Coordination of Genomic RNA Packaging with Viral Assembly in HIV-1

Hellmund, Chris; Lever, Andrew M. L.

doi:10.3390/v8070192

Cited by 9 publications

(17 citation statements)

References 107 publications

(182 reference statements)

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“…Surprisingly, the influence of the 5′-Cap moiety on dimerization was similar to that of adding a single phosphodiester-linked 5′ guanosine. Our findings support proposals that genome dimerization is a major determinant of RNA function (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(25)(26)(27)(28)(29)(30)(31)(32)(33) and suggest a paradigm in which the structure, function, and fate of the viral transcripts are modulated by heterogeneous TSS selection.…”

Section: Significancesupporting

confidence: 87%

“…These and other observations support a mechanism in which a single viral transcript equilibrates between structures associated with alternate replication functions (9,12,16,26,29). In these models, the equilibration is not rate limiting, and HIV-1 RNA fates are sealed by the binding of alternate sets of proteins associated with differing replication roles (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)33).…”

Section: Discussionsupporting

confidence: 52%

“…Because prior studies have established that genome dimerization likely controls packaging and other RNA-dependent functions (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(25)(26)(27)(28)(29)(30)(31)(32)(33), we examined the influence of TSS use on the in vitro dimerization properties of the HIV-1 NL4-3 5′-L (Fig. 4A).…”

Section: Resultsmentioning

confidence: 99%

“…These RNAs serve as the viral genome (gRNA) and are used as templates for reverse transcription during an early stage of the replication cycle. gRNAs are selected for packaging as dimers (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), enabling strand-transfermediated recombination during reverse transcription and facilitating genetic evolution under environmental and chemotherapeutic pressures (23).…”

mentioning

confidence: 99%

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Transcriptional start site heterogeneity modulates the structure and function of the HIV-1 genome

Kharytonchyk

Monti

Smaldino

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

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The promoter in HIV type 1 (HIV-1) proviral DNA contains three sequential guanosines at the U3-R boundary that have been proposed to function as sites for transcription initiation. Here we show that all three sites are used in cells infected with HIV-1 and that viral RNAs containing a single 5′ capped guanosine ( Cap 1G) are specifically selected for packaging in virions, consistent with a recent report [Masuda et al. (2015) Sci Rep 5:17680]. In addition, we now show that transcripts that begin with two or three capped guanosines ( Cap 2G or Cap 3G) are enriched on polysomes, indicating that RNAs synthesized from different transcription start sites have different functions in viral replication. Because genomes are selected for packaging as dimers, we examined the in vitro monomer-dimer equilibrium properties of Cap 1G, Cap 2G, and Cap 3G 5′-leader RNAs in the NL4-3 strain of HIV-1. Strikingly, under physiological-like ionic conditions in which the Cap 1G 5′-leader RNA adopts a dimeric structure, the Cap 2G and Cap 3G 5′-leader RNAs exist predominantly as monomers. Mutagenesis studies designed to probe for base-pairing interactions suggest that the additional guanosines of the 2G and 3G RNAs remodel the base of the PolyA hairpin, resulting in enhanced sequestration of dimerpromoting residues and stabilization of the monomer. Our studies suggest a mechanism through which the structure, function, and fate of the viral genome can be modulated by the transcriptionally controlled presence or absence of a single 5′ guanosine.HIV-1 | 5′-leader | transcription | RNA | structure

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Section: Significancesupporting

confidence: 87%

Section: Discussionsupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Transcriptional start site heterogeneity modulates the structure and function of the HIV-1 genome

Kharytonchyk

Monti

Smaldino

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

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“…Genetic studies indicate that the DIS is responsible for RNA:RNA partner selection [15,16], but other leader elements, including those overlapping the gag start codon (AUG, Figure 1), also play roles in dimerization [13,17,18,19]. Genome selection during virus assembly is mediated by interactions between the nucleocapsid (NC) domains of a small number of viral Gag polyproteins (~12 or fewer) [20] and packaging signals located within the 5′-leader of the viral RNA [8,10,11,14,21,22,23,24,25,26,27,28,29]. Additional Gag proteins associate with the genome after it is anchored to the PM, leading to further virus assembly and budding [30].…”

Section: Dimerization-dependent Control Of Human Immunodeficiency mentioning

confidence: 99%

NMR Studies of the Structure and Function of the HIV-1 5′-Leader

Keane

Summers

2016

Viruses

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The 5′-leader of the human immunodeficiency virus type 1 (HIV-1) genome plays several critical roles during viral replication, including differentially establishing mRNA versus genomic RNA (gRNA) fates. As observed for proteins, the function of the RNA is tightly regulated by its structure, and a common paradigm has been that genome function is temporally modulated by structural changes in the 5′-leader. Over the past 30 years, combinations of nucleotide reactivity mapping experiments with biochemistry, mutagenesis, and phylogenetic studies have provided clues regarding the secondary structures of stretches of residues within the leader that adopt functionally discrete domains. More recently, nuclear magnetic resonance (NMR) spectroscopy approaches have been developed that enable direct detection of intra- and inter-molecular interactions within the intact leader, providing detailed insights into the structural determinants and mechanisms that regulate HIV-1 genome packaging and function.

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The regulation of Endosomal Sorting Complex Required for Transport and accessory proteins in multivesicular body sorting and enveloped viral budding - An overview

Ahmed

Akram

Iqbal

et al. 2019

International Journal of Biological Macromolecules

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ESCRT (Endosomal sorting complex required for transport) machinery drives different cellular processes such as endosomal sorting, organelle biogenesis, vesicular trafficking, maintenance of plasma membrane integrity, membrane fission during cytokinesis and enveloped virus budding. The normal cycle of assembly and disassembly of some ESCRT complexes at the membrane requires the AAA-ATPase vacuolar protein sorting 4 (Vps4p). A number of ESCRT proteins are hijacked by clinically significant enveloped viruses including Ebola, and Human Immunodeficiency Virus (HIV) to enable enveloped virus budding and Vps4p provides energy for the disassembly/recycling of these ESCRT proteins. Several years ago, the failure of the terminal budding process of HIV following Vps4 protein inhibition was published; although at that time a detailed understanding of the molecular players was missing. However, later it was acknowledged that the ESCRT machinery has a role in enveloped virus budding from cells due to its role in the multivesicular body (MVB) sorting pathway. The MVB sorting pathway facilitates several cellular activities in uninfected cells, such as the down-regulation of signaling through cell surface receptors as well as the process of viral budding from infected host cells. In this review, we focus on summarising the functional organisation of ESCRT proteins at the membrane and the role of ESCRT machinery and Vps4p during MVB sorting and enveloped viral budding.

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Coordination of Genomic RNA Packaging with Viral Assembly in HIV-1

Cited by 9 publications

References 107 publications

Transcriptional start site heterogeneity modulates the structure and function of the HIV-1 genome

Transcriptional start site heterogeneity modulates the structure and function of the HIV-1 genome

NMR Studies of the Structure and Function of the HIV-1 5′-Leader

The regulation of Endosomal Sorting Complex Required for Transport and accessory proteins in multivesicular body sorting and enveloped viral budding - An overview

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