HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production

Harman, Andrew N.; Lai, Joey; Turville, Stuart; Samarajiwa, Shamith A.; Gray, Lachlan Robert; Marsden, Valerie; Mercier, Sarah; Jones, K.L.; Nasr, Najla; Rustagi, Arjun; Cumming, Helen E.; Donaghy, Heather; Mak, Johnson; Gale, Michael; Churchill, Melissa; Hertzog, Paul J.; Cunningham, Anthony L.

doi:10.1182/blood-2010-07-297721

Cited by 105 publications

(125 citation statements)

References 52 publications

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“…Vpr and Vif were already known to modulate the antiviral response through degradation of IRF3 (16). In addition, monocyte-derived dendritic cells infected with Vpr-null HIV-1 (although not Vif-null HIV-1) were shown to exhibit increased IFN␤ mRNA expression (15). We found that expression of Vpr or Vif in 293T cells induces IRF3 cleavage, although not as effectively as Vpu expression.…”

Section: Discussionmentioning

confidence: 65%

“…IRF3 plays important roles in the anti-viral immune response, promoting expression of type I IFNs and other anti-viral genes (33). In HIV-1 infected cells, IRF3 is not properly activated (15), suggesting that HIV-1 has mechanisms to interfere with IRF3 function. Previously, it was shown that Vpu depletes IRF3 by targeting it to lysosomal Gag , and the mature capsid protein, p24, are detected at about 55 and 24 kDa, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Through pattern recognition receptor signaling pathways, IRF3 induces the expression of type I IFN␣/␤ genes as well as other interferon-stimulated genes (13). In HIV-1 infection, anti-viral responses are not properly deployed and only show a limited profile of gene expression (14,15). Because of the blunted anti-viral response to HIV-1, it has been suggested that this virus might have a mechanism to antagonize IRF3 function.…”

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confidence: 99%

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HIV-1 Vpu Accessory Protein Induces Caspase-mediated Cleavage of IRF3 Transcription Factor

Park

Waheed

Zhang

et al. 2014

Journal of Biological Chemistry

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Background:The transcription factor IRF3 is not properly activated during HIV-1 infection. Results: Infection with VSV-G-pseudotyped HIV-1 induces caspase-mediated cleavage of IRF3, and Vpu contributes to this event. Conclusion:The product of IRF3 cleavage by HIV-1 interferes with IRF3-regulated gene expression. Significance: Our findings contribute to the understanding of how HIV-1 attenuates the innate anti-viral response.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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HIV-1 Vpu Accessory Protein Induces Caspase-mediated Cleavage of IRF3 Transcription Factor

Park

Waheed

Zhang

et al. 2014

Journal of Biological Chemistry

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“…This pathway is induced by host PRRs, among which nucleic acid sensors are known to play particularly important roles [2]. In contrast to the typical scenario, HIV-1 infection of T-cells and macrophages does not stimulate IRF3 activation and fails to induce IFN expression, but does lead to expression of a subset of ISGs [3][4][5]. However, it has been reported that HIV-1 genomic RNA can induce IFN responses in specific cell culture systems via toll-like receptor 7 and retinoid-acid inducible gene I [6][7][8].…”

Section: Human Immunodeficiency Virus Type 1 (Hiv-1) Is the Cause Ofmentioning

confidence: 99%

Caught in translation: innate restriction of HIV mRNA translation by a schlafen family protein

2012

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“…MDDCs were generated from CD14 monocytes derived from whole blood as described previously (28)(29)(30). CD4 lymphocyte contamination was ,0.1%, and monocytes were almost completely converted to CD14 2 , DC-SIGN + DCs.…”

Section: Generation Of Mddcs and Isolation Of Human Lcs And Other Skimentioning

confidence: 99%

Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

Marsden

Donaghy

Bertram

et al. 2015

The Journal of Immunology

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Prior HSV-2 infection enhances the acquisition of HIV-1 >3-fold. In genital herpes lesions, the superficial layers of stratified squamous epithelium are disrupted, allowing easier access of HIV-1 to Langerhans cells (LC) in the epidermis and perhaps even dendritic cells (DCs) in the outer dermis, as well as to lesion infiltrating activated T lymphocytes and macrophages. Therefore, we examined the effects of coinfection with HIV-1 and HSV-2 on monocyte-derived DCs (MDDC). With simultaneous coinfection, HSV-2 significantly stimulated HIV-1 DNA production 5-fold compared with HIV-1 infection alone. Because <1% of cells were dually infected, this was a field effect. Virus-stripped supernatants from HSV-2–infected MDDCs were shown to enhance HIV-1 infection, as measured by HIV-1–DNA and p24 Ag in MDDCs. Furthermore these supernatants markedly stimulated CCR5 expression on both MDDCs and LCs. TNF-α was by far the most prominent cytokine in the supernatant and also within HSV-2–infected MDDCs. HSV-2 infection of isolated immature epidermal LCs, but not keratinocytes, also produced TNF-α (and low levels of IFN-β). Neutralizing Ab to TNF-α and its receptor, TNF-R1, on MDDCs markedly inhibited the CCR5-stimulating effect of the supernatant. Therefore, these results suggest that HSV-2 infection of DCs in the skin during primary or recurrent genital herpes may enhance HIV-1 infection of adjacent DCs, thus contributing to acquisition of HIV-1 through herpetic lesions.

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HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production

Cited by 105 publications

References 52 publications

HIV-1 Vpu Accessory Protein Induces Caspase-mediated Cleavage of IRF3 Transcription Factor

HIV-1 Vpu Accessory Protein Induces Caspase-mediated Cleavage of IRF3 Transcription Factor

Caught in translation: innate restriction of HIV mRNA translation by a schlafen family protein

Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

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