Genetic associations of the vitamin D and antiviral pathways with natural resistance to HIV-1 infection are influenced by interpopulation variability

Vitamin D (VitD) may modulate anti-HIV-1 responses modifying the risk to acquire the HIV-1-infection. We performed a nested case-control exploratory study involving 413 individuals; HIV-1-exposed seropositives (cases) and seronegatives (HESN) (controls) from three cohorts: sexually-exposed from Colombia and Italy and parenterally-exposed from Spain. The association and interactions of 139 variants in 9 VitD pathway genes, and in 14 antiviral genes with resistance/susceptibility (R/S) to HIV-1 infection was evaluated. Associations between variants and mRNA levels were also analyzed in the Colombian samples. Variants and haplotypes in genes of VitD and antiviral pathways were associated with R/S, but specific associations were not reproduced in all cohorts. Allelic heterogeneity could explain such inconsistency since the associations found in all cohorts were consistently in the same genes: VDR and RXRA of the VitD pathway genes and in TLR2 and RNASE4. Remarkably, the multi-locus genotypes (interacting variants) observed in genes of VitD and antiviral pathways were present in most HESNs of all cohorts. Finally, HESNs carrying resistance-associated variants had higher levels of VitD in plasma, of VDR mRNA in blood cells, and of ELAFIN and defensins mRNA in the oral mucosa. In conclusion, despite allelic heterogeneity, most likely due to differences in the genetic history of the populations, the associations were locus dependent suggesting that genes of the VitD pathway might act in concert with antiviral genes modulating the resistance phenotype of the HESNs. Although these associations were significant after permutation test, only haplotype results remained statistically significant after Bonferroni test, requiring further replications in larger cohorts and functional analyzes to validate these conclusions.This work was supported by Departamento administrativo de ciencia, tecnología e innovación de Colombia, COLCIENCIAS (grant no. 111549326091); Universidad de Antioquia UdeA, Colombia (sostenibilidad); Universidad Cooperativa de Colombia (code INV1900); Consejería de Salud de la Junta de Andalucía (PI-0335/2009, PI-0118-2013, PI-0481-2012, and AC-0095-2013), Gilead (GLDL13-00145), the Ministerio de Sanidad (EC11-2086, PI021476, and PI10/01232), the Red de Investigación en SIDA (ISCIII-RETIC RD06/006 and RD12/0017), the Fundación Maratón TV3 (020730 and 020732) and the Universidad de Jaén (UJA2013/10/03 and UJA2013/08/12)

Antiviral molecules correlate with vitamin D pathway genes and are associated with natural resistance to HIV-1 infection

The relationship between the immunomodulatory effects of Vitamin D (VitD) and the expression of anti-HIV-1 molecules has not been explored in HIV-1-exposed seronegative individuals (HESNs). Higher mRNA levels of cathelicidin and HAD-4 in oral-mucosa and peripheral-blood, along with higher CYP24A1 mRNA in vaginal-mucosa and lower TLR2 mRNA in endocervical-mucosa were found in HESNs compared to non-exposed controls. Furthermore, the mRNA of anti-HIV molecules Elafin, TRIM5, Cathelicidin, HAD-4 and RNase7, previously associated with natural resistance to HIV-1 infection, positively correlated with the mRNA expression of VDR in HESNs, suggesting the potential participation of VitD in natural resistance to HIV-1. © 2016 Institut [email protected]

Antiviral molecules correlate with vitamin D pathway genes and are associated with natural resistance to HIV-1 infection

The relationship between the immunomodulatory effects of Vitamin D (VitD) and the expression of anti-HIV-1 molecules has not been explored in HIV-1-exposed seronegative individuals (HESNs). Higher mRNA levels of cathelicidin and HAD-4 in oral-mucosa and peripheral-blood, along with higher CYP24A1 mRNA in vaginal-mucosa and lower TLR2 mRNA in endocervical-mucosa were found in HESNs compared to non-exposed controls. Furthermore, the mRNA of anti-HIV molecules Elafin, TRIM5, Cathelicidin, HAD-4 and RNase7, previously associated with natural resistance to HIV-1 infection, positively correlated with the mRNA expression of VDR in HESNs, suggesting the potential participation of VitD in natural resistance to HIV-1. © 2016 Institut [email protected]

