Abstract
BackgroundSome multifunctional cellular proteins, as the monocyte chemotactic protein-induced protein 1 (ZC3H12A/MCPIP1) and the cyclin-dependent kinase inhibitor CDKN1A/p21, are able to modulate the cellular susceptibility to the human immunodeficiency virus type 1 (HIV-1). Several studies showed that CDKN1A/p21 is expressed at high levels ex vivo in cells from individuals who naturally control HIV-1 replication (HIC) and a recent study supports a coordinate regulation of ZC3H12A/MCPIP1 and CDKN1A/p21 transcripts in a model of renal carcinoma cells. Here, we explored the potential associations between mRNA expression of ZC3H12A/MCPIP1 and CDKN1A/p21 in HIC sustaining undetectable (elite controllers–EC) or low (viremic controllers–VC) viral loads.ResultsWe found a selective upregulation of ZC3H12A/MCPIP1 and CDKN1A/p21 mRNA levels in PBMC from HIC compared with both ART–suppressed and HIV–negative control groups (P≤ 0.02) and higher MCPIP1 and p21 proteins levels in HIC than in HIV-1 negative subjects. There was a moderate positive correlation (r ≥ 0.57; P ≤ 0.014) between expressions of both transcripts in HIC and in HIC combined with control groups. We found positive correlations between the mRNA level of CDKN1A/p21 with activated CD4+ T cells levels in HIC (r ≥ 0.53; P ≤ 0.017) and between the mRNA levels of both CDKN1A/p21 (r = 0.74; P = 0.005) and ZC3H12A/MCPIP1 (r = 0.58; P = 0.040) with plasmatic levels of sCD14 in EC. Reanalysis of published transcriptomic data confirmed the positive association between ZC3H12A/MCPIP1 and CDKN1A/p21 mRNA levels in CD4+ T cells and monocytes from disparate cohorts of HIC and other HIV-positive control groups.ConclusionsThese data show for the first time the simultaneous upregulation of ZC3H12A/MCPIP1 and CDKN1A/p21 transcripts in the setting of natural suppression of HIV-1 replication in vivo and the positive correlation of the expression of these cellular factors in disparate cohorts of HIV-positive individuals. The existence of a common regulatory pathway connecting ZC3H12A/MCPIP1 and CDKN1A/p21 could have a synergistic effect on HIV-1 replication control and pharmacological manipulation of these multifunctional host factors may open novel therapeutic perspectives to prevent HIV-1 replication and disease progression.
Highlights
Some multifunctional cellular proteins, as the monocyte chemotactic protein-induced protein 1 (ZC3H12A/monocyte chemotactic protein–induced protein 1 (MCPIP1)) and the cyclin-dependent kinase inhibitor Cyclin-dependent kinase inhibitor p21 (CDKN1A)/p21, are able to modulate the cellular suscep‐ tibility to the human immunodeficiency virus type 1 (HIV-1)
The ZC3H12A/MCPIP1 and CDKN1A/p21 mRNA and protein expression levels are upregulated in peripheral blood mononuclear cells (PBMC) from HIV-1 replication (HIC) Twenty-nine Human immunodeficiency virus (HIV)-1 positive (21 HIC and 8 ART-suppressed) and 10 HIV-negative individuals were included in this cross-sectional study
In this study, we described a positive correlation of ZC3H12A/MCPIP1 and CDKN1A/p21 mRNA expression in PBMC, CD4+ T cells and monocytes from HIV-infected and-uninfected subjects and we further detected that the mRNA levels of ZC3H12A/MCPIP1 and CDKN1A/p21 were significantly increased in PBMC of HIC compared to cells of HIV-negative and ART-suppressed individuals
Summary
As the monocyte chemotactic protein-induced protein 1 (ZC3H12A/MCPIP1) and the cyclin-dependent kinase inhibitor CDKN1A/p21, are able to modulate the cellular suscep‐ tibility to the human immunodeficiency virus type 1 (HIV-1). The cyclin-dependent kinase (CDK) inhibitor p21, encoded by the CDKN1A gene, modulates multiple relevant processes of the immune system, including proliferation of activated/ memory T cells, macrophage activation and inflammation [10,11,12,13,14,15,16,17] This protein indirectly limits the HIV-1 replication in vitro in various cellular systems by blocking the biosynthesis of dNTPs required for viral reverse transcription and by inhibiting the CDK9 activity required for HIV-1 mRNA transcription [18,19,20,21,22,23]. These pieces of evidence suggest that the inducibility of CDKN1A/p21 to immune activation is a singular characteristic of EC and may contribute to the natural control of HIV-1 replication in vivo
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