Cell biology of retroviral RNA packaging

Jouvenet, Nolwenn; Lainé, Sébastien; Pessel-Vivares, Lucie; Mougel, Marylène

doi:10.4161/rna.8.4.16030

Cited by 44 publications

(47 citation statements)

References 116 publications

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“…3C). In order to determine the packaging efficiency of these transcripts into the pelleted retroviral VLPs, we compared the levels of transcripts found in the pelleted retroviral VLPs to the ones found in the cellular RNA using a previously validated methodology (32,77,78). Of these transcripts, HK2 genes and Bogota HK2 appear to be the most abundant retroviral transcripts in NCCIT cellular RNA.…”

Section: Resultsmentioning

confidence: 99%

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Contreras-Galindo

Kaplan

Dube

et al. 2015

J Virol

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Human endogenous retroviruses (HERV) make up 8% of the human genome. While the youngest of these retroviruses, HERV-K(HML-2), termed HK2, is able to code for all viral proteins and produce virus-like particles, it is not known if these virus particles package and transmit HK2-related sequences. Here, we analyzed the capacity of HK2 for packaging and transmitting HK2 sequences. We created an HK2 probe, termed Bogota, which can be packaged into HK2 viruses, and transfected it into cells that make HK2 particles. Supernatants of the transfected cells, which contained HK2 viral particles, then were added to target cells, and the transmissibility of the HK2 Bogota reporter was tracked by G418 resistance. Our studies revealed that contemporary HK2 virions produced by some teratocarcinoma and breast cancer cell lines, as well as by peripheral blood lymphocytes from lymphoma patients, can package HK2 Bogota probes, and these viruses transmitted these probes to other cells. After transmission, HK2 Bogota transcripts undergo reverse transcription, a step impaired by antiretroviral agents or by introduction of mutations into the probe sequences required for reverse transcription. HK2 viruses were more efficiently transmitted in the presence of HK2 Rec or HIV-1 Tat and Vif. Transmitted Bogota probes formed episomes but did not integrate into the cellular genome. Resistance to integration might explain the relatively low number of HK2 insertions that were acquired during the last 25 million years of evolution. Whether transient transmission of modern HK2 sequences, which encode two putative oncoproteins, can lead to disease remains to be studied. IMPORTANCERetroviruses invaded the genome of human ancestors over the course of millions of years, yet these viruses generally have been inactivated during evolution, with only remnants of these infectious sequences remaining in the human genome. One of these viruses, termed HK2, still is capable of producing virus particles, although these particles have been regarded as being noninfectious. Using a genetic probe derived from HK2, we have discovered that HK2 viruses produced in modern humans can package HK2 sequences and transmit them to various other cells. Furthermore, the genetic sequences packaged in HK2 undergo reverse transcription. The transmitted probe circularized in the cell and failed to integrate into the cellular genome. These findings suggest that modern HK2 viruses can package viral RNA and transmit it to other cells. Contrary to previous views, we provide evidence of an extracellular viral phase of modern HK2 viruses. We have no evidence of sustained, spreading infection.A ctively replicating retroviruses infected the germ line multiple times over the millions of years of human evolution. These sequences were transmitted vertically in a Mendelian fashion to the next generation; therefore, they became a stable part of the inherited genetic material. Relics of these retroviral infections presently make up approximately 8% of the modern human genome. These retro...

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Section: Resultsmentioning

confidence: 99%

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Contreras-Galindo

Kaplan

Dube

et al. 2015

J Virol

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“…[38][39][40][41][42] In IAVs, many studies have shown that selective packaging may occur through direct interactions between different vRNAs. [22][23][24][25] The proposal that vRNAs form secondary structures in vRNPs was previously controversial because NP can melt secondary structures in vRNAs.…”

