Microbial Translocation Is Linked to a Specific Immune Activation Profile in HIV-1-Infected Adults With Suppressed Viremia

Abstract

Persistent immune activation in virologically suppressed HIV-1 patients, which may be the consequence of various factors including microbial translocation, is a major cause of comorbidities. We have previously shown that different profiles of immune activation may be distinguished in virological responders. Here, we tested the hypothesis that a particular profile might be the consequence of microbial translocation. To this aim, we measured 64 soluble and cell surface markers of inflammation and CD4+ and CD8+ T-cell, B cell, monocyte, NK cell, and endothelial activation in 140 adults under efficient antiretroviral therapy, and classified patients and markers using a double hierarchical clustering analysis. We also measured the plasma levels of the microbial translocation markers bacterial DNA, lipopolysaccharide binding protein (LBP), intestinal-fatty acid binding protein, and soluble CD14. We identified five different immune activation profiles. Patients with an immune activation profile characterized by a high percentage of CD38+CD8+ T-cells and a high level of the endothelial activation marker soluble Thrombomodulin, presented with higher LBP mean (± SEM) concentrations (33.3 ± 1.7 vs. 28.7 ± 0.9 μg/mL, p = 0.025) than patients with other profiles. Our data are consistent with the hypothesis that the immune activation profiles we described are the result of different etiological factors. We propose a model, where particular causes of immune activation, as microbial translocation, drive particular immune activation profiles responsible for particular comorbidities.

HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells

“…This setting leads to a pro-inflammatory state that disrupts the gut mucosal barrier and enhances microbial translocation. The increase in microbial translocation, as previously stated, is believed to be one of the most significant causes of the increased immune activation observed in HIVinfected patients [80,81,104], highlighting the importance of Th17 cells for the control of immune activation in the context of HIV infection.…”

“…These data reinforce the idea that, although driven by HIV infection, immune activation is boosted by factors that go beyond the direct effects of viral replication. Bystander activation of CD8 + T cells in HIV infection has been observed to be associated with the reactivation of other viruses [76,77] and with the circulation of proinflammatory cytokines [78,79], while microbial translocation due to CD4 + T cell depletion in the gut mucosa is considered one of the major mechanisms driving immune activation [80][81][82]. Besides, suboptimal penetration of drugs in anatomical sites such as the central nervous system, GALT, and lymph nodes is associated with persistence of viral replication in those tissues despite plasma viral load <LDL [83][84][85][86].…”

Influence of HIV‐1 V2 sequence variability on bacterial translocation in antiretroviral naïve HIV‐1 infected patients

“…However, multiple other molecular and cellular mechanisms, which are in part still unclear, might be at the origin of this process, including tumor necrosis factor α, interleukin (IL)-10, CD38, [23][24][25] LPS binding protein (LBP), and I-FABP. 26,27 Herein, we aimed to investigate whether the composition of In agreement with a previous study 14 from our group, where the composition of the 179-181 tripeptide was investigated, the most commonly observed triplets were LDV and LDI. However, no association between these two main variants and plasma levels of the investigated biomarkers was found; similarly, the overall V2 features in terms of length, NC, and the number of glycosylation sites did not appear to influence LPS and sCD14 plasma levels by either univariate or multivariate analysis.…”

Identification of distinct immune activation profiles in adult humans

“…A hierarchical clustering analysis identified 5 different IA profiles in these people 2 . To test whether the IA profiles were robust rather than specific to the 120 patients we had analyzed, we recruited 20 more HIV patients with divergent bioclinical characteristics, and performed the hierarchical clustering analysis again 3 . Once more, we observed 5 different IA profiles in these 140 HIV patients.…”

“…2 Institute of Human Genetics, CNRS-Montpellier University UMR9002, 141 rue de la Cardonille, 34396 Montpellier Cedex 5, France. 3 Institute of Functional Genomics UMR5203 and BCM, CNRS-INSERM-Montpellier University, 141 rue de la Cardonille, 34396 Montpellier, France. 4 Biochemestry Department, Montpellier University Hospital, 371 Avenue du Doyen Gaston Giraud, 34295 Montpellier, France.…”