A selective defect of interferon alpha production in human immunodeficiency virus-infected monocytes.

Gendelman, Howard Eliot; Friedman, Robert M.; Joe, Steve; Baca, L M; Turpin, Jim A.; Dveksler, Gabriela S.; Meltzer, Monte S.; Dieffenbach, Carl W.

doi:10.1084/jem.172.5.1433

Cited by 132 publications

(45 citation statements)

References 45 publications

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“…All these restriction factors are encoded by IFN-stimulated genes (26) and may contribute to the TLR3-and TLR4-induced HIV-inhibitory effects. Surprisingly, IFN-␣ was not increased in response to the various TLR agonists; however, we observed a quite impressive increase of IFN-␤ in response to poly(I·C), as reported by Gendelman et al (23). Irrespective of whether IFN levels were detectable or not, the partial reversion of the TLR3-and 4-mediated anti-HIV activity when neutralizing the IFN axis may be explained by prevention of the upregulation of IFN-dependent HIV restriction factors.…”

Section: Figsupporting

confidence: 67%

“…Notably, HIV replication was massively increased in MDMs when IFN-R was blocked, suggesting that HIV-infected macrophages are modulated by type I IFNs. We verified that the viral stock was free of endotoxin (23). Irrespective of this issue, the production or release of IFN-␣ does not explain the potent HIV-inhibitory effect of the TLR8 agonist 3M-002.…”

Section: Resultsmentioning

confidence: 71%

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Triggering TLR2, -3, -4, -5, and -8 Reinforces the Restrictive Nature of M1- and M2-Polarized Macrophages to HIV

Schlaepfer

Rochat

et al. 2014

J Virol

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Macrophages must react to a large number of pathogens and their effects. In chronic HIV infection, the microenvironment changes with an influx of microbial products that trigger Toll-like receptors (TLRs). That dynamic nature can be replicated ex vivo by the proinflammatory (M1-polarized) and alternatively activated (M2-polarized) macrophages. Thus, we determined how polarized macrophages primed by various TLR agonists support HIV replication. Triggering of TLR2, -3, -4, -5, and -8 reinforced the low level of permissiveness in polarized macrophages. HIV was inhibited even more in M1-polarized macrophages than in macrophages activated only by TLR agonists. HIV was inhibited before its integration into the host chromosome. Polarization and triggering by various TLR agonists resulted in distinct cytokine profiles, endocytic activity, and distinct upregulation of restriction factors of HIV. Thus, different mechanisms likely contribute to the HIV-inhibitory effects. In chronic HIV infection, macrophages might become less permissive to HIV due to changes in the microenvironment. The high level of reactivity of polarized macrophages to TLR triggering may be exploited for immunotherapeutic strategies. IMPORTANCEMacrophages are a major target of HIV-1 infection. Different cell types in this very heterogeneous cell population respond differently to stimuli. In vitro, the heterogeneity is mimicked by their polarization into proinflammatory and alternatively activated macrophages. Here we explored the extent to which agonists triggering the TLR family affect HIV replication in polarized macrophages. We found that a number of TLR agonists blocked HIV replication substantially when given before infection. We also report the mechanisms of how TLR agonists exert their inhibitory action. Our findings may advance our understanding of which and how TLR agonists block HIV infection in polarized macrophages and may facilitate the design of novel immunotherapeutic approaches.

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Section: Figsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 71%

Triggering TLR2, -3, -4, -5, and -8 Reinforces the Restrictive Nature of M1- and M2-Polarized Macrophages to HIV

Schlaepfer

Rochat

et al. 2014

J Virol

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“…As a consequence the blood pDC levels decline during HIV infection, which reduces the IFN response [65, 66]. In addition, HIV downregulates IRF3 especially in CD4 + T cells and thus suppresses the induction of type I IFN [67, 68]. During chronic HIV infection IFN-α might be associated with disease progression.…”

