Mechanism of interferon-stimulated gene induction in HIV-1- infected macrophages

Najla Nasr, Abdullateef A. Alshehri, Thomas K. Wright, Maryam Shahid, Bonnie M. Heiner, Andrew N. Harman, Rachel A. Botting, Karla J. Helbig, Michael R. Beard, Kazuo Suzuki, Anthony D. Kelleher, Paul Hertzog, Anthony L. Cunningham

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Viruses manipulate the complex interferon and interferon-stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells, many of which are antiviral. Here, we examine the mechanism of induction of ISGs and show this occurs in two phases. The first phase was transient (0 to 24 h postinfection [hpi]), induced mainly by extracellular vesicles and one of its component proteins, HSP90α, contained within the HIV inoculum. The second, dominant, and persistent phase (>48 hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knockdown of the RIGI adaptor, MAVS, by small interfering RNA (siRNA) and the inhibition of both the initiation and elongation of HIV transcription by short hairpin RNA (shRNA) transcriptional silencing. We further define the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1, and IRF7, also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also show that the ISGs IFIT1 to -3 inhibit HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, noncytopathic infection, while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs in vivo. Elucidating the mechanisms of ISG induction may help in devising immunotherapeutic strategies to limit the size of these reservoirs.

Original languageEnglish
Article numbere00744-17
Number of pages19
JournalJournal of Virology
Volume91
Issue number20
DOIs
Publication statusPublished - 1 Oct 2017

Keywords

  • HIV-1 infection
  • Interferon
  • Interferon-stimulated genes
  • Macrophages

Cite this

Nasr, N., Alshehri, A. A., Wright, T. K., Shahid, M., Heiner, B. M., Harman, A. N., ... Cunningham, A. L. (2017). Mechanism of interferon-stimulated gene induction in HIV-1- infected macrophages. Journal of Virology, 91(20), [e00744-17]. https://doi.org/10.1128/JVI.00744-17
Nasr, Najla ; Alshehri, Abdullateef A. ; Wright, Thomas K. ; Shahid, Maryam ; Heiner, Bonnie M. ; Harman, Andrew N. ; Botting, Rachel A. ; Helbig, Karla J. ; Beard, Michael R. ; Suzuki, Kazuo ; Kelleher, Anthony D. ; Hertzog, Paul ; Cunningham, Anthony L. / Mechanism of interferon-stimulated gene induction in HIV-1- infected macrophages. In: Journal of Virology. 2017 ; Vol. 91, No. 20.
@article{3be6a5f5ae17464b9ecbcc9396fc7453,
title = "Mechanism of interferon-stimulated gene induction in HIV-1- infected macrophages",
abstract = "Viruses manipulate the complex interferon and interferon-stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells, many of which are antiviral. Here, we examine the mechanism of induction of ISGs and show this occurs in two phases. The first phase was transient (0 to 24 h postinfection [hpi]), induced mainly by extracellular vesicles and one of its component proteins, HSP90α, contained within the HIV inoculum. The second, dominant, and persistent phase (>48 hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knockdown of the RIGI adaptor, MAVS, by small interfering RNA (siRNA) and the inhibition of both the initiation and elongation of HIV transcription by short hairpin RNA (shRNA) transcriptional silencing. We further define the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1, and IRF7, also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also show that the ISGs IFIT1 to -3 inhibit HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, noncytopathic infection, while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs in vivo. Elucidating the mechanisms of ISG induction may help in devising immunotherapeutic strategies to limit the size of these reservoirs.",
keywords = "HIV-1 infection, Interferon, Interferon-stimulated genes, Macrophages",
author = "Najla Nasr and Alshehri, {Abdullateef A.} and Wright, {Thomas K.} and Maryam Shahid and Heiner, {Bonnie M.} and Harman, {Andrew N.} and Botting, {Rachel A.} and Helbig, {Karla J.} and Beard, {Michael R.} and Kazuo Suzuki and Kelleher, {Anthony D.} and Paul Hertzog and Cunningham, {Anthony L.}",
year = "2017",
month = "10",
day = "1",
doi = "10.1128/JVI.00744-17",
language = "English",
volume = "91",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "20",