Vitamina D no combate às infeções

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de FarmáciaNa última década, tem-se vindo a dar especial destaque às propriedades imunomoduladoras e anti-inflamatórias da vitamina D e ao seu envolvimento no controlo de infeções. Na resposta inata, a vitamina D promove a libertação de péptidos antimicrobianos, sobretudo em monócitos e macrófagos, e regula a produção de citocinas pró-inflamatórias. Na imunidade adaptativa, induz a inibição da diferenciação de células Th0 em Th1 e Th17 e a proliferação de células Th2 e T reguladoras, levando a uma diminuição das respostas pró-inflamatórias e a um aumento da reparação de tecidos e resposta anti-inflamatória. A deficiência de vitamina D está associada a um risco acrescido de infeção. Infeções causadas por vírus, como o vírus da hepatite B (HBV), o vírus da imunodeficiência humana (HIV) e o coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2), ou bactérias como o bacilo da tuberculose (Mycobacterium tuberculosis) são exemplos onde os efeitos da vitamina D se mostraram relevantes no controlo quer dos patógenos quer da resposta inflamatória. Da mesma forma, polimorfismos nos genes que codificam o recetor da vitamina D (VDR) e o recetor da proteína ligante da vitamina D (DBP) podem contribuir para um aumento da suscetibilidade a infeções. Apesar de ainda não existir um consenso acerca dos níveis ótimos de vitamina D que garantam um correto funcionamento do sistema imunitário, a suplementação de vitamina D pode desempenhar um papel importante na redução da incidência de algumas infeções. A vitamina D também parece beneficiar a resposta à vacinação, nomeadamente através dos seus efeitos na imunidade inata, mais particularmente nas células dendríticas. Para além deste efeito, a sua adição como adjuvante a uma variedade de vacinas mostrou melhorar a resposta imune contra alguns vírus. No presente trabalho, fez-se uma revisão de conjunto sobre o estado da arte do envolvimento da vitamina D nas várias vertentes da resposta inata e adaptativa e do seu potencial uso na profilaxia e controlo de infeções.Over the past decade, special attention has been given to the immunomodulatory and anti-inflammatory properties of vitamin D and its involvement in infection control. In innate response, vitamin D promotes the release of antimicrobial peptides, especially in monocytes and macrophages, and regulates the production of pro-inflammatory cytokines. In adaptive immunity, it induces the inhibition of Th0 cell differentiation into Th1 and Th17 and the proliferation of Th2 and regulatory T cells, leading to a decrease in pro-inflammatory responses and an increase in tissue repair and anti-inflammatory response. Vitamin D deficiency is associated with an increased risk of infection. Infections caused by viruses, like the hepatitis B virus (HBV), the human immunodeficiency virus (HIV) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and bacteria like the tuberculosis bacillus (Mycobacterium tuberculosis) are examples where the effects of vitamin D have been shown to be relevant in the control of both pathogens and the inflammatory response. Likewise, vitamin D receptor (VDR) and vitamin D binding protein (DBP) genetic polymorphisms may contribute to increased susceptibility to infections. Although there is still no consensus about the optimal levels of vitamin D that guarantee a correct functioning of the immune system, vitamin D supplementation can play an important role in reducing the incidence of some infections. Vitamin D also appears to benefit the response to vaccination, notably through its effects on innate immunity, more particularly in dendritic cells. In addition to this effect, its addition as an adjuvant to a variety of vaccines has been shown to improve immune response against some viruses. In the present work, an overview of the state of the art of the involvement of vitamin D in the various aspects of the innate and adaptive response and its potential use in the prophylaxis and control of infections was carried out