HIV-1 infection increases microRNAs that inhibit Dicer1, HRB and HIV-EP2, thereby reducing viral replication

Modai, Shira; Farberov, Luba; Herzig, Eytan; Isakov, Ofer; Hizi, Amnon; Shomron, Noam

doi:10.1371/journal.pone.0211111

Cited by 29 publications

(23 citation statements)

References 52 publications

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“…The work of Telwatte et al (2018) and Yukl et al (2018) and also of Pace et al (2012) have highlighted the importance of post-transcriptional blocks in HIV-1 latency. Post-transcriptional blocks of the nuclear export of various viral transcripts including unspliced, partially spliced, multiply-spliced, and translation of HIV-1 RNA by miRNAs have also been reported (Pomerantz et al, 1990;Malim and Cullen, 1991;Lassen et al, 2006;Weng et al, 2014;Modai et al, 2019). Interestingly, a recent study from the group of Alessandro Marcello has demonstrated that the expression level of MATR3 and PSF, two known posttranscriptional cofactors of the HIV-1 protein Rev required for Rev-mediated export of RRE-containing HIV-1 RNAs (Kula et al, 2011(Kula et al, , 2013, are poorly expressed in latently-infected patients cells (Sarracino et al, 2018), suggesting a novel posttranscriptional block linked to RNA export.…”

Section: Complexity Of Molecular Mechanisms Regulating Hiv-1 Latencymentioning

confidence: 98%

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Aït-Ammar

Kula

Darcis³

et al. 2020

Front. Microbiol.

138

150

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Quantitative polymerase chain reaction; QVOA, quantitative viral outgrowth assays; Rev, regulator of virion expression; RNA, ribonucleic acid; RNAPII, RNA polymerase II; RT-ddPCR, teverse transcription droplet digital PCR; SAHA, suberoylanilide hydroxamic acid; SIV, simian immunodeficiency virus; SMAC, second mitochondrial activator of caspases; SMYD2, SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2; Sp1, specificity protein 1; STAT5, signal transducer and activator of transcription 5; Suv39H1, Suppressor of variegation 3-9 homolog 1

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Section: Complexity Of Molecular Mechanisms Regulating Hiv-1 Latencymentioning

confidence: 98%

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Aït-Ammar

Kula

Darcis³

et al. 2020

Front. Microbiol.

138

150

View full text Add to dashboard Cite

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“…In addition, miR-378g was also found to target 4 confidently annotated sites in 3′ UTR of human HIV-1 enhancer binding protein 3 (HIVEP3) (ENST00000372583.1) located at 582-588, 2026-2032, 2208-2214 and 2580-2586 nucleotides (data not shown). Although, the role of HIVEP3 in HIV-1 replication is not clear, targeting HIVEP2 by miRNAs is known to reduce HIV-1 replication 87 . The effect of miR-378g on HIV-1 replication and MTCT must be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Expression profiling of human milk derived exosomal microRNAs and their targets in HIV-1 infected mothers

