SD (2006) Mortality in the highly active antiretroviral therapy era: Changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 43:27–34.). There is no “one fits all” therapy, since some individuals receiving ARVs are not able to suppress the viral load to undetectable levels as expected (virological failure) (Coelho et al., 2013Coelho AVC, Silva SPS, de Alencar LC, Stocco G, Crovella S, Brandão LA and Guimarães RL (2013) ABCB1 and ABCC1 variants associated with virological failure of first-line protease inhibitors antiretroviral regimens in Northeast Brazil patients. J Clin Pharmacol 53:1286–1293.). On the other hand, some individuals with undetectable viral load, cannot recover the quasi-normal CD4+ T-cell count (immunological failure) (Kelley et al., 2009Kelley CF, Kitchen CMR, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, Crane HM, Willig J, Mugavero M, Saag M et al. (2009) Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 48:787–94.). These phenomena might be due to the hosts’ genetics, immunological factors, and viral profiles (Geretti et al., 2009Geretti AM, Harrison L, Green H, Sabin C, Hill T, Fearnhill E, Pillay D and Dunn D (2009) Effect of HIV-1 subtype on virologic and immunologic response to starting highly active antiretroviral therapy. Clin Infect Dis 48:1296–1305.; Robbins et al., 2009Robbins GK, Spritzler JG, Chan ES, Asmuth DM, Gandhi RT, Rodriguez BA, Skowron G, Skolnik PR, Shafer RW and Pollard RB (2009) Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group Protocol 384. Clin Infect Dis 48:350–361.).

1,25-dihydroxy vitamin D (1,25[OH]2D) exerts potent immunologic roles in both innate and adaptive responses. Its binding with vitamin D receptor (VDR) promotes a series of intracellular events culminating in the modulation of expression levels of various target genes. These effects may promote the control of intracellular pathogens, mainly by producing antimicrobial peptides, and stimulating phagocytic activity in macrophages (Prietl et al., 2013Prietl B, Treiber G, Pieber TR and Amrein K (2013) Vitamin D and immune function. Nutrients 5:2502–2521.).

In HIV-1 infection, variable levels of 1,25[OH]2D may decrease the immune system activation during the acute phase, or induce a less effective T-helper lymphocyte response throughout the chronic phase (Appay and Sauce, 2008Appay V and Sauce D (2008) Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 214:231–241.; Giusti and Penco, 2011Giusti A and Penco GP (2011) Vitamin D deficiency in HIV-infected patients: A systematic review. Nutr Diet Suppl 3:101–111.). Indeed, individuals with adequate levels of this vitamin, have been seen to better counteract HIV replication (Lake and Adams, 2011Lake JE and Adams JS (2011) Vitamin D in HIV-Infected patients. Curr HIV/AIDS Rep 8:133–141.).

In addition, ARVs may alter the circulating levels of 25-hydroxy vitamin D (25[OH]D) (1,25[OH]2D metabolic precursor), as these compounds share common cytochrome P450 enzymes involved in their synthesis (1,25[OH]2D) and excretory (ARVs) metabolic pathways (Mueller et al., 2010Mueller NJ, Fux C, Ledergerber B, Elzi L, Schmid P, Dang T, Magenta L, Calmy A, Vergopoulos A and Bischoff-Ferrari H (2010) High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. Aids 24:1127–1134.; Welz et al., 2010Welz T, Childs K, Ibrahim F, Poulton M, Taylor CB, Moniz CF and Post FA (2010) Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS 24:1923–1928.). Interestingly, 1,25[OH]2D insufficiency/deficiency has been associated with the usage of ARVs (Cozzolino et al., 2003Cozzolino M, Vidal M, Arcidiacono MV, Tebas P, Yarasheski KE and Dusso AS (2003) HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D. Aids 17:513–520.; Brown and McComsey, 2010Brown T and McComsey G (2010) Association between initiation of anti-retroviral therapy with efavirenz and decreases in 25-hydroxyvitamin. Antivir Ther 15:425–9.).

