Neisseria gonorrhoeae effectively blocks HIV-1 replication by eliciting a potent TLR9-dependent interferon-α response from plasmacytoid dendritic cells

Dobson-Belaire, Wendy; Rebbapragada, Anu; Malott, Rebecca J.; Yue, Feng Yun; Kovacs, Colin; Kaul, Rupert; Ostrowski, Mario; Gray-Owen, Scott D.

doi:10.1111/j.1462-5822.2010.01502.x

Cited by 21 publications

(26 citation statements)

References 54 publications

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“…PBMCs were isolated from healthy (HIV-uninfected) volunteer blood donors, as described in Dobson-Belaire et al. (20). Informed consent was obtained from participants in accordance with the guidelines for conduct of clinical research at the University of Toronto and St. Michael's Hospital, Toronto, Ontario, Canada.…”

Section: Methodsmentioning

confidence: 99%

Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication

Shkreta

Blanchette

Toutant

et al. 2016

Nucleic Acids Research

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We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro. Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10. Depleting SRSF10 by RNA interference affected viral splicing and, like 1C8, decreased expression of Tat, Gag and Env. Incubating cells with 1C8 promoted the dephosphorylation of SRSF10 and increased its interaction with hTra2β, a protein previously implicated in the control of HIV-1 RNA splicing. While 1C8 affects the alternative splicing of cellular transcripts controlled by SRSF10 and hTra2β, concentrations greater than those needed to inhibit HIV-1 replication were required to elicit significant alterations. Thus, the ability of 1C8 to alter the SRSF10-dependent splicing of HIV-1 transcripts, with minor effects on cellular splicing, supports the view that SRSF10 may be used as a target for the development of new anti-viral agents.

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Section: Methodsmentioning

confidence: 99%

Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication

Shkreta

Blanchette

Toutant

et al. 2016

Nucleic Acids Research

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“…GC exposure blocks HIV production in CD8-depleted PBMCs from HIV-infected individuals as well as in vitro HIV-infected PBMCs [59]. Anti-IFNα Ab blocks the HIV inhibitory effect of conditioned media from GC-exposed PBMCs depleted of CD8+ T cells.…”

Section: In Vitro Effect Of Gc Infection Of Hiv Target Cellsmentioning

confidence: 99%

“…Anti-IFNα Ab blocks the HIV inhibitory effect of conditioned media from GC-exposed PBMCs depleted of CD8+ T cells. GC exposure induces IFNα production in plasmacytoid dendritic cells (pDCs) through TLR9 activation [59]. An elegant study by Li et al .…”

Section: In Vitro Effect Of Gc Infection Of Hiv Target Cellsmentioning

confidence: 99%

Modulation of HIV Transmission by Neisseria gonorrhoeae: Molecular and Immunological Aspects

Jarvis¹,

Chang²

2012

CHR

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Neisseria gonorrhoeae (GC), a major cause of pelvic inflammatory disease, can facilitate HIV transmission. In response to GC infection, genital epithelial cells can produce cytokines, chemokines and defensins to modulate HIV infection and infectivity. GC can also induce the production of cytokines and chemokines in monocytes and modulate T cell activation. In vivo, an increase in the number of endocervical CD4+ T cells has been found in GC-infected women. Additionally, GC appears to modulate HIV-specific immune responses in HIV-exposed sex workers. Interestingly, in vitro, GC exhibits HIV enhancing or inhibitory effects depending on the HIV target cells. This review summarizes molecular and immunological aspects of the modulation of HIV infection and transmission by GC. Future studies using a multi-cellular system or in animal models will offer insight into the mechanisms by which GC increases HIV transmission.

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“…The best-characterized class of these receptors is the family of Toll-like receptors (TLRs) that, upon recognition of conserved microbial-associated molecular patterns (MAMPs), trigger a cascade of signaling events that modulate both the adaptive and innate immune responses (19). TLR activation modulates HIV-1 infection and/or transmission, and, depending on the specific TLR agonist and the target cell, TLR activation can either promote or inhibit HIV-1 expression in vitro (17,18,(20)(21)(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression

Malott¹,

Keller

Gaudet³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Clinical and epidemiological synergy exists between the globally important sexually transmitted infections, gonorrhea and HIV. Neisseria gonorrhoeae , which causes gonorrhea, is particularly adept at driving HIV-1 expression, but the molecular determinants of this relationship remain undefined. N. gonorrhoeae liberates a soluble factor that potently induces expression from the HIV-1 LTR in coinfected cluster of differentiation 4-positive (CD4 + ) T lymphocytes, but this factor is not a previously described innate effector. A genome-wide mutagenesis approach was undertaken to reveal which component(s) of N. gonorrhoeae induce HIV-1 expression in CD4 + T lymphocytes. A mutation in the ADP-heptose biosynthesis gene, hldA , rendered the bacteria unable to induce HIV-1 expression. The hldA mutant has a truncated lipooligosaccharide structure, contains lipid A in its outer membrane, and remains bioactive in a TLR4 reporter-based assay but did not induce HIV-1 expression. Mass spectrometry analysis of extensively fractionated N. gonorrhoeae- derived supernatants revealed that the LTR-inducing fraction contained a compound having a mass consistent with heptose-monophosphate (HMP). Heptose is a carbohydrate common in microbes but is absent from the mammalian glycome. Although ADP-heptose biosynthesis is common among Gram-negative bacteria, and heptose is a core component of most lipopolysaccharides, N. gonorrhoeae is peculiar in that it effectively liberates HMP during growth. This N. gonorrhoeae- derived HMP activates CD4 + T cells to invoke an NF-κB–dependent transcriptional response that drives HIV-1 expression and viral production. Our study thereby shows that heptose is a microbial-specific product that is sensed as an innate immune agonist and unveils the molecular link between N. gonorrhoeae and HIV-1.

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Neisseria gonorrhoeae effectively blocks HIV-1 replication by eliciting a potent TLR9-dependent interferon-α response from plasmacytoid dendritic cells

Cited by 21 publications

References 54 publications

Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication

Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication

Modulation of HIV Transmission by Neisseria gonorrhoeae: Molecular and Immunological Aspects

Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression

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