AUTHOR=Aguilar-Jimenez Wbeimar , Saulle Irma , Trabattoni Daria , Vichi Francesca , Lo Caputo Sergio , Mazzotta Francesco , Rugeles Maria T. , Clerici Mario , Biasin Mara 

TITLE=High Expression of Antiviral and Vitamin D Pathway Genes Are a Natural Characteristic of a Small Cohort of HIV-1-Exposed Seronegative Individuals

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00136

DOI=10.3389/fimmu.2017.00136

ISSN=1664-3224

ABSTRACT=<p>Natural resistance to HIV-1 infection is influenced by genetics, viral-exposure, and endogenous immunomodulators such as vitamin D (VitD), being a multifactorial phenomenon that characterizes HIV-1-exposed seronegative individuals (HESNs). We compared mRNA expression of 10 antivirals, 5 immunoregulators, and 3 VitD pathway genes by qRT-PCR in cells of a small cohort of 11 HESNs, 16 healthy-controls (HCs), and 11 seropositives (SPs) at baseline, in response to calcidiol (VitD precursor) and/or aldithriol-2-(AT2)-inactivated HIV-1. In addition, the expression of TIM-3 on T and NK cells of six HCs after calcidiol and calcitriol (active VitD) treatments was evaluated by flow cytometry. Calcidiol increased the mRNA expression of <italic>HAVCR2</italic> (TIM-3; Th1-cells inhibitor) in HCs and HESNs. AT2-HIV-1 increased the mRNA expression of the activating VitD enzyme <italic>CYP27B1</italic>, of the endogenous antiviral proteins <italic>MX2, TRIM22, APOBEC3G</italic>, and of immunoregulators <italic>ERAP2</italic> and <italic>HAVCR2</italic>, but reduced the mRNA expression of VitD receptor (<italic>VDR</italic>) and antiviral peptides <italic>PI3</italic> and <italic>CAMP</italic> in all groups. Remarkably, higher mRNA levels of <italic>VDR, CYP27B1, PI3, CAMP, SLPI</italic>, and of <italic>ERAP2</italic> were found in HESNs compared to HCs either at baseline or after stimuli. Furthermore, calcitriol increases the percentage of CD4+ T cells expressing TIM-3 protein compared to EtOH controls. These results suggest that high mRNA expression of antiviral and VitD pathway genes could be genetically determined in HESNs more than viral-induced at least in peripheral blood mononuclear cells. Moreover, the virus could potentiate bio-activation and use of VitD, maintaining the homeostasis of the immune system. Interestingly, VitD-induced TIM-3 on T cells, a T cell inhibitory and anti-HIV-1 molecule, requires further studies to analyze the functional outcomes during HIV-1 infection.</p>