Single nucleotide polymorphisms (SNPs) in the VDR gene (12q13.11) have been associated to susceptibility and progression of HIV/AIDS, since they may alter gene function and compromise the role of 1,25[OH]2D (de la Torre et al., 2008De La Torre MS, Torres C, Nieto G, Vergara S, Carrero AJ, Macías J, Pineda JA, Caruz A and Fibla J (2008) Vitamin D receptor gene haplotypes and susceptibility to HIV-1 infection in injection drug users. J Infect Dis 197:405–10.; Alagarasu et al., 2009Alagarasu K, Selvaraj P, Swaminathan S, Narendran G and Narayanan PR (2009) 5’ regulatory and 3’ untranslated region polymorphisms of vitamin D receptor gene in south Indian HIV and HIV-TB patients. J Clin Immunol 29:196–204.; Aguilar-Jiménez et al., 2013Aguilar-Jiménez W, Zapata W, Caruz A and Rugeles MT (2013) 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 8:e82717.; Laplana et al., 2014Laplana M, Sánchez-de-la-Torre M, Puig T, Caruz A and Fibla J (2014) Vitamin-D pathway genes and HIV-1 disease progression in injection drug users. Gene 545:163–169.). However, there are no reports associating these genetic variants with successful treatment and immune recovery.

In this work, we investigated the distribution of VDR SNPs in HIV-1 infected individuals (HIV-1+) to unravel their relation with treatment response and immune recovery.

We analyzed 195 HIV-1+ individuals from Recife and minor towns of the state of Pernambuco (Northeastern Brazil), recruited from 2011 to 2014 at the Institute of Integral Medicine Professor Fernando Figueira (Human Research Ethics Committee register nr. 2629-13). Individuals lacking pre-existing viral hepatitis co-infection, and who have adhered for at least one year to ARVs have been selected for this study (Coelho et al., 2013Coelho AVC, Silva SPS, de Alencar LC, Stocco G, Crovella S, Brandão LA and Guimarães RL (2013) ABCB1 and ABCC1 variants associated with virological failure of first-line protease inhibitors antiretroviral regimens in Northeast Brazil patients. J Clin Pharmacol 53:1286–1293.). The studied population was stratified into 132 individuals with undetectable viral load (< 50 copies/mL) (virological success/suppression) and 63 individuals having detectable viral load (> 50 copies/mL) (virological failure). In addition, based on the comparison between CD4+ T-cell count before treatment (baseline) and after one year of treatment (Li et al., 2011Li T, Wu N, Dai Y, Qiu Z, Han Y, Xie J, Zhu T and Li Y (2011) Reduced thymic output is a major mechanism of immune reconstitution failure in HIV-infected patients after long-term antiretroviral therapy. Clin Infect Dis 53:944–951.), individuals possessing virological suppression were divided as immunological success (65) (recovery of CD4+ > 200 cells/mm3) and immunological failure (67) (non-recovery CD4+ < 200 cells/mm3).

Individuals manifesting virological failure were mostly female (66.7%), with a median age of 35 years (p=0.009, Mann-Whitney test), and receiving therapeutic regimens containing protease inhibitors (2 non-nucleoside reverse transcriptase inhibitor + protease inhibitor [NNRTI+PI]; 55.6%, p=0.037, Chi-square test). Furthermore, the NNRTI-containing regimen resulted more frequently in individuals with immunological failure (68.7%) in comparison to the immunological successful ones (53.1%, p=0.047, Chi-square test) (Table 1).

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Table 1
Clinical and Epidemiological characteristics of the study population.

