Impaired gut junctional complexes feature late-treated individuals with suboptimal CD4+ T-cell recovery upon virologically suppressive combination antiretroviral therapy

Tincati, Camilla; Merlini, Esther; Braidotti, Paola; Ancona, Giuseppe; Savi, Federica; Tosi, Delfina; Borghi, Elisa; Callegari, Maria Luisa; Mangiavillano, Benedetto; Barassi, Alessandra; Bulfamante, Gaetano; Monforte, Antonella d’Arminio; Romagnoli, Solange; Chomont, Nicolas; Marchetti, Giulia

doi:10.1097/qad.0000000000001015

Cited by 62 publications

(61 citation statements)

References 75 publications

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“…Because clinical and translational research strongly suggests that chronic activation of innate immunity drives morbidity/mortality in treated HIV (64–68), our data provide in vitro evidence (tested in culture from both whole PBMCs and MDMs) of how monocyte/macrophages from cART patients might be preferentially activated by circulating bacterial products. Given the persistence of gut damage and microbial translocation during cART (9, 25, 26, 29, 69), we hereby provide an indication of how the systemic exposure to bacterial TLR agonists translocated from a damaged gut may contribute to excessive morbidity/mortality in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…showed that the level of HIV‐1 reservoirs, measured as the frequencies of cells harboring total and integrated HIV‐DNA as well as 2 long terminal repeat circles, in both peripheral CD4 + T cells and intestinal tissue was comparable between HIV‐1‐infected INRs and IRs. However, HIV reservoirs in both peripheral blood and the gut negatively correlate with CD4 + T‐cell reconstitution, suggesting that poor immune recovery on ART may be associated with increased HIV reservoirs . Agrati et al.…”

Section: Potential Mechanisms Of Incomplete Immune Reconstitutionmentioning

confidence: 99%

“…Total CD4 + T-cell count > 350 cells/µl and/or increase in the CD4 + T-cell count > 30% from baseline at 1-10 years after ART initiation, with an undetectable plasma VL. 144,177,242,243 Total CD4 + T-cell count < 500 cells/µl and CD4/CD8 ratio < 1 at 8 years after ART initiation, with plasma HIV RNA < 50 copies/ml.…”

Section: Definition Of "Immunological Nonresponder" Definition Of "Immentioning

confidence: 99%

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Yang

Zhang

et al. 2020

Journal of Leukocyte Biology

191

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The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

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“…Indeed, a reduced expression of ileum and colonic gut junctional complex proteins (cadherins, claudins, occludins) features long-term treated subjects [49][50][51] and is linked to increased gut permeability and persistent levels of microbial translocation [51]. Moreover, the negative correlation between LPS-dependent immune activation (sCD14 plasma levels, peripheral CD8 + CD38 + T-cell frequencies) and gut junctional proteins [49,51] further highlights that GI tract defects may contribute to inflammation. In line with this finding, a cohort study showed that peripheral blood levels of intestinal fatty acid binding protein, marker of intestinal damage, and zonulin-1 are independent predictors of mortality in cART-treated subjects [52].…”

Section: More Recently Studies Have Shed Light On the Underlying Mecmentioning

confidence: 99%

Biomarkers of aging in HIV: inflammation and the microbiome

et al. 2018

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PurposeHIV-infected subjects present increased levels of inflammatory cytokines and T-cell activation in the peripheral blood despite suppressive combination antiretroviral therapy which renders them at increased risk of premature aging. The purpose of the present work is to review existing evidence on the ways in which the anatomical and microbiological abnormalities of the gastrointestinal tract can represent a major cause of organ disease in HIV infection. MethodsWe conducted a systematic review of the Pubmed database for articles published from 2014 to 2018. We included studies on inflammatory/activation biomarkers associated with cardiovascular and bone disease, neurocognitive impairment and serious non-AIDS events in HIV-infected subjects. We also included researches which linked peripheral inflammation/activation to the anatomical, immune and microbiological alterations of the gastrointestinal tract. Results Recent literature data confirm the association between non-infectious comorbidities andinflammation in HIV infection which may be driven by gastrointestinal tract abnormalities, specifically microbial translocation and dysbiosis. Furthermore, there is mounting evidence on the possible role of metabolic functions of the microbiota in the pathogenesis of premature aging in the HIV-infected population ConclusionsBiomarkers need to be validated for their use in the management of HIV infection. Compounds which counteract microbial translocation, inflammation and dysbiosis have been investigated as alternative therapeutic strategies in viro-suppressed HIV-infected individuals, but appear to have limited efficacy, probably due to the multifactorial pathogenesis of non-infectious comorbidities in this setting.3

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Impaired gut junctional complexes feature late-treated individuals with suboptimal CD4+ T-cell recovery upon virologically suppressive combination antiretroviral therapy

Abstract: These observations establish gut damage and the size of the HIV reservoir as features of deficient immunological response to cART and provide new elements for interventional strategies in this setting.

Cited by 62 publications

References 75 publications

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

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

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Biomarkers of aging in HIV: inflammation and the microbiome

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