High-resolution View of HIV-1 Reverse Transcriptase Initiation Complexes and Inhibition by NNRTI Drugs

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 5

PMID 33947853

Citations 11

Authors

Betty Ha

Kevin P Larsen

Jingji Zhang

Ziao Fu

Elizabeth Montabana

Lynnette N Jackson

Dong-Hua Chen

Elisabetta Viani Puglisi

Affiliations

Soon will be listed here.

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 tRNA 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-tRNA 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.

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