Inadequate Clearance of Translocated Bacterial Products in HIV-Infected Humanized Mice

Hofer, Ursula; Schlaepfer, Erika; Baenziger, Stefan; Nischang, Marc; Regenass, Stephan; Schwendener, Reto A.; Kempf, Werner; Nadal, David; Speck, Roberto F.

doi:10.1371/journal.ppat.1000867

Cited by 54 publications

(50 citation statements)

References 55 publications

(56 reference statements)

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“…During remission, macrophage clearance may decrease, yet permeability remains; so higher serum LPS levels are observed in inactive disease, as we report here. This hypothesis is supported by evidence from a mouse model of colitis, 41 where intestinal epithelial damage alone did not result in an increase in blood LPS, but had to be coupled with a depletion of phagocytic cells. In the absence of LPS-scavenging mucosal cells 42 and Kupffer cells of the liver, 40,41 LPS levels in plasma are increased.…”

Section: Discussionmentioning

confidence: 74%

Circulating CD4⁺ and CD8⁺ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

et al. 2013

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SummaryInflammatory bowel disease (IBD) is characterized by damage to the gut mucosa and systemic inflammation. We sought to evaluate the role of chronic inflammation on circulating T-cell activation in human subjects with Crohn's disease and ulcerative colitis. We studied 54 patients with IBD and 28 healthy controls. T-cell activation and cycling were assessed in whole blood samples by flow cytometry. Levels of lipopolysaccharide (LPS) were measured in serum by Limulus amoebocyte lysate assay, and plasma levels of inflammatory markers and LPS-binding proteins were measured by ELISA. The proportions of circulating CD4 + and CD8 + T lymphocytes in cycle (Ki67 + ) are increased in patients with IBD compared with these proportions in controls. CD8 + T cells from patients with IBD are also enriched for cells that expressed CD38 and HLA-DR, and proportions of these cells are related to plasma levels of interleukin-6 and C-reactive protein in these patients. Intracellular interleukin-2 and interferon-c levels were elevated in resting and polyclonally activated CD4 + and CD8 + T cells in patients with IBD when compared with levels from healthy controls. Surprisingly, we did not find increased levels of LPS in the serum of patients with IBD. We did, however, find a signature of recent microbial translocation, as levels of LPS-binding protein are increased in the plasma of patients with IBD compared with plasma levels in healthy controls; LPS-binding protein levels are also directly related to proportions of CD38 HLA-DR-expressing CD4 + and CD8 + T cells. Local damage to the gastrointestinal tract in IBD may result in systemic inflammation and T-cell activation.

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Section: Discussionmentioning

confidence: 74%

Circulating CD4⁺ and CD8⁺ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

et al. 2013

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“…Indeed, we showed that chronic HIV infection in HIV-infected humanized mice results in an increased rate of bacterial translocation, which is most likely at the origin of the malfunctioning of macrophages observed in this model (16).…”

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confidence: 74%

“…The TLR-dependent reduction in endocytosis is reminiscent of a proposed vitamin D-and cyclic AMP-dependent autophagic mechanism that apparently inhibits HIV replication in response to a TLR8 agonist (30). Reduced endocytosis is also observed in macrophages from HIV-infected humanized mice (16). The finding that endocytosis in M2-polarized or TLR2 agonistprimed macrophages was similar to that in MDMs suggests that endocytosis most likely has no role in the anti-HIV effects in this setting.…”

Section: Figmentioning

confidence: 93%

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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“…This suggests that in vitro mitogenic stimulation generates cells with an activated phenotype without altering the CD4:CD8 ratios. In a more relevant in vivo model, Hofer et al (42) demonstrated that experimental induction of intestinal damage and microbial translocation in humanized mice resulted in immune activation but failed to alter CD4:CD8 ratio or induce a specific loss of CD4+ T cells.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients

Joshi

Sedano

Beauchamp

et al. 2016

The Journal of Immunology

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The mechanism behind the selective depletion of CD4+ cells in HIV infections remains undetermined. Although HIV selectively infects CD4+ cells, the relatively few infected cells in vivo cannot account for the extent of CD4+ T cell depletion suggesting indirect or bystander mechanisms. The role of virus replication, Env glycoprotein phenotype and immune activation (IA) in this bystander phenomenon remains controversial. Using samples derived from HIV-infected patients; we demonstrate that while IA in both CD4+ and CD8+ subsets correlates with CD4 decline, apoptosis in CD4+ and not CD8+ cells is associated with disease progression. As HIV-1 Env glycoprotein has been implicated in bystander apoptosis, we cloned full length Envs from plasma of viremic patients and tested their Apoptosis Inducing Potential (AIP). Interestingly, AIP of HIV-1 Env glycoproteins were found to correlate inversely with CD4:CD8 ratios suggesting a role of Env phenotype in disease progression. In vitro mitogenic stimulation of PBMCs resulted in upregulation of IA markers but failed to alter the CD4:CD8 ratio. However, co-culture of normal PBMCs with Env expressing cells resulted in selective CD4 loss that was significantly enhanced by IA. Our study demonstrates that AIP of HIV-1 Env and IA collectively determine CD4 loss in HIV infection.

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Inadequate Clearance of Translocated Bacterial Products in HIV-Infected Humanized Mice

Cited by 54 publications

References 55 publications

Circulating CD4⁺ and CD8⁺ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

Circulating CD4⁺ and CD8⁺ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

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

HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients

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Inadequate Clearance of Translocated Bacterial Products in HIV-Infected Humanized Mice

Cited by 54 publications

References 55 publications

Circulating CD4+ and CD8+ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

Circulating CD4+ and CD8+ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

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

HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients

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Circulating CD4⁺ and CD8⁺ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

Circulating CD4⁺ and CD8⁺ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation