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

Autor:	Plitnik T; Department of Microbiology & Immunology; Miller School of Medicine, University of Miami; Miami, Florida., Sharkey ME; Department of Medicine; Miller School of Medicine, University of Miami; Miami, Florida., Mahboubi B; Department of Pediatrics, Emory University; Atlanta, Georgia.; Center for Drug Discovery, Children's Healthcare of Atlanta; Atlanta, Georgia., Kim B; Department of Pediatrics, Emory University; Atlanta, Georgia.; Center for Drug Discovery, Children's Healthcare of Atlanta; Atlanta, Georgia.; Department of Pharmacy, Kyung-Hee University; Seoul; South Korea., Stevenson M; Department of Microbiology & Immunology; Miller School of Medicine, University of Miami; Miami, Florida.; Department of Medicine; Miller School of Medicine, University of Miami; Miami, Florida.
Jazyk:	angličtina
Zdroj:	Pathogens & immunity [Pathog Immun] 2018; Vol. 3 (2), pp. 197-223. Date of Electronic Publication: 2018 Dec 06.
DOI:	10.20411/pai.v3i2.263
Abstrakt:	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. Competing Interests: CONFLICT OF INTEREST The authors have no competing financial interests.
Databáze:	MEDLINE
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