Incomplete Suppression of HIV-1 by SAMHD1 Permits Efficient Macrophage Infection.

• Type of Material: Article
• Authors: Timothy Plitnik, University of Miami; Mark E. Sharkey, University of Miami; Bijan Mahboubi, Emory University; Baek Kim, Emory University; Mario Stevenson, University of Miami
• Language: English
• Date: 2018
• Publisher: Case Western Reserve University
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2018 Timothy Plitnik, Mark E. Sharkey, Bijan Mahboubi, Baek Kim, Mario Stevenson
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.20411/pai.v3i2.263
• Title of Journal or Parent Work: Pathogens and Immunity
• ISSN: 2469-2964
• Volume: 3
• Issue: 2
• Start Page: 197
• End Page: 223
• Grant/Funding Information: We acknowledge support from the Miami Center for AIDS Research (CFAR) at the University of Miami Miller School of Medicine which is funded by a grant (P30AI073961) from the National Institutes of Health (NIH).; We acknowledge grant support from National Institutes of Health (MH100942, MH093306, MH116701) to M.S., grants (AI136581 and GM104198) to B.K., and grant (AI131568) to Hartigan-O’Connor.
• Keywords: HIV-1; macrophages; SAMHD1
• Research Categories: Health Sciences, Pharmacy; Biology, Microbiology; Health Sciences, Immunology

Abstract

Background: Sterile alpha motif and histidine/aspartic acid domain-containing protein (SAMHD1) is a dNTP triphosphorylase that reduces cellular dNTP levels in non-dividing cells, such as macrophages. Since dNTPs are required for reverse transcription, HIV-2 and most SIVs encode a Vpx protein that promotes proteasomal degradation of SAMHD1. It is unclear how HIV-1, which does not appear to harbor a SAMHD1 escape mechanism, is able to infect macrophages in the face of SAMHD1 restriction. Methods: To assess whether HIV-1 had a mechanism to negate SAMHD1 activity, we compared SAMHD1 and dNTP levels in macrophages infected by HIV-1 and SIV. We examined whether macrophages infected by HIV-1 still harbored antiviral levels of SAMHD1 by assessing their susceptibility to superinfection by vpx-deleted SIV. Finally, to assess whether HIV-1 reverse transcriptase (RT) has adapted to a low dNTP environment, we evaluated SAMHD1 sensitivity of chimeric HIV-1 and SIV variants in which the RT regions were functionally exchanged. Results: Here, we demonstrate that HIV-1 efficiently infects macrophages without modulating SAMHD1 activity or cellular dNTP levels, and that macrophages permissive to HIV-1 infection remained refractory to superinfection by vpx-deleted SIV. Furthermore, through the use of chimeric HIV/SIV, we demonstrate that the differential sensitivity of HIV-1 and SIV to SAMHD1 restriction is not dictated by RT. Conclusions: Our study reveals fundamental differences between HIV-1 and SIV in the strategy used to evade restriction by SAMHD1 and suggests a degree of resistance of HIV-1 to the antiviral environment created by SAMHD1. Understanding how these cellular restrictions antagonize viral replication will be important for the design of novel antiviral strategies.