Reduction of Immune Activation and Partial Recovery of Staphylococcal Enterotoxin B-Induced Cytokine Production After Switching to an Integrase Strand Transfer Inhibitor-Containing Regimen: Results from an Observational Cohort Study

Merlini, Esther; Cazzaniga, Federico Angelo; Casabianca, Anna; Orlandi, Chiara; Magnani, Mauro; Ancona, Giuseppe; Tincati, Camilla; Monforte, Antonella d’Arminio; Marchetti, Giulia

doi:10.1007/s40261-019-00840-2

Cited by 3 publications

(3 citation statements)

References 45 publications

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“…Moreover, we only assessed HIV DNA in peripheral blood cells, as blood is the most accessible source of cells containing latent HIV-1 and is the most thoroughly studied and understood reservoir, but many other cell types and tissues also contribute to the persistence of HIV DNA and should therefore also be explored [1]. However, carefully selecting the most suitable DNA extraction method allowed us to adapt the U-assay to alternative sample types such as purified CD4+ T cells, PBMC, macrophages [55,56,70] and tissue biopsies (Marchetti G. Gut damage and dysfunction: any insight toward an HIV cure? Personal communications.…”

Section: Discussionmentioning

confidence: 99%

A comparative analysis of unintegrated HIV-1 DNA measurement as a potential biomarker of the cellular reservoir in the blood of patients controlling and non-controlling viral replication

et al. 2020

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Background: The persistence of HIV-1 in reservoir cells is one of the major obstacles to eradicating the virus in infected individuals receiving combination antiretroviral therapy (ART). HIV-1 persists in infected cells as a stable integrated genome and more labile unintegrated DNA (uDNA), which includes linear, 1-LTR and 2-LTR circular DNA. 2-LTR circle DNA, although less abundant, is considered a surrogate marker of recent infection events and is currently used instead of the other unintegrated species as a diagnostic tool. This pilot study aimed to investigate how to best achieve the measurement of uDNA. Methods: A comparative analysis of two qPCR-based methods (U-assay and 2-LTR assay) was performed on the blood of 12 ART-naïve, 14 viremic and 29 aviremic On-ART patients and 20 untreated spontaneous controllers (HIC), sampled at a single time point. Results: The U-assay, which quantified all unintegrated DNA species, showed greater sensitivity than the 2-LTR assay (up to 75%, p < 0.0001), especially in viremic subjects, in whom other forms, in addition to 2-LTR circles, may also accumulate due to active viral replication. Indeed, in aviremic On-ART samples, the U-assay unexpectedly measured uDNA in a higher proportion of samples (76%, 22/29) than the 2-LTR assay (41%, 12/29), (p = 0.0164). A trend towards lower uDNA levels was observed in aviremic vs viremic On-ART patients, reaching significance when we combined aviremic On-ART and HIC (controllers) vs Off-ART and viremic On-ART subjects (non-controllers) (p = 0.0003), whereas 2-LTR circle levels remained constant (p ≥ 0.2174). These data were supported by the high correlation found between uDNA and total DNA (r = 0.69, p < 0.001). Conclusions: The great advantage of the U-assay is that, unlike the 2-LTR assay, it allows the accurate evaluation of the totality of uDNA that can still be measured even during successful ART when plasma viremia is below the cutoff of common clinical tests (< 50 copies/mL) and 2-LTR circles are more likely to be under the quantification limit. UDNA measurement in blood cells may be used as a biomarker to reveal a so far hidden or underestimated viral reservoir.

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Section: Discussionmentioning

confidence: 99%

A comparative analysis of unintegrated HIV-1 DNA measurement as a potential biomarker of the cellular reservoir in the blood of patients controlling and non-controlling viral replication

et al. 2020

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“…The amount of integrated HIV DNA was obtained by subtracting the amount of uDNA from the amount of total HIV DNA (tDNA). Total/unintegrated/ integrated HIV DNA copy numbers were normalized (as described in [23][24][25][26][27][28][29]) to 1 mg of cellular DNA (equivalent to 142 857 cells) [30].…”

Section: Markers Of Microbial Translocationmentioning

confidence: 99%

Primary HIV infection features colonic damage and neutrophil inflammation yet containment of microbial translocation

