High-resolution view of HIV-1 reverse transcriptase initiation complexes and inhibition by NNRTI drugs

Betty Ha, Kevin P. Larsen, Jingji Zhang, Ziao Fu, Elizabeth Montabana, Lynnette N. Jackson, Dong-Hua Chen and Elisabetta Viani Puglisi ()
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Betty Ha: Stanford University School of Medicine
Kevin P. Larsen: Stanford University School of Medicine
Jingji Zhang: Stanford University School of Medicine
Ziao Fu: Columbia University
Elizabeth Montabana: Stanford University School of Medicine
Lynnette N. Jackson: Stanford University School of Medicine
Dong-Hua Chen: Stanford University School of Medicine
Elisabetta Viani Puglisi: Stanford University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Reverse transcription of the HIV-1 viral RNA genome (vRNA) is an integral step in virus replication. Upon viral entry, HIV-1 reverse transcriptase (RT) initiates from a host tRNALys3 primer bound to the vRNA genome and is the target of key antivirals, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Initiation proceeds slowly with discrete pausing events along the vRNA template. Despite prior medium-resolution structural characterization of reverse transcriptase initiation complexes (RTICs), higher-resolution structures of the RTIC are needed to understand the molecular mechanisms that underlie initiation. Here we report cryo-EM structures of the core RTIC, RTIC–nevirapine, and RTIC–efavirenz complexes at 2.8, 3.1, and 2.9 Å, respectively. In combination with biochemical studies, these data suggest a basis for rapid dissociation kinetics of RT from the vRNA–tRNALys3 initiation complex and reveal a specific structural mechanism of nucleic acid conformational stabilization during initiation. Finally, our results show that NNRTIs inhibit the RTIC and exacerbate discrete pausing during early reverse transcription.

Date: 2021
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DOI: 10.1038/s41467-021-22628-9

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