Downregulation of miRNA-26a by HIV-1 Enhances CD59 Expression and Packaging Impacting Virus Susceptibility to Antibody-Dependent Complement-Mediated Lysis

• DOI: 10.20944/preprints202406.0241.v1
• Publication Date: 2024-06-06T12:35:01Z
• Authors: Nicolas Bellini; Chengyu Ye; Oluwaseun Ajibola; Thomas T Murooka; Robert Lodge; Eric A Cohen
• Keywords: CD4-Positive T-Lymphocytes; miRNA-26a; Virus Assembly; Antibody-Dependent Cell Cytotoxicity; viral evasion; Down-Regulation; CD59 Antigens; HIV Infections; Complement System Proteins; Microbiology; complement-mediated lysis; QR1-502; Article; MicroRNAs; HIV-1; Humans; innate immunity; CD59

MicroRNAs (miRNAs) play important roles in the control of HIV-1 infection. Here, we performed RNAseq profilings of miRNAs and mRNAs expressed in CD4+ T-lymphocytes upon HIV-1 infection. Our results reveal significant alterations of miRNAs and mRNAs expression profiles in infected relative to uninfected cells. One of the miRNAs markedly downregulated in infected cells is miRNA-26a. Among the putative targets of miRNA-26a are CD59 receptor transcripts, which are significantly upregulated in infected CD4+ T-cells. Addition of miRNA-26a mimics to CD4+ T-cells reduces CD59 at both mRNA and surface protein levels, validating CD59 as a miRNA-26a target. Consistent with the reported inhibitory role of CD59 in complement-mediated lysis (CML), knocking-out CD59 in CD4+ T-cells renders both HIV-1 infected cells and progeny virions more prone to antibody-dependent CML (ADCML). Addition of miRNA-26a mimics to infected cells leads to enhanced sensitivity of progeny virions to ADCML, a condition linked to a reduction of CD59 packaging into released virions. Lastly, HIV-1-mediated downregulation of miRNA-26a expression is shown to be dependent on integrated HIV-1 expression but does not involve viral accessory proteins. Overall, these results highlight a novel mechanism by which HIV-1 limits ADCML by upregulating CD59 expression via miRNA-26a downmodulation.