Studies in Latin American populations (Bello et al., 2011Bello EJM, Correia AF, Marins JRP, Merchan-Hamann E and Kanzaki LIB (2011) Predictors of virologic failure in HIV/AIDS patients treated with highly active antiretroviral therapy in Brasilia, Brazil, during 2002-2008. Drug Target Insights 5:33–41.; Alave et al., 2013Alave J, Paz J, González E, Campos M, Rodríguez M, Willig J and Echevarría J (2013) Risk factors associated with virologic failure in HIV- infected patients receiving antiretroviral therapy at a public hospital in Peru. Rev Chilena Infectol 30:42–48.; Cesar et al., 2015Cesar C, Jenkins CA, Shepherd BE, Padgett D, Mejía F, Ribeiro SR, Cortes CP, Pape JW, Madero JS, Fink V et al. (2015) Incidence of virological failure and major regimen change of initial combination antiretroviral therapy in the Latin America and the Caribbean: An observational cohort study. Lancet HIV 2:e492–e500.) also identified as risk factors for virological failure parameters such as younger age (20 years), infection pathway (Cesar et al., 2015Cesar C, Jenkins CA, Shepherd BE, Padgett D, Mejía F, Ribeiro SR, Cortes CP, Pape JW, Madero JS, Fink V et al. (2015) Incidence of virological failure and major regimen change of initial combination antiretroviral therapy in the Latin America and the Caribbean: An observational cohort study. Lancet HIV 2:e492–e500.), antiretroviral use history before starting a new therapy regimen, therapy change due to toxicity, opportunistic infections, baseline CD4+ T-cells count below 100 cells/μL, adherence, advanced clinical stage (Alave et al., 2013Alave J, Paz J, González E, Campos M, Rodríguez M, Willig J and Echevarría J (2013) Risk factors associated with virologic failure in HIV- infected patients receiving antiretroviral therapy at a public hospital in Peru. Rev Chilena Infectol 30:42–48.), geographical origin, and Mycobacterium tuberculosis co-infection (Bello et al., 2011Bello EJM, Correia AF, Marins JRP, Merchan-Hamann E and Kanzaki LIB (2011) Predictors of virologic failure in HIV/AIDS patients treated with highly active antiretroviral therapy in Brasilia, Brazil, during 2002-2008. Drug Target Insights 5:33–41.).

Besides the clinical-epidemiological characteristics, a panel of four tag-SNPs in the intronic region within the VDR gene (rs3890733, rs4760648, rs1540339, rs2248098) and two functional ones, namely rs2228570 (Fok1 – missense variation – stat lost) and rs11568820 (Cdx2 – regulatory variation) were studied. SNP selection was based on public data bank as well as literature data (de la Torre et al., 2008De La Torre MS, Torres C, Nieto G, Vergara S, Carrero AJ, Macías J, Pineda JA, Caruz A and Fibla J (2008) Vitamin D receptor gene haplotypes and susceptibility to HIV-1 infection in injection drug users. J Infect Dis 197:405–10.; Alagarasu et al., 2009Alagarasu K, Selvaraj P, Swaminathan S, Narendran G and Narayanan PR (2009) 5’ regulatory and 3’ untranslated region polymorphisms of vitamin D receptor gene in south Indian HIV and HIV-TB patients. J Clin Immunol 29:196–204.; Laplana et al., 2014Laplana M, Sánchez-de-la-Torre M, Puig T, Caruz A and Fibla J (2014) Vitamin-D pathway genes and HIV-1 disease progression in injection drug users. Gene 545:163–169.; Xu et al., 2015Xu C, Tang P, Ding C, Li C, Chen J, Xu Z, Mao Y, Wu M and Zhao J (2015) Vitamin D receptor gene foki polymorphism contributes to increasing the risk of HIV-negative tuberculosis: Evidence from a meta-analysis. PLoS One 10:e0140634.). All variants were genotyped using allele-specific fluorogenic probes by real-time PCR and presented minor allele frequency (MAF) ≥ 10% in Caucasian (CEU) and Yoruba (YRI) populations, considering them as proxies to Brazil’s ancestral populations (Coelho et al., 2015Coelho A, Moura R, Cavalcanti C, Guimaraes R, Sandrin-Garcia P, Crovella S and Brandão LAC (2015) A rapid screening of ancestry for genetic association studies in an admixed population from Pernambuco, Brazil. Genet Mol Res 14:2876–2884.).

