Pro-Inflammatory Alterations of Circulating Monocytes in Latent Tuberculosis Infection.

Background: Latent tuberculosis infection (LTBI) has been associated with increased cardiovascular risk. We investigated the activation and pro-inflammatory profile of monocytes in individuals with LTBI and their association with coronary artery disease (CAD). Methods: Individuals 40-70 years old in Lima, Peru, underwent QuantiFERON-TB testing to define LTBI, completed a coronary computed tomography angiography to evaluate CAD, and provided blood for monocyte profiling using flow cytometry. Cells were stimulated with lipopolysaccharide to assess interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α responses. Results: The clinical characteristics of the LTBI (n = 28) and non-LTBI (n = 41) groups were similar. All monocyte subsets from LTBI individuals exhibited higher mean fluorescence intensity (MFI) of CX3CR1 and CD36 compared with non-LTBI individuals. LTBI individuals had an increased proportion of nonclassical monocytes expressing IL-6 (44.9 vs 26.9; P = .014), TNF-α (62.3 vs 35.1; P = .014), and TNF-α+IL-6+ (43.2 vs 36.6; P = .042). Among LTBI individuals, CAD was associated with lower CX3CR1 MFI on classical monocytes and lower CD36 MFI across all monocyte subsets. In multivariable analyses, lower CD36 MFI on total monocytes (b = -0.17; P = .002) and all subsets remained independently associated with CAD in LTBI. Conclusions: Individuals with LTBI have distinct monocyte alterations suggestive of an exacerbated inflammatory response and tissue migration. Whether these alterations contribute to cardiovascular disease pathogenesis warrants further investigation.

A Sex-Stratified Analysis of Monocyte Phenotypes Associated with HIV Infection in Uganda.

Women with HIV may experience higher rates of non-AIDS comorbidities compared to men with HIV, but the underlying mechanisms are not well understood. We investigated sex-related differences in the effects of HIV on monocyte phenotypes within the Ugandan Study of HIV effects on the Myocardium and Atherosclerosis (mUTIMA). Of 133 participants who provided blood for flow cytometry assays, 86 (65%) were women and 91 (68%) were persons living with HIV (PLWH) on antiretroviral therapy. The median age was 57 (interquartile range, 52-63) years. PLWH exhibited a lower proportion of circulating CD14+CD16- classical monocytes (66.3% vs. 75.1%; p < 0.001), and higher proportion of CD14+CD16+ inflammatory monocytes (17% vs. 11.7%; p = 0.005) compared to HIV-uninfected participants. PLWH had an increased expression of the chemokine receptor CX3CR1 in total monocytes (CX3CR1+ monocytes, 24.5% vs. 4.7%; p < 0.001) and monocyte subsets. These findings were generally similar when analyzed by sex, with no significant interactions between sex and HIV status in adjusted models. Our data show that the inflammatory monocyte subset is expanded and monocyte CX3CR1 chemokine receptor expression is enhanced among PLWH, regardless of sex. Whether these parameters differentially affect risk for non-AIDS comorbidities and clinical outcomes in women with HIV requires additional investigation.

Induction of Follicular-Like CXCR5+ CD8+ T Cells by TGF-ß1/IL-23 Is Limited During HIV Infection.

Follicular CD4+ T cells are the main HIV reservoirs due to, among other factors, the low frequency of CD8+ T cells in lymphoid follicles. Follicular CXCR5+ CD8+ T cells are associated with HIV control, but their differentiation conditions are yet undefined. In this study, we explored the in vitro effect of transforming growth factor (TGF)-ß1, interleukin (IL)-12, and IL-23 on the induction of CXCR5, the follicle homing receptor, in human circulating CD8+ T cells from seronegative, and treated HIV-infected individuals. The combination of TGF-ß1 plus IL-23 induced the highest expression of CXCR5 in purified CD8+ T cells. These CXCR5+ CD8+ T cells also expressed a transcriptional and phenotypic profile similar to that of follicular CD4+ T cells, such as the upregulation of BCL6, inducible costimulator and CD40L, and downregulation of PRDM1. These cells responded in vitro to CXCL13 and had low expression of CCR7. In addition, after polyclonal stimulation, they produced IL-21, interferon-γ, and de novo perforin. However, in comparison with seronegative individuals, CD8+ T cells from HIV-infected patients had a lower response to TGF-ß1/IL-23, a defect that was restored with the blockade of the programmed cell death 1 inhibitory receptor. Thus, TGF-ß1 plus IL-23 induce follicular-like CXCR5+ CD8+ T cells in seronegative individuals, but in HIV-infected patients there is a limited response which could impair the generation of this cell population.

A Low Frequency of IL-17-Producing CD8+ T-Cells Is Associated With Persistent Immune Activation in People Living With HIV Despite HAART-Induced Viral Suppression.

