Architecture of an HIV-1 reverse transcriptase initiation complex

Kevin P. Larsen, Yamuna Kalyani Mathiharan, Kalli Kappel, Aaron T. Coey, Dong-Hua Chen, Daniel Barrero, Lauren Madigan, Joseph D. Puglisi, Georgios Skiniotis and Elisabetta Viani Puglisi ()
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Kevin P. Larsen: Stanford University
Yamuna Kalyani Mathiharan: Stanford University School of Medicine
Kalli Kappel: Stanford University
Aaron T. Coey: Stanford University
Dong-Hua Chen: Stanford University School of Medicine
Daniel Barrero: Stanford University School of Medicine
Lauren Madigan: Stanford University School of Medicine
Joseph D. Puglisi: Stanford University School of Medicine
Georgios Skiniotis: Stanford University School of Medicine
Elisabetta Viani Puglisi: Stanford University School of Medicine

Nature, 2018, vol. 557, issue 7703, 118-122

Abstract: Abstract Reverse transcription of the HIV-1 RNA genome into double-stranded DNA is a central step in viral infection1 and a common target of antiretroviral drugs2. The reaction is catalysed by viral reverse transcriptase (RT)3,4 that is packaged in an infectious virion with two copies of viral genomic RNA5 each bound to host lysine 3 transfer RNA (tRNALys3), which acts as a primer for initiation of reverse transcription6,7. Upon viral entry into cells, initiation is slow and non-processive compared to elongation8,9. Despite extensive efforts, the structural basis of RT function during initiation has remained a mystery. Here we use cryo-electron microscopy to determine a three-dimensional structure of an HIV-1 RT initiation complex. In our structure, RT is in an inactive polymerase conformation with open fingers and thumb and with the nucleic acid primer–template complex shifted away from the active site. The primer binding site (PBS) helix formed between tRNALys3 and HIV-1 RNA lies in the cleft of RT and is extended by additional pairing interactions. The 5′ end of the tRNA refolds and stacks on the PBS to create a long helical structure, while the remaining viral RNA forms two helical stems positioned above the RT active site, with a linker that connects these helices to the RNase H region of the PBS. Our results illustrate how RNA structure in the initiation complex alters RT conformation to decrease activity, highlighting a potential target for drug action.

Date: 2018
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DOI: 10.1038/s41586-018-0055-9

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