LncRNA MALAT1 Facilitates HIV-1 Replication by Upregulation of CHCHD2 and Downregulation of IFN-I Expression

Long noncoding RNAs (lncRNAs) are effective regulators of both RNA and protein functions throughout cell biology, including viral replication. Emerging studies have shown that lncRNAs activate or inhibit the replication and latency of HIV-1 by regulating different cellular mechanisms. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic lncRNA required for paraspeckle integrity and has been proven to be linked to viral infection. However, the mechanisms by which it influences HIV-1 infection in macrophages remain unclear. In this study, we performed RNA-deep sequencing to compare the profiles of lncRNAs in macrophages with or without HIV-1 and found that MALAT1 was dramatically upregulated in HIV-1-infected macrophages. MALAT1 knockdown inhibited HIV-1 infection, whereas MALAT1 overexpression enhanced viral replication, indicating that MALAT1 promotes HIV-1 replication. We further performed proteomics analysis and found that coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) was the most downregulated protein affected by RNAi-mediated knockdown of MALAT1. We next demonstrated that MALAT1 favored HIV-1 replication in a CHCHD2-dependent manner and functioned as a competing endogenous RNA to regulate CHCHD2 expression by sponging miR-145-5p, which could mutually bind the MALAT1 and 3'UTR of chchd2 mRNA. Furthermore, knockdown of endogenous MALAT1 or CHCHD2 with specific small interfering RNAs (siRNAs) promoted the expression of IRF7, and enhanced the promoter activities of interferons-α and -β, increasing their production as well as that of a critical interferon-stimulated gene (ISG), myxovirus resistance protein B (MxB). Moreover, MALAT1 or CHCHD2 knockdown promoted the expression of STAT2 to enhance the production of downstream MxB, which expanded the role of CHCHD2 as a negative regulator of the innate immune response. These findings improve our understanding of MALAT1/miR-145-5p/CHCHD2 pathway regulation of HIV-1 replication in macrophages, providing new insights into potential targeted therapeutic interventions.