On the role of four small hairpins in the HIV-1 RNA genome

Knoepfel, Stefanie A; Berkhout, Ben

doi:10.4161/rna.24133

Cited by 15 publications

(17 citation statements)

References 65 publications

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“…Strong conservation of these hairpins in some HA subtypes and their disappearance in others is consistent with frequently observed non-random reassortment of compatible segments26303132. In positive-sense mRNA, locally stable structures may be involved in modulation of protein folding, with their folding free energies slowing down the ribosome movement and thus facilitating correct cotranslational formation of native domain structures55, or in interference with host innate immunity5657.…”

Section: Discussionsupporting

confidence: 75%

“…Plaque assays of mutant viruses with disrupted or destabilized structures predicted in the HA cleavage site region also did not reveal any replication defects (Supplementary Figs S6 and S7). Similar inconsistency between evolutionary conservation of virus structures and their influence on virus replication assays was previously noted for HIV-1 and murine norovirus5657. It has been suggested that RNA folding could have a function that contributes to virus fitness and persistence in nature but is not essential for basic replication under the experimental conditions.…”

Section: Discussionmentioning

confidence: 56%

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Subtype-specific structural constraints in the evolution of influenza A virus hemagglutinin genes

Gultyaev

Spronken

Richard

et al. 2016

Sci Rep

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The influenza A virus genome consists of eight RNA segments. RNA structures within these segments and complementary (cRNA) and protein-coding mRNAs may play a role in virus replication. Here, conserved putative secondary structures that impose significant evolutionary constraints on the gene segment encoding the surface glycoprotein hemagglutinin (HA) were investigated using available sequence data on tens of thousands of virus strains. Structural constraints were identified by analysis of covariations of nucleotides suggested to be paired by structure prediction algorithms. The significance of covariations was estimated by mutual information calculations and tracing multiple covariation events during virus evolution. Covariation patterns demonstrated that structured domains in HA RNAs were mostly subtype-specific, whereas some structures were conserved in several subtypes. The influence of RNA folding on virus replication was studied by plaque assays of mutant viruses with disrupted structures. The results suggest that over the whole length of the HA segment there are local structured domains which contribute to the virus fitness but individually are not essential for the virus. Existence of subtype-specific structured regions in the segments of the influenza A virus genome is apparently an important factor in virus evolution and reassortment of its genes.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 56%

Subtype-specific structural constraints in the evolution of influenza A virus hemagglutinin genes

Gultyaev

Spronken

Richard

et al. 2016

Sci Rep

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“…Computer models of RNA folding predict stable hairpins in these regions that have been suggested to be functional and termed "insulating stems" (10,33). The weak selection against synonymous variants is compatible with the negative results of in vitro replication assays investigating the fitness effects of small RNA hairpins in HIV-1 (43): it would take hundreds of cell culture passages to detect fitness effects of the order of one per thousand. The longitudinal data, however, span many years, and our analysis is able to quantify the subtle fitness effect of RNA structure in intrapatient evolution.…”

Section: Discussionmentioning

confidence: 78%

Quantifying Selection against Synonymous Mutations in HIV-1 env Evolution

Zanini

Neher

2013

J Virol

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Intrapatient evolution of human immunodeficiency virus type 1 (HIV-1) is driven by the adaptive immune system resulting in rapid change of HIV-1 proteins. When cytotoxic CD8؉ T cells or neutralizing antibodies target a new epitope, the virus often escapes via nonsynonymous mutations that impair recognition. Synonymous mutations do not affect this interplay and are often assumed to be neutral. We test this assumption by tracking synonymous mutations in longitudinal intrapatient data from the C2-V5 part of the env gene. We find that most synonymous variants are lost even though they often reach high frequencies in the viral population, suggesting a cost to the virus. Using published data from SHAPE (selective 2=-hydroxyl acylation analyzed by primer extension) assays, we find that synonymous mutations that disrupt base pairs in RNA stems flanking the variable loops of gp120 are more likely to be lost than other synonymous changes: these RNA hairpins might be important for HIV-1. Computational modeling indicates that, to be consistent with the data, a large fraction of synonymous mutations in this genomic region need to be deleterious with a cost on the order of 0.002 per day. This weak selection against synonymous substitutions does not result in a strong pattern of conservation in cross-sectional data but slows down the rate of evolution considerably. Our findings are consistent with the notion that large-scale patterns of RNA structure are functionally relevant, whereas the precise base pairing pattern is not. Human immunodeficiency virus type 1 (HIV-1) evolves rapidly within a single host during the course of the infection. This evolution is driven by strong selection imposed by the host immune system via cytotoxic CD8 ϩ T cells (CTLs) and neutralizing antibodies (nAbs) (1) and is facilitated by HIV-1's high mutation rate (2, 3). Escape mutations in epitopes targeted by CTLs are typically observed during early infection and spread rapidly through the population (4). During chronic infection, the most rapidly evolving parts of the HIV-1 genome are the variable loops (V1 to V5) in the envelope protein gp120 (V loops), which change to avoid recognition by nAbs. Escape mutations in env, the gene encoding gp120, spread through the viral population within a few months. Consistent with this time scale, it is found that serum from a particular time typically neutralizes autologous virus extracted more than 3 to 6 months earlier but not contemporary virus (5).Escape mutations are selected because they change the amino acid sequences of viral proteins in a way that reduces antibody binding or epitope presentation. Conversely, synonymous mutations do not modify the viral proteins and are commonly used as approximately neutral markers in studies of viral evolution, i.e., as a negative control for detecting selected sites (6-8). In addition to maintaining protein function and avoiding the adaptive immune recognition, however, the HIV-1 genome has to ensure efficient processing and translation, nuclear export, and packaging ...

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“…One of the possible functions of structured regions in RNA genomes is to interfere with the host innate systems recognizing a pathogen RNA. 2,[57][58][59] Future experimental studies will elucidate the structurefunction relationships in the influenza virus RNA genome. Apparently, RNA folding is an important factor contributing to the virus evolution.…”

Section: Discussionmentioning

confidence: 99%

RNA structural constraints in the evolution of the influenza A virus genome NP segment

Gultyaev

Tsyganov-Bodounov

Spronken³

et al. 2014

RNA Biology

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Conserved RNA secondary structures were predicted in the nucleoprotein (NP) segment of the influenza A virus genome using comparative sequence and structure analysis. A number of structural elements exhibiting nucleotide covariations were identified over the whole segment length, including protein-coding regions. Calculations of mutual information values at the paired nucleotide positions demonstrate that these structures impose considerable constraints on the virus genome evolution. Functional importance of a pseudoknot structure, predicted in the NP packaging signal region, was confirmed by plaque assays of the mutant viruses with disrupted structure and those with restored folding using compensatory substitutions. Possible functions of the conserved RNA folding patterns in the influenza A virus genome are discussed.

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On the role of four small hairpins in the HIV-1 RNA genome

Cited by 15 publications

References 65 publications

Subtype-specific structural constraints in the evolution of influenza A virus hemagglutinin genes

Subtype-specific structural constraints in the evolution of influenza A virus hemagglutinin genes

Quantifying Selection against Synonymous Mutations in HIV-1 env Evolution

RNA structural constraints in the evolution of the influenza A virus genome NP segment

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