HIV-1 controllers exhibit an enhanced antiviral state characterized by overexpression of p21 and MCPIP1

Abstract

Some multifunctional cellular proteins, as the monocyte chemotactic protein-induced protein 1 (MCPIP1) and the cyclin-dependent kinase inhibitor p21, have also shown to be able to modulate the cellular susceptibility to the human immunodeficiency virus type 1 (HIV-1). Several studies described that p21 is expressed at high levels ex vivo in cells from individuals who naturally control HIV-1 replication (HIC). The expression level of MCPIP1 in HIC was never described before, but a recent study in a model of renal carcinoma cells showed that MCPIP1 overexpression was associated with an increase of both p21 transcripts and proteins levels. Here, we explored the potential associations between MCPIP1 and p21 expression, as well as with cellular activation in HIC, sustaining undetectable (elite controllers - EC) or low (viremic controllers - VC) viral loads. We found a selective upregulation of MCPIP1 and p21 mRNA levels in PBMC from HIC compared with both ART- suppressed and HIV-negative control groups (P [≤] 0.02) and a strong positive correlation (r [≥] 0.57; P [≤] 0.014) between expressions of both transcripts independently of the VL, treatment condition and HIV status. The mRNA levels of p21, but not of MCPIP1, were positively correlated with activated CD4+ T cells levels in HIC and EC (r [≥] 0.53; P [≤] 0.017). In relation to the monocyte activation, the mRNA levels of both p21 (r = 0.74; P = 0.005) and MCPIP1 (r = 0.58; P = 0.040) were positively correlated with plasmatic levels of sCD14 only in EC. Multivariate analysis confirmed the association between MCPIP1 and p21 mRNA levels, and between the latter with the frequency of activated CD4+ T cells. These data show for the first time the simultaneous overexpression and positive correlation of MCPIP1 and p21 transcripts in the setting of natural suppression of HIV-1 replication in vivo. The positive correlation between MCPIP1 and p21 transcripts supports a common regulatory pathway connecting these multifunctional host factors and a possible synergistic effect on HIV-1 replication control. Pharmacological manipulation of these cellular proteins may open novel therapeutic perspectives to prevent HIV-1 replication and disease progression.