Allelic and genotypic frequencies of VDR SNPs in treatment and immunological response groups are reported in Table 1. All the considered SNPs studied were in accordance with Hardy-Weinberg equilibrium in all groups, except for SNP rs3890733. No significant differences were observed for the tested SNPs relative to treatment response, but the SNP rs11568820 (C > T) was found to be associated with immune recovery.

The C allele (rs11568820) was significantly more frequent in individuals presenting immunological failure (62.1%), rather than in those showing immunological success (48.4%; OR=1.74; 95%CI=1.01-3.03; p=0.037, Fisher’s exact test). Similarly, the C/C genotype was significantly more frequent in immunological failure (34.5%) in comparison to individuals with immunological success (19.7%; OR=3.78; 95%CI=1.03-15.57; p=0.045, Fisher’s exact test) (Table 2).

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Table 2
Allelic and genotypic frequencies of VDR SNPs in HIV-1+ patients in HAART treatment as to the virological and immunological response.

No haplotype block was observed for VDR functional SNPs in all studied groups (D’ > 0.20). Allelic combination analyses revealed that only the GC allele combination (rs2228570-rs11568820) was associated with immunological failure (OR=2.19; 95%CI=1.09-4.45; p=0.023, Fisher’s exact test) (Table S1).

Two multivariate analyses were performed containing variables with p ≤ 0.2 obtained during univariate analyses. Age, gender, antiretroviral drugs classes, and rs2248098 genotypes were included as clinic-epidemiological and genetic variables to assess whether they influenced the overall virological response, but no significant associations were found. The second analysis included the pre-treatment (baseline) CD4+ T-cells count, gender, and antiretroviral drugs classes. In the second multivariate analysis we intended to assess whether rs2248098 and rs11568820 genotypes had any influence on immunological response. Again, the rs11568820 C/C genotype was associated with immunological failure (OR=6.00; 95%CI=1.52-23.72; p-value=0.01) (Table S2).

None of the studied SNPs were involved in viral load control before treatment and CD4+ T-cell count baseline, even when classified according to virological treatment response or immunological recovery (p-values > 0.05; Kruskal-Wallis test, data not shown).

The C allele and C/C genotype of SNP rs11568820 and the GC allelic combination (rs2228570-rs11568820) were associated with immunological failure in individuals that achieved the viral load suppression following ARVs. The understanding of this immunological impairment in viral-suppressed HIV-1 individuals remains elusive mainly due to its multifactorial character. In our work, we addressed a SNP as a candidate for contributing in the immune recovery modulation. The rs11568820 SNP (known as Cdx-2), located within the VDR promoter region, acts at the transcriptional level. Therefore, the presence of the C allele (rs11568820) may result in a decreased transcriptional activity and, consequently, in lower VDR expression (Arai et al., 2001Arai H, Miyamoto KI, Yoshida M, Yamamoto H, Taketani Y, Morita K, Kubota M, Yoshida S, Ikeda M, Watabe F et al. (2001) The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Min Res 16:1256–1264.).

Finally, the levels of 25(OH)D in plasma were obtained from medical records of 31 individuals deriving from our sample groups (19 immunological success and 12 immunological failure). A Cochran-Mantel-Haenszel test was applied to assess whether the interaction between 25(OH)D plasma levels and VDR genotypes had an impact on immunological failure risk, thus following the hypothesis that some VDR genotypes would not respond to 25(OH)D levels, even if they are adequate. However, no significant differences were found (success group median=35.2, IQR=28.1-41.1; failure group median=32.9, IQR=31.4-41.0; W=109; p-value=0.86, Table S3). Next, we stratified the individuals according to VDR genotypes and insufficient/sufficient status and evaluated, through a Cochran-Mantel-Haenszel test, whether the genotypes versus 25(OH)D influenced the risk of immunological failure. Also in this case, no associations were observed. Even deficient 25(OH)D levels have been found not to be associated with immunological failure, irrespective of VDR genotype (data not shown).

