The Role of MicroRNAs in HIV Infection

Abstract

MicroRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in regulating gene expression at the post-transcriptional level. These regulatory molecules are integral to many biological processes and have been implicated in the pathogenesis of various diseases, including Human Immunodeficiency Virus (HIV) infection. This review aims to cover the current understanding of the multifaceted roles miRNAs assume in the context of HIV infection and pathogenesis. The discourse is structured around three primary focal points: (i) elucidation of the mechanisms through which miRNAs regulate HIV replication, encompassing both direct targeting of viral transcripts and indirect modulation of host factors critical for viral replication; (ii) examination of the modulation of miRNA expression by HIV, mediated through either viral proteins or the activation of cellular pathways consequent to viral infection; and (iii) assessment of the impact of miRNAs on the immune response and the progression of disease in HIV-infected individuals. Further, this review delves into the potential utility of miRNAs as biomarkers and therapeutic agents in HIV infection, underscoring the challenges and prospects inherent to this line of inquiry. The synthesis of current evidence positions miRNAs as significant modulators of the host-virus interplay, offering promising avenues for enhancing the diagnosis, treatment, and prevention of HIV infection.

Keywords: HIV; HIV miRNAs; MicroRNA regulation; MicroRNAs; miRNA diagnostics; miRNA therapeutics.

Figure 1

microRNA-mediated HIV-1-human interactions reported in CD4+ T cells and T-cell lines. HIV-1 entry is facilitated by the chemokine receptor CXCR4. CXCR4 is silenced by miR-146a, which is upregulated upon HIV-1 infection, as well as by IFITM2, which is in turn silenced by miR-34c, whose expression is reduced upon HIV-1 infection. The next highly regulated step of HIV-1 replication is the transcription of the integrated provirus. This step is inhibited by the restriction factors MeCP2, FOXO1, PNUTS, and P21, which are silenced by miR-132, miR-139, miR-34a (upregulated upon HIV-1 infection) and let-7c (downregulated upon HIV-1 infection), respectively. HIV-1 transcription is dependent on host factors CCNT1, TRAF6, and PCAF, which are silenced by miR-27b, miR-146a, and miR-34c, respectively. The export of viral mRNA to the cytoplasm is promoted by DDXD3, which is silenced by miR-181 (upregulated upon HIV-1 infection), and by HRB, which is silenced by miR-222 and miR-186 (both upregulated upon HIV-1 infection). The translation of viral mRNA is inhibited by IFITM2, as well as by several miRNAs, some of which are upregulated upon HIV-1 infection (miR-223, miR-382), others downregulated (miR-150, miR-29a, miR-29b, miR-92a, miR-1290) and others with no reported modulation (miR-28, miR-196b, miR-125b, miR-149, miR-138, miR-133b, miR-326). The release and maturation of new HIV-1 particles is inhibited on the one hand by LARG, which is silenced by miR-34c, and on the other hand by TASK1, which is silenced by miR-34a and miR-124a. CD55, which protects the released virion from inactivation by human complement, is silenced by miR-34c. Finally, several cytokines with unclear roles in HIV-1 pathogenesis are regulated by microRNAs: IL-10 by let-7, IL-32 by miR-29b (downregulated upon HIV-1 infection) and IL-2 by let-7i (downregulated upon HIV-1 infection) and by miR-9 (through BLIMP1).

Figure 2

MicroRNA-mediated HIV-1-human interactions reported in macrophages and microglia. HIV-1 entry depends on the CD4 receptor, which is silenced by miR-221 and miR-222 (both upregulated upon HIV-1 infection). CCR5-mediated entry to macrophages/microglia, as well as CD4+ T cells, are inhibited by chemokine CCL8, which is silenced by miR-146a (upregulated upon HIV-1 infection). Reverse transcription of the HIV-1 genome is inhibited by the host restriction factor SAMHD1, which is in turn silenced by miR-155 and miR-181a (both upregulated upon HIV-1 infection). The translation of viral mRNA is inhibited by miR-28, miR-150 (downregulated upon HIV-1 infection), miR-223, and miR-382 (both upregulated upon HIV-1 infection). Packaging of the viral glycoprotein Env into nascent virions is inhibited by MARCH1, which is silenced by miR-25 and miR-93 (both upregulated upon HIV-1 infection). Secretion of chemokine CCL5, which promotes monocyte migration, is inhibited by miR-146a.

Figure 3

MicroRNA-mediated HIV-1-human interactions reported in monocytes. Monocytes are resistant to HIV-1 infection, as many HIV-1 dependency factors are suppressed by miRNAs. Pur-α, a DNA/RNA-binding protein that promotes HIV-1 transcription in synergy with the viral protein Tat, is maintained at low expression levels through its silencing by miR-15a, miR-15b, miR-16, miR-20a and miR-93 (upregulated upon HIV-1 infection). The HIV-1 dependency factor CCNT1, necessary for viral transcription, is silenced by miR-198. VprBP (or DCAF1) interacts with the viral protein Vpr to direct the degradation of host proteins engaged in epigenetic silencing of the HIV-1 unintegrated genome, thus promoting viral pre-integration transcription. VprBP, which shows low protein-level expression in monocytes compared to macrophages, is silenced by miR-1236, which is more highly expressed in monocytes. The chemokine IP-10 (or CXCL10), which is positively correlated to disease progression and is known to facilitate HIV-1 replication (particularly entry and integration) in CD4+ T cells and macrophages, is silenced by miR-21. IL-32, a pro-inflammatory cytokine known to suppress HIV-1 replication, is silenced by miR-29b, which is upregulated upon HIV-1 infection. miR-125b, miR-28, miR-223, miR-150, and miR-382 have not been conclusively demonstrated to target HIV-1 mRNA directly in monocytes; however, this interaction is likely, given that it has been demonstrated in CD4+ T cells.