HIV-1 Replication and the Cellular Eukaryotic  Translation Apparatus

Guerrero, Santiago; Batisse, Julien; Libre, Camille; Bernacchi, Serena; Marquet, Roland; Paillart, Jean-Christophe

doi:10.3390/v7010199

Cited by 46 publications

(38 citation statements)

References 93 publications

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“…For eIF2 specifically, the phosphorylation of alpha subunit of eIF2 blocks protein translation (43), allowing cells to conserve resources, and subsequently switch to a new gene expression program to prevent stress damage (44). Interestingly, due to additional interactions of HIV with cellular translational machinery, the synthesis of viral structural proteins is reported to be sustained (45). The downregulation of ribosome assembly in both CD4 ϩ T cells and NK cells may reflect a common effect of systemic HIV proteins on both lymphocyte populations.…”

Section: Discussionmentioning

confidence: 99%

Persistent Replication of HIV, Hepatitis C Virus (HCV), and HBV Results in Distinct Gene Expression Profiles by Human NK Cells

Boeijen

Hou

Groen

et al. 2019

J Virol

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NK cells during chronic viral infection have been well studied in the past. We performed an unbiased next-generation RNA-sequencing approach to identify commonalities or differences of the effect of HIV, HCV and HBV viremia on NK cell transcriptomes. Using cell sorting, we obtained CD3-CD56+ NK cells from blood of 6 HIV, 8 HCV, and 32 HBV infected patients without treatment. After library preparation and sequencing, we used an in-house analytic pipeline to compare expression levels with matched healthy controls. In NK cells from HIV, HCV and HBV patients, transcriptome analysis identified 272, 53, and 56 differentially expressed genes, respectively (fold change >1.5, q-value 0.2). Interferon stimulated genes were induced in NK cells from HIV/HCV patients, but not during HBV infection. HIV viremia downregulated ribosome assembly genes in NK cells. In HBV, viral load and ALT variation had little effect on genes related to NK effector function. In conclusion, we compare, for the first time, NK cell transcripts of viremic HIV, HCV and HBV patients. We clearly demonstrate distinctive NK cell gene signatures in 3 different populations, suggestive for a different degree of functional alterations of the NK cell compartment as compared to healthy individuals. Three viruses exist that can result in persistently high viral loads in immune competent humans: HIV, hepatitis C and hepatitis B. In the last decades, using flow cytometry and in vitro assays on NK cells from patients with these diseases, several impairments have been established, particularly during and possibly contributing to HIV viremia. However, the background of NK cell impairments in viremic patients is not well understood. In this study we describe the NK cell transcriptome of patients with high viral loads of different etiologies. We clearly demonstrate distinctive NK cell gene signatures, with regard to ISG induction, expression of genes coding for activation markers or proteins involved in cytotoxic action, as well immunological genes. This study provides important details necessary to uncover the origin of functional and phenotypical differences between viremic patients and healthy subjects, and provides many leads that can be confirmed using future in vitro manipulation experiments.

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Section: Discussionmentioning

confidence: 99%

Persistent Replication of HIV, Hepatitis C Virus (HCV), and HBV Results in Distinct Gene Expression Profiles by Human NK Cells

Boeijen

Hou

Groen

et al. 2019

J Virol

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“…Due to the apparent relevance in driving HIV-1 Gag protein synthesis when cap-dependent translation initiation is hindered [23][24][25][26][27]30], in this study, we focused on understanding the mechanism of translation driven by the IRES that is located within the 5 0 UTR of the HIV-1 full length mRNA (HIV IRES), [25,26,28]. To date, the molecular basis of HIV-1 IRES-mediated translation initiation remains poorly understood (reviewed in [70,71]). The HIV-1 IRES is active in HeLa and COS-7 cells (Figs 1-4), although, relative to other viral IRESs, its activity is low in HeLa cells ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural domains within the HIV‐1 mRNA and the ribosomal protein S25 influence cap‐independent translation initiation

et al. 2016

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The 5′leader of the HIV-1 genomic RNA is a multifunctional region that folds into secondary/tertiary structures that regulate multiple processes during viral replication including translation initiation. In this work we examine the internal ribosome entry site (IRES) located in the 5′leader that drives translation initiation of the viral Gag protein under conditions that hinder cap-dependent translation initiation. We show that activity of the HIV-1 IRES relies on ribosomal protein S25 (eS25). Additionally, a mechanistic and mutational analysis revealed that the HIV-1 IRES is modular in nature and that once the 40S ribosomal subunit is recruited to the IRES, translation initiates without the need of ribosome scanning. These findings elucidate a mechanism of initiation by the HIV-1 IRES whereby a number of highly structured sites present within the HIV-1 5′leader leads to the recruitment of the 40S subunit directly at the site of initiation of protein synthesis.

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“…However, these studies were performed using expression vectors lacking the authentic 5′ and 3′ untranslated regions (UTRs) of A3G mRNA, which could play key role(s) in A3G translation3839, and they thus may not faithfully recapitulate events occurring with endogenous A3G mRNA. Indeed, an in vitro translation study highlighted the importance of the 5′-UTRs of A3G mRNA in the inhibition of A3G translation by Vif4041. However, the relative importance of the translational inhibition of A3G by Vif, compared to the well-documented A3G degradation, and its impact on viral infectivity remained to be established.…”

mentioning

confidence: 99%

Translational regulation of APOBEC3G mRNA by Vif requires its 5′UTR and contributes to restoring HIV-1 infectivity

Guerrero

Libre

Batisse

et al. 2016

Sci Rep

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The essential HIV-1 viral infectivity factor (Vif) allows productive infection of non-permissive cells expressing cytidine deaminases APOBEC3G (A3G) and A3F by decreasing their cellular level, and preventing their incorporation into virions. Unlike the Vif-induced degradation of A3G, the functional role of the inhibition of A3G translation by Vif remained unclear. Here, we show that two stem-loop structures within the 5′-untranslated region of A3G mRNA are crucial for translation inhibition by Vif in cells, and most Vif alleles neutralize A3G translation efficiently. Interestingly, K26R mutation in Vif abolishes degradation of A3G by the proteasome but has no effect at the translational level, indicating these two pathways are independent. These two mechanisms, proteasomal degradation and translational inhibition, similarly contribute to decrease the cellular level of A3G by Vif and to prevent its incorporation into virions. Importantly, inhibition of A3G translation is sufficient to partially restore viral infectivity in the absence of proteosomal degradation. These findings demonstrate that HIV-1 has evolved redundant mechanisms to specifically inhibit the potent antiviral activity of A3G.

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HIV-1 Replication and the Cellular Eukaryotic Translation Apparatus

Cited by 46 publications

References 93 publications

Persistent Replication of HIV, Hepatitis C Virus (HCV), and HBV Results in Distinct Gene Expression Profiles by Human NK Cells

Persistent Replication of HIV, Hepatitis C Virus (HCV), and HBV Results in Distinct Gene Expression Profiles by Human NK Cells

Structural domains within the HIV‐1 mRNA and the ribosomal protein S25 influence cap‐independent translation initiation

Translational regulation of APOBEC3G mRNA by Vif requires its 5′UTR and contributes to restoring HIV-1 infectivity

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