IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis
- Medical Research Council Laboratory of Molecular Biology, United Kingdom
- University of New South Wales, Australia
- University College London, United Kingdom
Abstract
The HIV capsid is semi-permeable and covered in electropositive pores that are essential for viral DNA synthesis and infection. Here we show that these pores bind the abundant cellular polyanion IP6, transforming viral stability from minutes to hours and allowing newly synthesised DNA to accumulate inside the capsid. An arginine ring within the pore coordinates IP6, which strengthens capsid hexamers by almost 10°C. Single molecule measurements demonstrate that this renders native HIV capsids highly stable and protected from spontaneous collapse. Moreover, encapsidated reverse transcription assays reveal that, once stabilised by IP6, the accumulation of new viral DNA inside the capsid increases > 100-fold. Remarkably, isotopic labelling of inositol in virus producing cells reveals that HIV selectively packages over 300 IP6 molecules per infectious virion. We propose that HIV recruits IP6 to regulate capsid stability and uncoating, analogous to picornavirus pocket factors.
Data availability
Diffraction data have been deposited in PDB under the accession code 6ERM, 6ERN and 6ES8.
Article and author information
Author details
Funding
Medical Research Council (U105181010)
- Leo C James
Wellcome
- Leo C James
National Health and Medical Research Council (339223)
- Till Böcking
National Health and Medical Research Council (GNT1036521)
- David A Jacques
Wellcome (206248/Z/17/Z)
- William A McEwan
Wellcome
- Gregory J Towers
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Mallery et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 6,719
- views
-
- 891
- downloads
-
- 143
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis
eLife 7:e35335.
https://doi.org/10.7554/eLife.35335
Further reading
-
- Microbiology and Infectious Disease
- Structural Biology and Molecular Biophysics
Structural and biophysical studies help to follow the disassembly of the HIV-1 capsid in vitro, and reveal the role of a small molecule called IP6 in regulating capsid stability.
-
- Microbiology and Infectious Disease
Bacterial regional demonstration after global dissemination is an essential pathway for selecting distinct finesses. However, the evolution of the resistome during the transition to endemicity remains unaddressed. Using the most comprehensive whole-genome sequencing dataset of Salmonella enterica serovar Gallinarum (S. Gallinarum) collected from 15 countries, including 45 newly recovered samples from two related local regions, we established the relationship among avian-specific pathogen genetic profiles and localization patterns. Initially, we revealed the international transmission and evolutionary history of S. Gallinarum to recent endemicity through phylogenetic analysis conducted using a spatiotemporal Bayesian framework. Our findings indicate that the independent acquisition of the resistome via the mobilome, primarily through plasmids and transposons, shapes a unique antimicrobial resistance profile among different lineages. Notably, the mobilome-resistome combination among distinct lineages exhibits a geographical-specific manner, further supporting a localized endemic mobilome-driven process. Collectively, this study elucidates resistome adaptation in the endemic transition of an avian-specific pathogen, likely driven by the localized farming style, and provides valuable insights for targeted interventions.
