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HIV-1 nef suppression by virally encoded microRNA.

ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are 21 to approximately 25-nucleotides (nt) long and interact with mRNAs to trigger either translational repression or RNA cleavage through RNA interference (RNAi), depending on the degree of complementarity with the target mRNAs. Our recent study has shown that HIV-1 nef dsRNA from AIDS patients who are long-term non-progressors (LTNPs) inhibited the transcription of HIV-1. RESULTS: Here, we show the possibility that nef-derived miRNAs are produced in HIV-1 persistently infected cells. Furthermore, nef short hairpin RNA (shRNA) that corresponded to a predicted nef miRNA (approximately 25 nt, miR-N367) can block HIV-1 Nef expression in vitro and the suppression by shRNA/miR-N367 would be related with low viremia in an LTNP (15-2-2). In the 15-2-2 model mice, the weight loss, which may be rendered by nef was also inhibited by shRNA/miR-N367 corresponding to suppression of nef expression in vivo. CONCLUSIONS: These data suggest that nef/U3 miRNAs produced in HIV-1-infected cells may suppress both Nef function and HIV-1 virulence through the RNAi pathway.

SUBMITTER: Omoto S

PROVIDER: S-EPMC544868 | biostudies-other | 2004

REPOSITORIES: biostudies-other

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HIV-1 nef suppression by virally encoded microRNA.

Omoto Shinya S Ito Masafumi M Tsutsumi Yutaka Y Ichikawa Yuko Y Okuyama Harumi H Brisibe Ebiamadon Andi EA Saksena Nitin K NK Fujii Yoichi R YR

Retrovirology 20041215

<h4>Background</h4>MicroRNAs (miRNAs) are 21 to approximately 25-nucleotides (nt) long and interact with mRNAs to trigger either translational repression or RNA cleavage through RNA interference (RNAi), depending on the degree of complementarity with the target mRNAs. Our recent study has shown that HIV-1 nef dsRNA from AIDS patients who are long-term non-progressors (LTNPs) inhibited the transcription of HIV-1.<h4>Results</h4>Here, we show the possibility that nef-derived miRNAs are produced in ...[more]

PMID: 15601474

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Project description:Objective: The objective of this study was to test our Viral Quinta Columna Strategy (VQCS), a new biological hypothesis predicting that specific multifunctional virally encoded cationic domains may have the capacity to penetrate human cells and interact with PP2A proteins to deregulate important human intracellular pathways, and may display LL37 cathelicidin-like antagonistic effects against multiple pathogens such as bacteria or viruses. Methods: We comparatively analyzed the host defense properties of adenodiaphorins and of some specific cationic sequences encoded by different viruses using two distinct biological models: U87G, a well-characterized cell tumor model; and a group B Streptococcus agalactiae NEM316 ΔdltA, highly sensitive to LL37 cathelicidin. Results: We found that the adenovirus type 2 E4orf4 is a cell-permeable protein containing a new E4orf464-95 protein transduction domain, named large adenodiaphorin or LadD64-95. Interestingly, the host defense LL37 peptide is the unique cathelicidin in humans. In this context, we also demonstrated that similarly to LL37 LadD64-95, several virally encoded cationic sequences including the C-terminus HIV-1 89.6 Vpr77-92, shorter adenodiaphorins AdD67-84/AdD/69-84/AdD69-83, as well as HIV-2 Tat67-90 and JC polyomavirus small t115-134, displayed similar toxicity against Gram-positive S. agalactiae NEM316 ΔdltA strain. Finally, LadD64-95, adenodiaphorin AdD67-84, AdD69-84, and LL37 and LL17-32 cathelicidin peptides also inhibited the survival of human U87G glioblastoma cells. Conclusion: In this study, we demonstrated that specific cationic sequences encoded by four different viruses displayed antibacterial activities against S. agalactiae NEM316 ΔdltA strain. In addition, HIV-1 Vpr71-92 and adenovirus 2 E4orf464-95, two cationic penetrating sequences that bind PP2A, inhibited the survival of U87G glioblastoma cells. These results illustrate the host defense properties of virally encoded sequences and could represent an initial step for future complete validation of the VQCS hypothesis.

Project description:Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several AIDS-related malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. The interaction of human immunodeficiency virus type 1 (HIV-1) and KSHV has a central role in promoting the aggressive manifestations of AIDS-KS. We have previously shown that negative factor (Nef), a secreted HIV-1 protein, synergizes with KSHV viral interleukin-6 (vIL-6) to promote angiogenesis and tumorigenesis by activating the AKT pathway (X. Zhu, et al., Oncogene, 22 April 2013, http://dx.doi.org/10.1038/onc.2013.136). Here, we further demonstrated the role of soluble and ectopic Nef in the regulation of KSHV latency. We found that both soluble Nef protein and ectopic expression of Nef by transfection suppressed the expression of KSHV viral lytic mRNA transcripts and proteins and the production of infectious viral particles. MicroRNA (miRNA) microarray analysis identified a number of Nef-regulated miRNAs. Bioinformatics and luciferase reporter analyses showed that one of the Nef-upregulated miRNAs, cellular miRNA 1258 (hsa-miR-1258), directly targeted a seed sequence in the 3' untranslated region (UTR) of the mRNA encoding the major lytic switch protein (RTA), which controls KSHV reactivation from latency. Ectopic expression of hsa-miR-1258 impaired RTA synthesis and enhanced Nef-mediated inhibition of KSHV replication, whereas repression of hsa-miR-1258 has the opposite effect. Mutation of the seed sequence in the RTA 3'UTR abolished downregulation of RTA by hsa-miR-1258. Collectively, these novel findings demonstrate that, by regulating cellular miRNA, Nef may inhibit KSHV replication to promote viral latency and contribute to the pathogenesis of AIDS-related malignancies.This study found that Nef, a secreted HIV-1 protein, suppressed KSHV lytic replication to promote KSHV latency. Mechanistic studies indicated that a Nef-upregulated cellular miRNA, hsa-miR-1258, inhibits KSHV replication by directly targeting a seed sequence in the KSHV RTA 3'UTR. These results illustrate that, in addition to viral miRNAs, cellular miRNAs also play an important role in regulating the life cycle of KSHV. Overall, this is the first study to report the involvement of Nef in KSHV latency, implying its likely important role in the pathogenesis of AIDS-related malignancies.

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HIV-1 nef suppression by virally encoded microRNA.

Publications

HIV-1 nef suppression by virally encoded microRNA.

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