Insight in miRNome of Long-Term Non-Progressors and Elite Controllers Exposes Potential RNAi Role in Restraining HIV-1 Infection

Abstract

Long-term non-progressors (LTNP) and elite controllers (EC) represent spontaneous natural models of efficient HIV-1 response in the absence of treatment. The main purposes of this work are to describe the miRNome of HIV-1 infected patients with different extreme phenotypes and identify potentially altered pathways regulated by differentially expressed (DE) miRNAs. The miRNomes from peripheral blood mononuclear cells (PBMCs) of dual phenotype EC-LTNP or LTNP with detectable viremia and HIV-infected patients with typical progression before and after treatment, were obtained through miRNA-Seq and compared among them. The administration of treatment produces 18 DE miRNAs in typical progressors. LTNP condition shows 14 DE miRNA when compared to typical progressors, allowing LTNP phenotype differentiation. A set of four miRNAs: miR-144-3p, miR-18a-5p, miR-451a, and miR-324 is strongly downregulated in LTNP and related to protein regulation as AKT, mTOR, ERK or IKK, involved in immune response pathways. Deregulation of 28 miRNA is observed between EC-LTNP and viremic-LTNP, including previously described anti-HIV miRNAs: miR-29a, associated with LTNP phenotype, and miR-155, targeting different pre-integration complexes such as ADAM10 and TNPO3. A holistic perspective of the changes observed in the miRNome of patients with different phenotypes of HIV-control and non-progression is provided.

MiRNA-103 downmodulates CCR5 expression reducing human immunodeficiency virus type-1 entry and impacting latency establishment in CD4+ T cells

“…Several studies have shown that PBMCs from ECs have a miRNA repertoire that is distinct from that of HIV-1 ART-naïve progressors, and such a difference may in part explain the control of viral infection in ECs ( Witwer et al., 2012 ; Reynoso et al., 2014 ; Ayala-Suárez et al., 2020 ). In this context, we assessed the levels of miRNA-103 and CCR5 mRNA in CD4 + T cells from ECs and ART-naïve progressors and found that CCR5 mRNA in CD4 + T cells obtained from ECs was significantly decreased when compared to that in CD4 + T cells from ART-naïve progressors, in line with recently published results ( Claireaux et al., 2022 ; Gonzalo-Gil et al., 2019 ; Meijerink et al., 2014 ).…”

“…Previous meta-analyses of genetic studies showed a genome-wide significant association between the CCR5 locus and viral load, highlighting the impact of CCR5 expression limitation on HIV-1 replication and control ( McLaren et al., 2015 ). Indeed, it has been shown that PBMCs from ART-naïve progressors may have less total miRNAs than cells from ECs ( Ayala-Suárez et al., 2020 ). As well, viral infection can have an impact on miRNA expression ( Bennasser et al., 2005 ; Triboulet et al., 2007 ) as viral proteins such as Tat and Vpr have been reported to act as RNA silencing suppressors ( Casey Klockow et al., 2013 ; Cojo et al., 2017 ).…”

Selective miRNA inhibition in CD8+ cytotoxic T lymphocytes enhances HIV-1 specific cytotoxic responses

“…Another interesting strategy consists of restoring the killing capacity of cells by miRNA modulation. Therefore, the involvement of miRNAs in CD8 + T cells cytotoxicity has also been investigated (29)(30)(31)(32)(33)(34)(35). However, to our knowledge, no attempts have been made to restore the killing capacity of cells by miRNA modulation.…”

Dodging the Host Interferon-Stimulated Gene Mediated Innate Immunity by HIV-1: A Brief Update on Intrinsic Mechanisms and Counter-Mechanisms

“…Additionally, it is debated that whether host RNA interference (RNAi) contributes to immune responses against HIV-1. Nevertheless, several miRNAs are differentially regulated in HIV-1 elite controllers as compared to typical progressor patients, suggesting that HIV-1 interferes with host RNAi ( 95 ). HIV-1 manipulates host RNAi mechanisms through its RNA elements such as RRE (Rev Response Element) and TAR (Trans Activation Response) as well as Rev and Tat proteins.…”