Tincati,

Bono,

Cannizzo

et al. 2023

Aids

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Introduction: Impairment of the gastrointestinal (GI) barrier leads to microbial translocation and peripheral immune activation which are linked to disease progression. Data in the setting of primary HIV/SIV infection suggest that gut barrier damage is one of the first events of the pathogenic cascade, preceding mucosal immune dysfunction and microbial translocation. We assessed gut structure and immunity as well as microbial translocation in acutely- and chronically-infected, combination cART-naïve individuals. Methods: Fifteen people with Primary HIV infection (P-HIV) and 13 with Chronic HIV infection (C-HIV) c-ART naïve participants were cross-sectionally studied. Gut biopsies were analyzed in terms of gut reservoirs (total, integrated and unintegrated HIV DNA); tight junction proteins (E-cadherin, Zonula Occludens-1), CD4 expression, neutrophil myeloperoxidase (histochemical staining); collagen deposition (Masson staining). Flow cytometry was used to assess γδ T-cell frequency (CD3+panγδ+Vδ1+/Vδ2+). In plasma we measured microbial translocation (LPS, sCD14, EndoCAb) and gut barrier function (I-FABP) markers (ELISA). Results: P-HIV displayed significantly higher tissue HIV DNA, yet neutrophil infiltration and collagen deposition in the gut were similar in the two groups. In contrast, microbial translocation markers were significantly lower in P-HIV compared to C-HIV. A trend to higher mucosal E-cadherin, and gut γδ T-cells was also observed in P-HIV. Conclusions: Early HIV infection features higher HIV DNA in the gut, yet comparable mucosal alterations to those observed in chronic infection. In contrast, microbial translocation is contained in primary HIV infection, likely due to a partial preservation of E-cadherin and mucosal immune subsets, namely γδ T-cells.

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“…Other potential beneficial effects of INSTIs have been described following treatment with EVG that resulted in immune activation and partially restored T-cell function [ 97 ].…”

Section: Differences In Immune Recovery According To Cart Regimen?mentioning

confidence: 99%

Do Combination Antiretroviral Therapy Regimens for HIV Infection Feature Diverse T-Cell Phenotypes and Inflammatory Profiles?

Tincati

Mondatore

Bai

et al. 2020

Open Forum Infectious Diseases

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Immune abnormalities featuring HIV infection persist despite the use of effective combination antiretroviral therapy (cART) and may be linked to the development of non-infectious comorbidities. The aim of the present narrative, non-systematic literature review is to understand whether cART regimens account for qualitative differences in immune reconstitution. Many studies have reported differences in T-cell homeostasis, inflammation, coagulation and microbial translocation parameters across cART classes and in the course of triple versus dual regimens, yet such evidence is conflicting and not consistent. Possible reasons for discrepant results in the literature are the paucity of randomized-controlled clinical trials, the relatively short follow-up of observational studies, the lack of clinical validation of the numerous inflammatory biomarkers utilized and the absence of research on the effects of cART in tissues. We are currently thus unable to establish if cART classes and regimens are truly accountable for the differences observed in immune/inflammation parameters in different clinical settings. Questions still remain as to whether an early introduction of cART, specifically in the acute stage of disease, or if newer drugs and novel dual-drug regimens are able to significantly impact on the quality of immune reconstitution and the risk of disease progression in HIV-infected subjects.

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Reduction of Immune Activation and Partial Recovery of Staphylococcal Enterotoxin B-Induced Cytokine Production After Switching to an Integrase Strand Transfer Inhibitor-Containing Regimen: Results from an Observational Cohort Study

Cited by 3 publications

References 45 publications

A comparative analysis of unintegrated HIV-1 DNA measurement as a potential biomarker of the cellular reservoir in the blood of patients controlling and non-controlling viral replication

A comparative analysis of unintegrated HIV-1 DNA measurement as a potential biomarker of the cellular reservoir in the blood of patients controlling and non-controlling viral replication

Primary HIV infection features colonic damage and neutrophil inflammation yet containment of microbial translocation

Do Combination Antiretroviral Therapy Regimens for HIV Infection Feature Diverse T-Cell Phenotypes and Inflammatory Profiles?

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