Conservation of tRNA mimicry in the 5'-untranslated region of distinct HIV-1 subtypes

RNA. 2017 Dec;23(12):1850-1859. doi: 10.1261/rna.062182.117. Epub 2017 Aug 31.


Human tRNALys3 serves as the primer for reverse transcription in human immunodeficiency virus type-1 (HIV-1) and anneals to the complementary primer binding site (PBS) in the genome. All tRNALys isoacceptors interact with human lysyl-tRNA synthetase (hLysRS) and are selectively packaged into virions. tRNALys3 must be released from hLysRS in order to anneal to the PBS, and this process is proposed to be facilitated by the interaction of hLysRS with a tRNA-like element (TLE) first identified in the HIV-1 5'-untranslated region (5'-UTR) of the subtype B NL4-3 virus. However, a significant subset of HIV-1 strains represented by the MAL isolate possess a different secondary structure in this region of the genome. Thus, to establish the conservation of this mechanism for primer targeting and release, we investigated the subtype A-like 5'-UTR of the MAL isolate. hLysRS bound to a 229-nt MAL RNA containing the PBS domain with high affinity (Kd = 47 nM), and to a 98-nt truncated construct with ∼10-fold reduced affinity. These results resemble previous studies using analogous NL4-3-derived RNAs. However, in contrast to studies with NL4-3, no binding was observed to smaller stem-loop elements within the MAL PBS domain. The tertiary structure of the 98-nt construct was analyzed using small-angle X-ray scattering, revealing remarkable global structural similarity to the corresponding NL4-3 PBS/TLE region. These results suggest that the tRNA-like structure within the 5'-UTR is conserved across distinct HIV-1 subtypes and that hLysRS recognition of the MAL isolate is likely not conferred by specific sequence elements but by 3D structure.

Keywords: HIV-1; SAXS; human lysyl-tRNA synthetase; primer binding site; tRNA-like element.

Publication types

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

MeSH terms

  • 5' Untranslated Regions / genetics*
  • Base Sequence
  • Binding Sites
  • Gene Expression Regulation, Viral
  • Genome, Viral
  • HIV Infections / genetics*
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / classification
  • HIV-1 / genetics*
  • Humans
  • Lysine-tRNA Ligase / genetics
  • Lysine-tRNA Ligase / metabolism*
  • Molecular Mimicry*
  • Nucleic Acid Conformation
  • RNA, Transfer, Lys / genetics*
  • RNA, Viral / genetics*
  • Virus Replication


  • 5' Untranslated Regions
  • RNA, Transfer, Lys
  • RNA, Viral
  • Lysine-tRNA Ligase