Zahoor

Yao

Henrick

et al. 2020

Sci Rep

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Despite the use of antiretroviral therapy (ART) in HIV-1 infected mothers approximately 5% of new HIV-1 infections still occur in breastfed infants annually, which warrants for the development of novel strategies to prevent new HIV-1 infections in infants. Human milk (HM) exosomes are highly enriched in microRNAs (miRNAs), which play an important role in neonatal immunity. Furthermore, HM exosomes from healthy donors are known to inhibit HIV-1 infection and transmission; however, the effect of HIV-1 on HM exosomal miRNA signatures remains unknown. In this study, we used nCounter NanoString technology and investigated miRNAs expression profiles in first week postpartum HM exosomes from HIV-1 infected and uninfected control mothers (n = 36). Our results indicated that HIV-1 perturbed the differential expression patterns of 19 miRNAs (13 upregulated and 6 downregulated) in HIV-1 infected women compared to healthy controls. DIANA-miR functional pathway analyses revealed that multiple biological pathways are involved including cell cycle, pathways in cancer, TGF-β signaling, FoxO signaling, fatty acid biosynthesis, p53 signaling and apoptosis. Moreover, the receiver operating characteristics (ROC) curve analyses of miR-630 and miR-378g yielded areas under the ROC curves of 0.82 (95% CI 0.67 to 0.82) and 0.83 (95% CI 0.67 to 0.83), respectively highlighting their potential to serve as biomarkers to identify HIV-1 infection in women. These data may contribute to the development of new therapeutic strategies in prevention of motherto-child transmission (MTCT) of HIV-1. Devastating statistics indicate more than 110,000 children die each year from HIV-1/AIDS related disorders and over 15,000 children are newly infected with HIV-1 every month 1 , which make up a substantial proportion of the approximately 40 million people are currently living with HIV-1 worldwide 1,2. Indeed mother-to-child transmission (MTCT) of HIV-1 is an important source of HIV-1 infection in infants and can occur in utero, during delivery and through breastfeeding. Prophylactic strategies have greatly reduced the risk of MTCT HIV transmission from 35% to less than 5%; however, new HIV-1 infection in infants who are breastfed by HIV-1 positive mothers breastfeeding remains a major source of pediatric HIV-1 infection. Paradoxically, an intervention that promotes exclusive breastfeeding, regardless of HIV status of the mother shows decreased vertical HIV transmission rates compared to infants who are non-exclusively breastfed 1,3. The mechanisms underlying this phenomenon remain unknown; however, data presented here may provide new insights into potential preventative and therapeutic strategies that may be useful for both infants and adults in the future 4 .

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“…In addition, miR-378 g was also found to target 4 confidently annotated sites in 3'UTR of human HIV-1 enhancer binding protein 3 (HIVEP3) (ENST00000372583.1) located at 582-588, 2026-2032, 2208-2214 and 2580-2586 nucleotides (data not shown). Although, role of HIVEP3 in HIV-1 replication is not clear, targeting HIVEP2 by miRNAs is known to reduce HIV-1 replication [62]. The effect of miR-378 g on HIV-1 replication and MTCT must be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

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

Zahoor¹,

Yao²,

Henrick³

et al. 2020

Preprint

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Background: Despite the use of antiretroviral therapy (ART) in HIV-1 infected mothers approximately 5% of new HIV-1 infections still occur in breastfed infants annually which warrant for the development of new additional strategies to completely prevent new HIV-1 infections in infants. Human Milk (HM) exosomes are highly enriched in maternal microRNAs (miRNAs) which after ingestion and absorption play an important role in neonatal immunity. Although, HM exosomes from healthy donors are known to inhibit HIV-1 transmission; the effect of HIV-1 on HM exosomal miRNA signatures remains unknown. In the present study, HM derived exosomal miRNA profiles were investigated in HIV-1 infected lactating women. Methods: First week postpartum HM exosomes were purified from uninfected control and HIV-1 infected mothers (n=36), processed for RNA extraction and subjected to miRNA expression profiling by NanoString technology. The data were analyzed, and targets were predicted. Results: We describe that HIV-1 perturbed the differential expression pattern of 19 miRNAs (13 up and 6 downregulated) in HIV-1 infected women compared to healthy controls. DIANA-miR functional Pathway analyses revealed that multiple biological pathways are involved including Cell cycle, Pathways in Cancer, TGF-β signaling, FoxO signaling, Fatty Acid Biosynthesis, p53 signaling and Apoptosis. Further, the receiver operating characteristics (ROC) curve analyses of two of the identified miRNAs, miR-630 and miR-378g for separating HIV-1 infected women from healthy controls yielded areas under the ROC curves of 0.82 (95% CI= 0.67 to 0.82) and 0.83 (95% CI= 0.67 to 0.83), respectively highlighting their potential to serve as biomarkers of HIV-1 infection in women. Conclusions: Our studies provide new information that HIV-1 perturbs the expression levels of HM derived exosomal miRNAs in lactating women. The stability of HM exosomes at room temperature raises the possibility of their utility in HIV-1 screening prior to HIV-1 specific testing in countries like Nigeria. Further, our data may also contribute to the development of new therapeutic strategies in prevention of mother-to-child transmission (MTCT) of HIV-1 in infants.

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HIV-1 infection increases microRNAs that inhibit Dicer1, HRB and HIV-EP2, thereby reducing viral replication

Cited by 29 publications

References 52 publications

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Expression profiling of human milk derived exosomal microRNAs and their targets in HIV-1 infected mothers

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

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