High efficiency of HIV-1 genomic RNA packaging and heterozygote formation revealed by single virion analysis

Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13535-40. doi: 10.1073/pnas.0906822106. Epub 2009 Jul 23.

Abstract

A long-standing question in retrovirus biology is how RNA genomes are distributed among virions. In the studies presented in this report, we addressed this issue by directly examining HIV-1 RNAs in virions using a modified HIV-1 genome that contained recognition sites for BglG, an antitermination protein in the Escherichia coli bgl operon, which was coexpressed with a fragment of BglG RNA binding protein fused to a fluorescent protein. Our results demonstrate that the majority of virions (>90%) contain viral RNAs. We also coexpressed HIV-1 genomes containing binding sites for BglG or the bacteriophage MS2 coat protein along with 2 fluorescent protein-tagged RNA binding proteins. This method allows simultaneously labeling and discrimination of 2 different RNAs at single-RNA-detection sensitivity. Using this strategy, we obtained physical evidence that virions contain RNAs derived from different parental viruses (heterozygous virion) at ratios expected from a random distribution, and we found that this ratio can be altered by changing the dimerization sequences. Our studies of heterozygous virions also support a generally accepted but unproven assumption that most particles contain 1 dimer. This study provides answers to long-standing questions in HIV-1 biology and illustrates the power and sensitivity of the 2-RNA labeling method, which can also be adapted to analyze various issues of RNA biogenesis including the detection of different RNAs in live cell imaging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / genetics
  • Base Pairing / genetics
  • Base Sequence
  • Capsid Proteins / metabolism
  • Cell Line
  • Fluorescence
  • Genome, Viral / genetics*
  • HIV-1 / genetics*
  • HIV-1 / physiology*
  • Heterozygote*
  • Homozygote
  • Humans
  • Levivirus / metabolism
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • Operon / genetics
  • RNA, Viral / chemistry
  • RNA, Viral / genetics*
  • RNA-Binding Proteins / genetics
  • Staining and Labeling
  • Virion / genetics*
  • Virus Assembly / genetics*

Substances

  • Bacterial Proteins
  • Capsid Proteins
  • RNA, Viral
  • RNA-Binding Proteins
  • antiterminator proteins, Bacteria