Host MicroRNAs-221 and -222 Inhibit HIV-1 Entry in Macrophages by Targeting the CD4 Viral Receptor

Abstract

Macrophages are heterogeneous immune cells with distinct origins, phenotypes, functions, and tissue localization. Their susceptibility to HIV-1 is subject to variations from permissiveness to resistance, owing in part to regulatory microRNAs. Here, we used RNA sequencing (RNA-seq) to examine the expression of >400 microRNAs in productively infected and bystander cells of HIV-1-exposed macrophage cultures. Two microRNAs upregulated in bystander macrophages, miR-221 and miR-222, were identified as negative regulators of CD4 expression and CD4-mediated HIV-1 entry. Both microRNAs were enhanced by tumor necrosis factor alpha (TNF-α), an inhibitor of CD4 expression. MiR-221/miR-222 inhibitors recovered HIV-1 entry in TNF-α-treated macrophages by enhancing CD4 expression and increased HIV-1 replication and spread in macrophages by countering TNF-α-enhanced miR-221/miR-222 expression in bystander cells. In line with these findings, HIV-1-resistant intestinal myeloid cells express higher levels of miR-221 than peripheral blood monocytes. Thus, miR-221/miR-222 act as effectors of the antiviral host response activated during macrophage infection that restrict HIV-1 entry.

“MicroRNA expression profiling of human milk derived exosomes identifies miR-630 and miR-378g as biomarkers in HIV-1 infected women”

“…Our finding is in agreement with a previous study where miR-630 was reported as a biomarker in chronic progressors of HIV-1 [38]. Interestingly, our HM exosomal miRNA data from the South Africa cohort where HIV-1 infected women were carrying HIV-1 load < 1 year (data not shown) showed downregulation of these miRNAs identified in the current study (Table 2 & Suppl Table 1) and correlated with a recent report where it was shown that acute HIV-1 leads to downregulation of miRNAs [32]. Nonetheless, miRNA data shown herein could be exploited for future studies to gain more insight into HIV-1 pathogenesis.…”

“…HIV-1 is known to cause dramatic changes in cellular miRNA expression profiles [32][33][34][35], however its effect on HM derived exosomal miRNAs remains to be determined. Here, we first demonstrate the miRNA expression profiling of HM derived exosomes from HIV-1 infected women and describe that HIV-1 significantly altered the expression levels of HM derived exosomal miRNAs in HIV-1 infected women.…”

“…miRNAs are thought to be involved in mediating immune suppression, establishment of viral latency [34,39] or suppress HIV-1 replication via decreasing HIV-1 dependency factors [40]. Some of the miRNAs we have identified have been previously implicated in HIV-1 infection including miR-630, miR-4516, miR-16-5p, miR-378, miR-93, miR-23, miR-30a [32,38,[41][42][43][44] thus strongly suggesting the reliability of the NanoString data obtained in the current study. Further, it has been described that NanoString can perform miRNA profiling with digital precision and the results do not require further validation by another method [45].…”

Post-transcriptional Regulation of PCSK9 by miR-191, miR-222, and miR-224

“…Our findings on the ability of miR-222 for regulating the expression of PCSK9, a LDLR negative regulator, is in line with its formerly identified roles in lipid metabolic diseases and susceptibility for developing obesity and heart failure. Finally, it has been very recently reported that miR-222 and mir-221 inhibit HIV-1 Entry in Macrophages by Targeting the CD4 Viral Receptor (Lodge et al, 2017 ). Thus, it is possible that miR-221 may also inhibit PCSK9 expression, as the levels of both miR221 and 222 are enhanced by tumor necrosis factor alpha (TNF-α).…”

HIV-associated sensory polyneuropathy and neuronal injury are associated with miRNA–455-3p induction

“…Furthermore, they are released into the circulation and have been investigated as potential biomarkers for the diagnosis of different diseases. Substantial evidence exists suggesting HIV/AIDS pathogenesis is modulated by miRNAs (20)(21)(22). Recently, the contribution of miRNAs to diabetic neuropathy as well as other painful peripheral neuropathies has been shown in both clinical and experimental studies (20,23).…”