We did not identify relationships between plasma levels and immunological failure, in spite of a VDR-associated genotype (rs11568820). This fact may be related to the small number of individuals used in the dosage and/or the absence of a proper classification of studied individuals referred to the infection stage, which in our population is almost impossible to perform, since the vast majority of HIV infected cases have a late diagnosis, thus arriving at health services presumably in a chronic stage, and finally the lack of control regarding seasonal variation in vitamin D. In our cohort it is assumed that such inter-individual variation is small, as there is a regular incidence of solar rays in the geographic region.

Nonetheless, we believe that individuals with immunological failure and VDR genotype (CC – rs11568820), related to low expression of VDR, can impair 1,25[OH]2D action, since its activity occurs through VDR binding (Selvaraj et al., 2012Selvaraj P, Harishankar M, Singh B, Banurekha VV and Jawahar MS (2012) Effect of vitamin D3 on chemokine expression in pulmonary tuberculosis. Cytokine 60:212–219.). A reduced 1,25[OH]2D activity compromises cell-mediated immune response, phagocytic activity in macrophages (Deluca and Cantorna 2001Deluca HF and Cantorna MT (2001) Vitamin D: Its role and uses in immunology. FASEB J 15:2579–2585.; Prietl et al., 2013Prietl B, Treiber G, Pieber TR and Amrein K (2013) Vitamin D and immune function. Nutrients 5:2502–2521.), suppresses T-cell activation, downregulates pro-inflammatory cytokine production, and decreases anti-microbial defence by peptides, which in turn impair viral replication (Beard et al., 2011Beard JA, Bearden A and Striker R (2011) Vitamin D and the anti-viral state. J Clin Virol 50:194–200.).

Furthermore, Chandel et al. (2013)Chandel N, Husain M, Goel H, Salhan D, Lan X, Malhotra A, McGowan J and Singhal PC (2013) VDR hypermethylation and HIV-induced T cell loss. J Leukoc Biol 93:623–31. demonstrated that down-regulation of VDR expression in T-cells deriving from HIV-1+ individuals is due to hypermethylation in the promoter region. These epigenetic alterations increase the activation of the renin angiotensin system (RAS) and reactive oxygen species (ROS) production, inducing double-strand breaks (DSBs) and attenuated DNA repair response, therefore favouring T-cell apoptosis.

ARVs themselves might further compromise the action of 1,25[OH]2D, since some antiretroviral drugs (efavirenz, tenofovir and ritonavir) have been associated with changes in plasma levels of 1,25[OH]2D (Welz et al., 2010Welz T, Childs K, Ibrahim F, Poulton M, Taylor CB, Moniz CF and Post FA (2010) Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS 24:1923–1928.; Dao et al., 2011Dao CN, Patel P, Overton ET, Rhame F, Pals SL, Johnson C, Bush T and Brooks JT (2011) 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. Clin Infect Dis 52:396–405.). In our cohort, amongst individuals with available dosage, we observed that 50% of the cases showing immunological failure used a NNTRI-containing regimen and 50% received a PI-containing treatment. Among the individuals with immunological success, approximately 42% used a NNTRI-containing therapy, against 58% who used PI.

We cannot fail to recognize our limitations. Firstly, the small sample number is directly linked to the individuals treatment adherence. Despite a large number of patients undergoing treatment, the majority had low ARVs adherence. Secondly, for some SNPs the number of genotyped individuals resulted different in relations to others due to the quality of the biological samples, implying technical difficulties in the genotyping process. A further limitation was due to the lack of VDR expression analysis caused by the impossibility to extract RNA from certain biological samples.

