Incomplete suppression of hiv-1 by samhd1 permits efficient macrophage infection

Timothy Plitnik, Mark E. Sharkey, Bijan Mahboubi, Baek Kim, Mario Stevenson

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Sterile alpha motif and histidine/aspartic acid domain-containing protein (SAM-HD1) 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.

Original languageEnglish (US)
Pages (from-to)197-223
Number of pages27
JournalPathogens and Immunity
Volume3
Issue number2
DOIs
StatePublished - 2018

Keywords

  • HIV-1
  • Macrophages
  • SAMHD1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Biology
  • Microbiology (medical)
  • Infectious Diseases

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