Efficient pre-catalytic conformational change of reverse transcriptases from SAMHD1 non-counteracting primate lentiviruses during dNTP incorporation

• Type of Material: Article
• Authors: Si'Ana Coggins, Emory University; Jessica M. Holler, Emory University; Jason T. Kimata, Baylor College of Medicine; Raymond Schinazi, Emory University; Baek Kim, Emory University
• Language: English
• Date: 2019-11-01
• Publisher: Academic Press Inc. Elsevier Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 The Authors. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.virol.2019.08.010
• Title of Journal or Parent Work: Virology
• Volume: 537
• Start Page: 36
• End Page: 44
• Grant/Funding Information: This work was supported by NIH AI136581 (B.K.), AI150451 (B.K.), and MH116695 (R.F.S.).
• Keywords: Vpr; Virology; Macrophages; Simian Immunodeficiency Virus; Vpx; Mechanism; State kinetic; E3 Ubiquitin Ligase; Restriction factor SAMHD1; Steady-state; Fidelity; DNA-polymerase I; Replication; Lentiviruses; Life Sciences & Biomedicine; Conformational change; SAMHD1; HIV-1; Science & Technology; dNTPs; Reverse transcriptase
• Research Categories: Biology, Microbiology; Biology, Molecular; Health Sciences, Epidemiology; Biology, Virology

Abstract

Unlike HIV-1, HIV-2 and some SIV strains replicate at high dNTP concentrations even in macrophages due to their accessory proteins, Vpx or Vpr, that target SAMHD1 dNTPase for proteasomal degradation. We previously reported that HIV-1 reverse transcriptase (RT) efficiently synthesizes DNA even at low dNTP concentrations because HIV-1 RT displays faster pre-steady state kpol values than SAMHD1 counteracting lentiviral RTs. Here, since the kpol step consists of two sequential sub-steps post dNTP binding, conformational change and chemistry, we investigated which of the two sub-steps RTs from SAMHD1 non-counteracting viruses accelerate in order to complete reverse transcription in the limited dNTP pools found in macrophages. Our study demonstrates that RTs of SAMHD1 non-counteracting lentiviruses have a faster conformational change rate during dNTP incorporation, supporting that these lentiviruses may have evolved to harbor RTs that can efficiently execute the conformational change step in order to circumvent SAMHD1 restriction and dNTP depletion in macrophages.