In conclusion, our results lead us to hypothesize (Figure 1) that genetic variations in VDR (rs11568820 – C allele and C/C genotype; CG allelic combination) might decrease VDR expression, influencing the binding of 1,25[OH]2D to VDR (possibly disrupting the 1,25[OH]2D action) and inducing apoptosis, consequently affecting CD4+ T-cells recovery. Our work reports for the first time the existence of a relationship between SNPs in the VDR gene and the immunological recovery in HIV-1 + individuals undergoing ARVs.

Figure 1
Hypothetical model of the VDR receptor involvement in HIV-infected individuals treated with antiretroviral therapy and showing immunological failure.

Acknowledgments

We thank all individuals involved in this study and the IMIP-PE. This research received funding from Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco (FACEPE) (APQ-0599-2.02/14) and through a Programa Nacional de Pós-Doutorado (PNPD) grant from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001 .

Conflict of interest

The authors declare no conflict of interest.

Author contributions

RCS, conceived, designed, conducted the experiments, analyzed the data and wrote the manuscript; NMPA, conducted the experiments and wrote the manuscript, JJSP, conducted the experiments, AVCC, analyzed the data, LCA, LACB and SC, critically analyzed the data and contributed in manuscript writing and JAS, conceived, designed the study, critically analized the data and manuscript writing. All authors read and approved the final version.

