The Inhibition of HIV-1 Entry Imposed by Interferon Inducible Transmembrane Proteins Is Independent of Co-Receptor Usage
1
Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA
2
Department of Veterinary Biosciences, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA
3
Viruses and Emerging Pathogens Program, Infectious Diseases Institute, The Ohio State University, Columbus, OH 43210, USA
*
Author to whom correspondence should be addressed.
Viruses 2018, 10(8), 413; https://doi.org/10.3390/v10080413
Received: 24 June 2018
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Revised: 3 August 2018
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Accepted: 4 August 2018
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Published: 7 August 2018
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
Interferon inducible transmembrane proteins (IFITMs) are one of several IFN-stimulated genes (ISGs) that restrict entry of enveloped viruses, including flaviviruses, filoviruses and retroviruses. It has been recently reported that in U87 glioblastoma cells IFITM proteins inhibit HIV-1 entry in a co-receptor-dependent manner, that is, IFITM1 is more inhibitory on CCR5 tropic HIV-1 whereas IFITM2/3 confers a greater suppression of CXCR4 counterparts. However, how entry of HIV-1 with distinct co-receptor usage is modulated by different IFITM orthologs in physiologically relevant CD4+ T cells and monocytes/macrophages has not been investigated in detail. Here, we report that overexpression of IFITM1, 2 and 3 in human CD4+ HuT78 cells, SupT1 cells, monocytic THP-1 cells and U87 cells expressing CD4 and co-receptor CCR5 or CXCR4, suppressed entry of CXCR4 tropic viruses NL4.3 and HXB2, CCR5 tropic viruses AD8 and JRFL, dual tropic 89.6 virus, as well as a panel of 32 transmitted founder (T/F) viruses, with a consistent order of potency, that is, IFITM3 > IFITM2 > IFITM1. Consistent with previous reports, we found that some CCR5-using HIV-1 isolates, such as AD8 and JRFL, were relatively resistant to inhibition by IFITM2 and IFITM3, although the effect can be cell-type dependent. However, in no case have we observed that IFITM1 had a stronger inhibition on entry of any HIV-1 strains tested, including those of CCR5-using T/Fs. We knocked down the endogenous IFITMs in peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells and observed that, while this treatment did greatly enhance the multiple-round of HIV-1 replication but had modest effect to rescue the single-round HIV-1 infection, reinforcing our previous conclusion that the predominant effect of IFITMs on HIV-1 infection is in viral producer cells, rather than in target cells to block viral entry. Overall, our results argue against the idea that IFITM proteins distinguish co-receptors CCR5 and CXCR4 to inhibit entry but emphasize that the predominant role of IFITMs on HIV-1 is in producer cells that intrinsically impair the viral infectivity.
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Keywords:
IFITM; HIV-1; entry; co-receptor
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MDPI and ACS Style
Yu, J.; Liu, S.-L. The Inhibition of HIV-1 Entry Imposed by Interferon Inducible Transmembrane Proteins Is Independent of Co-Receptor Usage. Viruses 2018, 10, 413. https://doi.org/10.3390/v10080413
AMA Style
Yu J, Liu S-L. The Inhibition of HIV-1 Entry Imposed by Interferon Inducible Transmembrane Proteins Is Independent of Co-Receptor Usage. Viruses. 2018; 10(8):413. https://doi.org/10.3390/v10080413
Chicago/Turabian StyleYu, Jingyou, and Shan-Lu Liu. 2018. "The Inhibition of HIV-1 Entry Imposed by Interferon Inducible Transmembrane Proteins Is Independent of Co-Receptor Usage" Viruses 10, no. 8: 413. https://doi.org/10.3390/v10080413
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