Section: Discussionmentioning

confidence: 99%

Computational and molecular analysis of conserved influenza A virus RNA secondary structures involved in infectious virion production

et al. 2016

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As well as encoding viral proteins, genomes of RNA viruses harbor secondary and tertiary RNA structures that have been associated with functions essential for successful replication and propagation. Here, we identified stem-loop structures that are extremely conserved among 1,884 M segment sequences of influenza A virus (IAV) strains from various subtypes and host species using computational and evolutionary methods. These structures were predicted within the 3 0 and 5 0 ends of the coding regions of M1 and M2, respectively, where packaging signals have been previously proposed to exist. These signals are thought to be required for the incorporation of a single copy of 8 different negative-strand RNA segments (vRNAs) into an IAV particle. To directly test the functionality of conserved stem-loop structures, we undertook reverse genetic experiments to introduce synonymous mutations designed to disrupt secondary structures predicted at 3 locations and found them to attenuate infectivity of recombinant virus. In one mutant, predicted to disrupt stem loop structure at nucleotide positions 219-240, attenuation was more evident at increased temperature and was accompanied by an increase in the production of defective virus particles. Our results suggest that the conserved secondary structures predicted in the M segment are involved in the production of infectious viral particles during IAV replication.

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“…Alternatively, cytosolic material from producer cells (nucleic acid, proteins, and metabolites) carried over by VLPs could be detected by MDM. 5=-Triphosphate RNA from stromal cells has been shown to induce an RIG-I-dependent IFN response in breast cancer cells through exosomal intercellular transport (41), and a similar mechanism could be proposed with cellular RNA associated with VLPs (42).…”

Section: Figmentioning

confidence: 99%

Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages

Decalf

Desdouits

Rodrigues

et al. 2017

J Virol

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Along with CD4 ϩ T lymphocytes, macrophages are a major cellular source of HIV-1 replication and a potential viral reservoir. Following entry and reverse transcription in macrophages, cloaking of the viral cDNA by the HIV-1 capsid limits its cytosolic detection, enabling efficient replication. However, whether incoming HIV-1 particles are sensed by macrophages prior to reverse transcription remains unclear. Here, we show that HIV-1 triggers a broad expression of interferon (IFN)-stimulated genes (ISG) in monocyte-derived macrophages within a few hours after infection. This response does not require viral reverse transcription or the presence of HIV-1 RNA within particles, but viral fusion is essential. This response is elicited by viruses carrying different envelope proteins and thus different receptors to proceed for viral entry. Expression of ISG in response to viral entry requires TBK1 activity and type I IFNs signaling. Remarkably, the ISG response is transient but affects subsequent viral spread. Together, our results shed light on an early step of HIV-1 sensing by macrophages at the level of entry, which confers an early protection through type I IFN signaling and has potential implications in controlling the infection.IMPORTANCE HIV infection is restricted to T lymphocytes and macrophages. HIV-1-infected macrophages are found in many tissues of infected patients, even under antiretroviral therapy, and are considered a viral reservoir. How HIV-1 is detected and what type of responses are elicited upon sensing remain in great part elusive. The kinetics and localization of the production of cytokines such as interferons in response to HIV is of critical importance to understanding how the infection and the immune response are established. Our study provides evidence that macrophages can detect HIV-1 as soon as it enters the cell. Interestingly, this sensing is independent of the presence of viral nucleic acids within the particles but requires their fusion with the macrophages. This triggers a low interferon response, which activates an antiviral program protecting cells against further viral challenge and thus potentially limiting the spread of the infection. KEYWORDS human immunodeficiency virus, innate immunity, interferons, macrophages, virus entry M acrophages are present in most tissues and endowed with many functions, including sensing and clearing of pathogens. However, pathogens frequently exploit macrophages as a privileged niche for their replication (1). This is the case for HIV-1, which mainly targets two cell types for replication: macrophages and CD4 ϩ T cells (2). Infected macrophages are considered to play an important role from the onset of infection to the development of the pathogenesis (3). The HIV-1 cycle in macrophages possesses specific features compared to T cells: macrophages are resistant to

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Cell biology of retroviral RNA packaging

Cited by 44 publications

References 116 publications

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Computational and molecular analysis of conserved influenza A virus RNA secondary structures involved in infectious virion production

Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages

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