Brief Report

Kim, Connie J.; Kovacs, Colin; Chun, Tae‐Wook; Kandel, Gabor; Osborne, B.; Huibner, Sanja; Shahabi, Kamnoosh; Yue, Feng-Yun; Benko, Erika; Ostowski, Mario; Kaul, Rupert

doi:10.1097/qai.0000000000000359

Cited by 14 publications

(6 citation statements)

References 11 publications

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“…Vesterbacka et al (2017) found that EC’s have a richer gut microbiota with a distinct metabolic profile that resembles that of HIV-uninfected adults, and that is vastly unique from ART-treated HIV-infected individuals (Table 1) [43**]. The increased frequency of Th17 cells in the gut mucosa of EC’s compared to ART-treated HIV-infected adults [48] may be responsible for their low levels of inflammation and seemingly “normal” gut microbiome. Understanding whether there is a direct interaction between the microbiome and reduced inflammation and immune activation and smaller reservoirs in ECs could inform pathogenesis and treatment of dysbiosis in HIV infection.…”

Section: Introductionmentioning

confidence: 99%

The microbiome and HIV persistence

Koay

Siems

Persaud³

2018

Current Opinion in HIV and AIDS

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Section: Introductionmentioning

confidence: 99%

The microbiome and HIV persistence

Koay

Siems

Persaud³

2018

Current Opinion in HIV and AIDS

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“…In accordance with these findings, also high levels of similar markers prior to the initiation of antiretrovirals were shown to predict non-AIDS morbid events on stable treatment [ 11 ] (Table 1 ). In contrast however, administration of cART in elite controllers did not affect markers of microbial translocation and inflammation [ 12 ]. In a recent report, our group showed that pre-cART levels of CRP, but not sCD14, LPS or EndoCAb predicted clinical events in a large cohort of treated HIV-infected subjects [ 13 ] and suggest, together with other literature evidence, that the occurrence of non-AIDS conditions may be only in part related to gut damage and microbial translocation (Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection

2016

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Over the past 10 years, extensive work has been carried out in the field of microbial translocation in HIV infection, ranging from studies on its clinical significance to investigations on its pathogenic features. In the present work, we review the most recent findings on this phenomenon, focusing on the predictive role of microbial translocation in HIV-related morbidity and mortality, the mechanisms by which it arises and potential therapeutic approaches. From a clinical perspective, current work has shown that markers of microbial translocation may be useful in predicting clinical events in untreated HIV infection, while conflicting data exist on their role in cART-experienced subjects, possibly due to the inclusion of extremely varied patient populations in cohort studies. Results from studies addressing the pathogenesis of microbial translocation have improved our knowledge of the damage of the gastrointestinal epithelial barrier occurring in HIV infection. However, the extent to which mucosal impairment translates directly to increased gastrointestinal permeability remains an open issue. In this respect, novel work has established a role for IL-17 and IL-22-secreting T cell populations in limiting microbial translocation and systemic T-cell activation/inflammation, thus representing a possible target of immune-therapeutic interventions shown to be promising in the animal model. Further, recent reports have not only confirmed the presence of a dysbiotic intestinal community in the course of HIV infection but have also shown that it may be linked to mucosal damage, microbial translocation and peripheral immune activation. Importantly, technical advances have also shed light on the metabolic activity of gut microbes, highlighting the need for novel therapeutic approaches to correct the function, as well as the composition, of the gastrointestinal microbiota.

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“…Indeed, HIV-1 encodes for various TLR7/8 ligands that can mediate direct activation of the immune system in vitro (22–24). Likewise, HIV-driven gut barrier damage is not reverted by cART (25–28) and leads to the passage of microbial products in peripheral blood, mainly lipopolysaccharide (LPS), which is a TLR4 agonist (29, 30). Circulating LPS levels have been associated with immune activation both in treated and untreated HIV (31–35); furthermore, exogenous in vivo LPS administration has been described to enhance immune activation (34).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of PBMC and Monocyte-Derived Macrophages via Toll-Like Receptor Activates Innate Immune Pathways in HIV-Infected Patients on Virally Suppressive Combination Antiretroviral Therapy

et al. 2016

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In HIV-infected, combination antiretroviral therapy (cART)-treated patients, immune activation and microbial translocation persist and associate with inadequate CD4 recovery and morbidity/mortality. We analyzed whether alterations in the toll-like receptor (TLR) pathway could be responsible for the immune hyperactivation seen in these patients. PBMC/monocyte-derived macrophages (MDMs) of 28 HIV+ untreated and 35 cART-treated patients with HIV-RNA < 40 cp/mL [20 Full Responders (FRs): CD4 ≥ 350; 15 Immunological Non-Responders (INRs): CD4 < 350], as well as of 16 healthy controls were stimulated with a panel of TLR agonists. We measured: CD4/CD8/CD14/CD38/HLA-DR/Ki67/AnnexinV/CD69/TLR4/8 (Flow Cytometry); PBMC expression of 84 TLR pathway genes (qPCR); PBMC/MDM cytokine release (Multiplex); and plasma lipopolysaccharide (LPS)/sCD14 (LAL/ELISA). PBMC/MDM from cART patients responded weakly to LPS stimulation but released high amounts of pro-inflammatory cytokines. MDM from these patients were characterized by a reduced expression of HLA-DR+ MDM and failed to expand activated HLA-DR+ CD38+ T-lymphocytes. PBMC/MDM from cART patients responded more robustly to ssRNA stimulation; this resulted in a significant expansion of activated CD38 + CD8 and the release of amounts of pro-inflammatory cytokines comparable to those seen in untreated viremic patients. Despite greater constitutive TLR pathway gene expression, PBMC from INRs seemed to upregulate only type I IFN genes following TLR stimulation, whereas PBMC from full responders showed a broader response. Systemic exposure to microbial antigens drives immune activation during cART by triggering TLRs. Bacterial stimulation modifies MDM function/pro-inflammatory profile in cART patients without affecting T-lymphocytes; this suggests translocating bacteria as selective stimulus to chronic innate activation during cART. High constitutive TLR activation is seen in patients lacking CD4 recovery, suggesting an exhausted immune milieu, anergic to further antigen encounters.

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Brief Report

Cited by 14 publications

References 11 publications

The microbiome and HIV persistence

The microbiome and HIV persistence

Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection

Stimulation of PBMC and Monocyte-Derived Macrophages via Toll-Like Receptor Activates Innate Immune Pathways in HIV-Infected Patients on Virally Suppressive Combination Antiretroviral Therapy

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