Immune activation is the hallmark of HIV infection, even in patients with highly active anti-retroviral therapy (HAART)-induced viral suppression. A major cause of immune activation during HIV infection is the intestinal microbial translocation as a consequence, among other factors, of the decrease and/or dysfunction of interleukin (IL)-17-producing T-cells, due to their role promoting the integrity of the intestinal barrier. A population of IL-17-producing CD8+ T-cells (Tc17 cells), characterized by the expression of CD161, has been described, but its relation with the persistent immune activation in non-viremic people living with HIV (PLWH) on HAART is unclear. By flow cytometry, we characterized the activation phenotype (evaluated by the expression of HLA-DR and CD38) of circulating CD161-expressing CD8+ T-cells; in addition, we explored the functionality of polyclonally-stimulated Tc17 cells in PLWH under HAART-induced viral suppression, and in healthy individuals. Finally, we determined the association of Tc17 cells with the expression of cellular and soluble activation markers. Circulating CD161-expressing CD8+ T-cells were decreased in PLWH compared with healthy individuals, despite their similar basal activation state. After polyclonal stimulation, IL-17 production was higher in CD8+ T-cells co-expressing HLA-DR and CD38 in healthy individuals. In contrast, although PLWH had a higher frequency of HLA-DR+ CD38+ CD8+ T-cells after stimulation, they had a lower production of IL-17. Interferon (IFN)-γ-producing CD8+ T-cells (Tc1 cells) were increased in PLWH. The low Tc17 cells response was associated with a high expression of CD38 and programmed death 1 protein, high levels of soluble CD14 and the treatment duration. Finally, to explore potential immunomodulatory strategies, the in vitro effect of the anti-inflammatory agent sulfasalazine was assessed on Tc17 cells. Interestingly, a decreased inflammatory environment, death of activated CD8+ T-cells, and an increased frequency of Tc17 cells were observed with sulfasalazine treatment. Thus, our findings suggest that activated CD8+ T-cells have a marked capacity to produce IL-17 in healthy individuals, but not in PLWH, despite HAART. This dysfunction of Tc17 cells is associated with the persistent immune activation observed in these patients, and can be partially restored by anti-inflammatory agents.

[Effects of prebiotics and probiotics on gastrointestinal tract lymphoid tissue in hiv infected patients]. / Efecto de la terapia con probióticos/prebióticos sobre la reconstitución del tejido linfoide asociado a la mucosa gastrointestinal durante la infección por el virus de la inmunodeficiencia humana-1.

HIV infection induces alterations in almost all immune cell populations, mainly in CD4+ T cells, leading to the development of opportunistic infections. The gut-associated lymphoid tissue (GALT) constitutes the most important site for viral replication, because the main target cells, memory T-cells, reside in this tissue. It is currently known that alterations in GALT are critical during the course of the infection, as HIV-1 induces loss of tissue integrity and promotes translocation of microbial products from the intestinal lumen to the systemic circulation, leading to a persistent immune activation state and immune exhaustion. Although antiretroviral treatment decreases viral load and substantially improves the prognosis of the infection, the alterations in GALT remains, having a great impact on the ability to establish effective immune responses. This emphasizes the importance of developing new therapeutic alternatives that may promote structural and functional integrity of this tissue. In this regard, therapy with probiotics/prebiotics has beneficial effects in GALT, mainly in syndromes characterized by intestinal dysbiosis, including the HIV-1 infection. In these patients, the consumption of probiotics/prebiotics decreased microbial products in plasma and CD4+ T cell activation, increased CD4+ T cell frequency, in particular Th17, and improved the intestinal flora. In this review, the most important findings on the potential impact of the probiotics/prebiotics therapy are discussed.

Efecto de la terapia con probióticos/prebióticos sobre la reconstitución del tejido linfoide asociado a la mucosa gastrointestinal durante la infección por el virus de la inmunodeficiencia humana-1 / Effects of prebiotics and probiotics on gastrointestinal tract lymphoid tissue in hiv infected patients

HIV infection induces alterations in almost all immune cell populations, mainly in CD4+ T cells, leading to the development of opportunistic infections. The gut-associated lymphoid tissue (GALT) constitutes the most important site for viral replication, because the main target cells, memory T-cells, reside in this tissue. It is currently known that alterations in GALT are critical during the course of the infection, as HIV-1 induces loss of tissue integrity and promotes translocation of microbial products from the intestinal lumen to the systemic circulation, leading to a persistent immune activation state and immune exhaustion. Although antiretroviral treatment decreases viral load and substantially improves the prognosis of the infection, the alterations in GALT remains, having a great impact on the ability to establish effective immune responses. This emphasizes the importance of developing new therapeutic alternatives that may promote structural and functional integrity of this tissue. In this regard, therapy with probiotics/prebiotics has beneficial effects in GALT, mainly in syndromes characterized by intestinal dysbiosis, including the HIV-1 infection. In these patients, the consumption of probiotics/prebiotics decreased microbial products in plasma and CD4+ T cell activation, increased CD4+ T cell frequency, in particular Th17, and improved the intestinal flora. In this review, the most important findings on the potential impact of the probiotics/prebiotics therapy are discussed.