References

  • Aguilar-Jiménez W, Zapata W, Caruz A and Rugeles MT (2013) 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 8:e82717.
  • Alagarasu K, Selvaraj P, Swaminathan S, Narendran G and Narayanan PR (2009) 5’ regulatory and 3’ untranslated region polymorphisms of vitamin D receptor gene in south Indian HIV and HIV-TB patients. J Clin Immunol 29:196–204.
  • Alave J, Paz J, González E, Campos M, Rodríguez M, Willig J and Echevarría J (2013) Risk factors associated with virologic failure in HIV- infected patients receiving antiretroviral therapy at a public hospital in Peru. Rev Chilena Infectol 30:42–48.
  • Appay V and Sauce D (2008) Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 214:231–241.
  • Arai H, Miyamoto KI, Yoshida M, Yamamoto H, Taketani Y, Morita K, Kubota M, Yoshida S, Ikeda M, Watabe F et al. (2001) The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Min Res 16:1256–1264.
  • Beard JA, Bearden A and Striker R (2011) Vitamin D and the anti-viral state. J Clin Virol 50:194–200.
  • Bello EJM, Correia AF, Marins JRP, Merchan-Hamann E and Kanzaki LIB (2011) Predictors of virologic failure in HIV/AIDS patients treated with highly active antiretroviral therapy in Brasilia, Brazil, during 2002-2008. Drug Target Insights 5:33–41.
  • Brown T and McComsey G (2010) Association between initiation of anti-retroviral therapy with efavirenz and decreases in 25-hydroxyvitamin. Antivir Ther 15:425–9.
  • Cesar C, Jenkins CA, Shepherd BE, Padgett D, Mejía F, Ribeiro SR, Cortes CP, Pape JW, Madero JS, Fink V et al. (2015) Incidence of virological failure and major regimen change of initial combination antiretroviral therapy in the Latin America and the Caribbean: An observational cohort study. Lancet HIV 2:e492–e500.
  • Chandel N, Husain M, Goel H, Salhan D, Lan X, Malhotra A, McGowan J and Singhal PC (2013) VDR hypermethylation and HIV-induced T cell loss. J Leukoc Biol 93:623–31.
  • Coelho AVC, Silva SPS, de Alencar LC, Stocco G, Crovella S, Brandão LA and Guimarães RL (2013) ABCB1 and ABCC1 variants associated with virological failure of first-line protease inhibitors antiretroviral regimens in Northeast Brazil patients. J Clin Pharmacol 53:1286–1293.
  • Coelho A, Moura R, Cavalcanti C, Guimaraes R, Sandrin-Garcia P, Crovella S and Brandão LAC (2015) A rapid screening of ancestry for genetic association studies in an admixed population from Pernambuco, Brazil. Genet Mol Res 14:2876–2884.
  • Cozzolino M, Vidal M, Arcidiacono MV, Tebas P, Yarasheski KE and Dusso AS (2003) HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D. Aids 17:513–520.
  • Dao CN, Patel P, Overton ET, Rhame F, Pals SL, Johnson C, Bush T and Brooks JT (2011) 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. Clin Infect Dis 52:396–405.
  • De La Torre MS, Torres C, Nieto G, Vergara S, Carrero AJ, Macías J, Pineda JA, Caruz A and Fibla J (2008) Vitamin D receptor gene haplotypes and susceptibility to HIV-1 infection in injection drug users. J Infect Dis 197:405–10.
  • Deluca HF and Cantorna MT (2001) Vitamin D: Its role and uses in immunology. FASEB J 15:2579–2585.
  • Geretti AM, Harrison L, Green H, Sabin C, Hill T, Fearnhill E, Pillay D and Dunn D (2009) Effect of HIV-1 subtype on virologic and immunologic response to starting highly active antiretroviral therapy. Clin Infect Dis 48:1296–1305.
  • Giusti A and Penco GP (2011) Vitamin D deficiency in HIV-infected patients: A systematic review. Nutr Diet Suppl 3:101–111.
  • Kelley CF, Kitchen CMR, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, Crane HM, Willig J, Mugavero M, Saag M et al. (2009) Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 48:787–94.
  • Lake JE and Adams JS (2011) Vitamin D in HIV-Infected patients. Curr HIV/AIDS Rep 8:133–141.
  • Laplana M, Sánchez-de-la-Torre M, Puig T, Caruz A and Fibla J (2014) Vitamin-D pathway genes and HIV-1 disease progression in injection drug users. Gene 545:163–169.
  • Li T, Wu N, Dai Y, Qiu Z, Han Y, Xie J, Zhu T and Li Y (2011) Reduced thymic output is a major mechanism of immune reconstitution failure in HIV-infected patients after long-term antiretroviral therapy. Clin Infect Dis 53:944–951.
  • Mueller NJ, Fux C, Ledergerber B, Elzi L, Schmid P, Dang T, Magenta L, Calmy A, Vergopoulos A and Bischoff-Ferrari H (2010) High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. Aids 24:1127–1134.
  • Palella FJ, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT and Holmberg SD (2006) Mortality in the highly active antiretroviral therapy era: Changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 43:27–34.
  • Prietl B, Treiber G, Pieber TR and Amrein K (2013) Vitamin D and immune function. Nutrients 5:2502–2521.
  • Robbins GK, Spritzler JG, Chan ES, Asmuth DM, Gandhi RT, Rodriguez BA, Skowron G, Skolnik PR, Shafer RW and Pollard RB (2009) Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group Protocol 384. Clin Infect Dis 48:350–361.
  • Selvaraj P, Harishankar M, Singh B, Banurekha VV and Jawahar MS (2012) Effect of vitamin D3 on chemokine expression in pulmonary tuberculosis. Cytokine 60:212–219.
  • Welz T, Childs K, Ibrahim F, Poulton M, Taylor CB, Moniz CF and Post FA (2010) Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS 24:1923–1928.
  • Xu C, Tang P, Ding C, Li C, Chen J, Xu Z, Mao Y, Wu M and Zhao J (2015) Vitamin D receptor gene foki polymorphism contributes to increasing the risk of HIV-negative tuberculosis: Evidence from a meta-analysis. PLoS One 10:e0140634.

Supplementary Material

The following online material is available for this article:

Table S1 Allelic combination of VDR functional SNPs. Table S2 Adjusted clinical variables logistic regression model of VDR genotypes. Table S3 Plasma levels of 25-hydroxy vitamin D.
  • Associate Editor: Regina C. Mingroni-Netto

Publication Dates

  • Publication in this collection
    27 June 2019
  • Date of issue
    Apr-Jun 2019

History

  • Received
    18 Sept 2017
  • Accepted
    14 Aug 2018
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