Section: Counter-regulation Of the Nk Cell Response By Retrovirusesmentioning

confidence: 99%

Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells

2016

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Natural killer (NK) cells belong to the innate immune system and protect against cancers and a variety of viruses including retroviruses by killing transformed or infected cells. They express activating and inhibitory receptors on their cell surface and often become activated after recognizing virus-infected cells. They have diverse antiviral effector functions like the release of cytotoxic granules, cytokine production and antibody dependent cellular cytotoxicity. The importance of NK cell activity in retroviral infections became evident due to the discovery of several viral strategies to escape recognition and elimination by NK cells. Mutational sequence polymorphisms as well as modulation of surface receptors and their ligands are mechanisms of the human immunodeficiency virus-1 to evade NK cell-mediated immune pressure. In Friend retrovirus infected mice the virus can manipulate molecular or cellular immune factors that in turn suppress the NK cell response. In this model NK cells lack cytokines for optimal activation and can be functionally suppressed by regulatory T cells. However, these inhibitory pathways can be overcome therapeutically to achieve full activation of NK cell responses and ultimately control dissemination of retroviral infection. One effective approach is to modulate the crosstalk between NK cells and dendritic cells, which produce NK cell-stimulating cytokines like type I interferons (IFN), IL-12, IL-15, and IL-18 upon retrovirus sensing or infection. Therapeutic administration of IFNα directly increases NK cell killing of retrovirus-infected cells. In addition, IL-2/anti-IL-2 complexes that direct IL-2 to NK cells have been shown to significantly improve control of retroviral infection by NK cells in vivo. In this review, we describe novel approaches to improve NK cell effector functions in retroviral infections. Immunotherapies that target NK cells of patients suffering from viral infections might be a promising treatment option for the future.

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“…IFNα-PC, which has usually been evaluated by the whole-blood method in vitro, reflects the immune status of patients with various diseases. IFNα-PC is suppressed in patients with lung cancer, myelodysplastic syndromes, non-insulin-dependent diabetes mellitus, pulmonary tuberculosis, HIV and hepatitis B infection [5, 14, 15]. These reports indicate that IFNα-PC is one of the main protective factors preventing the susceptibility to infection.…”

Section: Discussionmentioning

confidence: 99%

Correlation between the Severity of Clinicopathological Parameters and Whole Blood Interferon-α Production Capacity in Active Phase IgA Nephropathy Patients

Shirakawa

Muso

Nogaki

et al. 2001

Nephron

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Background/Aims: Patients with IgA nephropathy (IgA-N) are thought to have immune system disorders that frequently result in high serum IgA levels and a relatively high susceptibility to upper respiratory infections. Aims: To clarify the influence of the specific immune response of IgA-N patients on the clinicopathological features of the disease, we measured the whole-blood-producing capacity of interferon-α (IFNα-PC). We then compared these findings with clinical and histopathological parameters, including tissue macrophage infiltration, during both histologically active and latent phases. Patients and Methods: Fifty-one inpatients with IgA-N and 70 healthy controls were examined. According to the histological findings, 32 patients had disease in the active phase (AP), and 19 were in the latent phase (LP). Results: In AP patients, IFNα-PC showed positive correlations to serum creatinine, blood urea nitrogen, serum β₂-microglobulin (s-β₂MG), urinary total protein (U-TP), and urinary β₂MG, in addition to the number of infiltrated macrophages per area of interstitium. In LP patients, negative correlations were shown between IFNα-PC and s-β₂MG, U-TP, and U-N-acetyl-β-D-glucosaminidase. Conclusion: A significant positive relationship exists between IFNα-PC and the clinicopathological parameters of deteriorated renal lesions in the AP but not in the LP. Thus, the immune status influencing the functional damage may differ between these two phase.

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A selective defect of interferon alpha production in human immunodeficiency virus-infected monocytes.

Cited by 132 publications

References 45 publications

Triggering TLR2, -3, -4, -5, and -8 Reinforces the Restrictive Nature of M1- and M2-Polarized Macrophages to HIV

Triggering TLR2, -3, -4, -5, and -8 Reinforces the Restrictive Nature of M1- and M2-Polarized Macrophages to HIV

Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells

Correlation between the Severity of Clinicopathological Parameters and Whole Blood Interferon-α Production Capacity in Active Phase IgA Nephropathy Patients

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