}

Nasr, N, Alshehri, AA, Wright, TK, Shahid, M, Heiner, BM, Harman, AN, Botting, RA, Helbig, KJ, Beard, MR, Suzuki, K, Kelleher, AD, Hertzog, P & Cunningham, AL 2017, 'Mechanism of interferon-stimulated gene induction in HIV-1- infected macrophages', Journal of Virology, vol. 91, no. 20, e00744-17. https://doi.org/10.1128/JVI.00744-17

Mechanism of interferon-stimulated gene induction in HIV-1- infected macrophages. / Nasr, Najla; Alshehri, Abdullateef A.; Wright, Thomas K.; Shahid, Maryam; Heiner, Bonnie M.; Harman, Andrew N.; Botting, Rachel A.; Helbig, Karla J.; Beard, Michael R.; Suzuki, Kazuo; Kelleher, Anthony D.; Hertzog, Paul; Cunningham, Anthony L.

In: Journal of Virology, Vol. 91, No. 20, e00744-17, 01.10.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Mechanism of interferon-stimulated gene induction in HIV-1- infected macrophages

AU - Nasr, Najla

AU - Alshehri, Abdullateef A.

AU - Wright, Thomas K.

AU - Shahid, Maryam

AU - Heiner, Bonnie M.

AU - Harman, Andrew N.

AU - Botting, Rachel A.

AU - Helbig, Karla J.

AU - Beard, Michael R.

AU - Suzuki, Kazuo

AU - Kelleher, Anthony D.

AU - Hertzog, Paul

AU - Cunningham, Anthony L.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Viruses manipulate the complex interferon and interferon-stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells, many of which are antiviral. Here, we examine the mechanism of induction of ISGs and show this occurs in two phases. The first phase was transient (0 to 24 h postinfection [hpi]), induced mainly by extracellular vesicles and one of its component proteins, HSP90α, contained within the HIV inoculum. The second, dominant, and persistent phase (>48 hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knockdown of the RIGI adaptor, MAVS, by small interfering RNA (siRNA) and the inhibition of both the initiation and elongation of HIV transcription by short hairpin RNA (shRNA) transcriptional silencing. We further define the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1, and IRF7, also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also show that the ISGs IFIT1 to -3 inhibit HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, noncytopathic infection, while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs in vivo. Elucidating the mechanisms of ISG induction may help in devising immunotherapeutic strategies to limit the size of these reservoirs.

AB - Viruses manipulate the complex interferon and interferon-stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells, many of which are antiviral. Here, we examine the mechanism of induction of ISGs and show this occurs in two phases. The first phase was transient (0 to 24 h postinfection [hpi]), induced mainly by extracellular vesicles and one of its component proteins, HSP90α, contained within the HIV inoculum. The second, dominant, and persistent phase (>48 hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knockdown of the RIGI adaptor, MAVS, by small interfering RNA (siRNA) and the inhibition of both the initiation and elongation of HIV transcription by short hairpin RNA (shRNA) transcriptional silencing. We further define the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1, and IRF7, also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also show that the ISGs IFIT1 to -3 inhibit HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, noncytopathic infection, while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs in vivo. Elucidating the mechanisms of ISG induction may help in devising immunotherapeutic strategies to limit the size of these reservoirs.

KW - HIV-1 infection

KW - Interferon

KW - Interferon-stimulated genes

KW - Macrophages

UR - http://www.scopus.com/inward/record.url?scp=85030123696&partnerID=8YFLogxK

U2 - 10.1128/JVI.00744-17

DO - 10.1128/JVI.00744-17

M3 - Article

C2 - 28768867

AN - SCOPUS:85030123696

VL - 91

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 20

M1 - e00744-17

ER -

Nasr N, Alshehri AA, Wright TK, Shahid M, Heiner BM, Harman AN et al. Mechanism of interferon-stimulated gene induction in HIV-1- infected macrophages. Journal of Virology. 2017 Oct 1;91(20). e00744-17. https://doi.org/10.1128/JVI.00744-17