Name: Transcription profiling by array of human monocytes to study their involement in HIV-Tuberculosis associated Immune Reconstitution Inflammatory Syndrome at the initiation of combined antiretroviral therapy
Keywords: transcription profiling by array

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Transcription profiling by array of human monocytes to study their involement in HIV-Tuberculosis associated Immune Reconstitution Inflammatory Syndrome at the initiation of combined antiretroviral therapy

ABSTRACT: Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) is a common complication in HIV-TB co-infected patients receiving combined antiretroviral therapy (cART). While monocytes/macrophages play major roles in both HIV- and TB-infection individually, a putative contribution of monocytes to the development of TB-IRIS remains unexamined. We performed a genome-wide array analysis on MOs purified from peripheral blood mononuclear cells (PBMCs) obtained before initiation of combined antiretroviral therapy (cART) to verify whether the transcriptome of MOs was already significantly modulated (even before receiving cART) in HIV+/TB+ patients who later developed TB-IRIS compared to control HIV+/TB+ patients who did not develop the complication . The subjects under study included a subset of 18 TB-IRIS patients and controls matched for age, gender and CD4 count.

INSTRUMENT(S): 418 [Affymetrix]

ORGANISM(S): Homo Sapiens

DISEASE(S): Hiv-tuberculosis With Immune Reconstitution Inflammatory Syndrome,Hiv-tuberculosis Without Immune Reconstitution Inflammatory Syndrome

SUBMITTER: THANH HUYEN T TRAN

PROVIDER: E-MEXP-3618 | ArrayExpress | 2013-04-01

REPOSITORIES: ArrayExpress

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Project description:Tuberculosis (TB) is the most common comorbidity and the leading cause of death among HIV-infected individuals. Although the combined antiretroviral therapy (cART) during TB treatment improves the survival of TB/HIV patients, the occurrence of immune reconstitution inflammatory syndrome (IRIS) in some patients poses clinical and scientific challenges. This work aimed to evaluate blood innate lymphocytes during therapeutic intervention for both diseases and their implications for the onset of IRIS. Natural killer (NK) cells, invariant NKT cells (iNKT), ?? T cell subsets, and <i>in vitro</i> NK functional activity were characterized by multiparametric flow cytometry in the following groups: 33 TB/HIV patients (four with paradoxical IRIS), 27 TB and 25 HIV mono-infected subjects (prior to initiation of TB treatment and/or cART and during clinical follow-up to 24 weeks), and 25 healthy controls (HC). Concerning the NK cell repertoire, several activation and inhibitory receptors were skewed in the TB/HIV patients compared to those in the other groups, especially the HCs. Significantly higher expression of CD158a (<i>p</i> = 0.025), NKp80 (<i>p</i> = 0.033), and NKG2C (<i>p</i> = 0.0076) receptors was detected in the TB/HIV IRIS patients than in the non-IRIS patients. Although more NK degranulation was observed in the TB/HIV patients than in the other groups, the therapeutic intervention did not alter the frequency during follow-up (weeks 2-24). A higher frequency of the ?? T cell population was observed in the TB/HIV patients with inversion of the V?2<sup>+</sup>/V?2<sup>-</sup> ratio, especially for those presenting pulmonary TB, suggesting an expansion of particular ?? T subsets during TB/HIV co-infection. In conclusion, HIV infection impacts the frequency of circulating NK cells and ?? T cell subsets in TB/HIV patients. Important modifications of the NK cell repertoire were observed after anti-TB treatment (week 2) but not during the cART/TB follow-up (weeks 6-24). An increase of CD161<sup>+</sup> NK cells was related to an unfavorable outcome. Despite the low number of cases, a more preserved NK cell profile was detected in IRIS patients previous to treatment, suggesting a role for these cells in IRIS onset. Longitudinal evaluation of the NK repertoire showed the impact of TB treatment and implicated these cells in TB pathogenesis in TB/HIV co-infected patients.

Project description:<h4>Background</h4>Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory complication in HIV-TB co-infected patients receiving antiretroviral therapy (ART). The exact contribution of T cells, natural killer (NK) cells, and monocytes to TB-IRIS development remains unclear. Here, we studied the expression of exhaustion markers on lymphocytes at different intervals during ART.<h4>Methods</h4>We compared 13 HIV-TB patients who developed TB-IRIS with 13 patients who did not (HIV+TB+), 13 HIV-patients without TB (HIV+TB-) and 9 HIV/TB-negative controls (HIV-TB-). Patients did not differ in age, gender, or CD4-count prior to ART. Frozen peripheral blood mononuclear cells, collected before ART and during 3 months and 9 months of ART, were analysed using flow cytometry. We examined expression of KLRG1, PD-1 and IL-27R on CD4+ and CD8hi T cells, as well as CD3-negative CD8lo lymphocytes as an approximate subset of NK cells. In addition, expression of TLR2, TLR4, IL1RL1, and TRAILR on CD14+ monocytes were investigated.<h4>Results</h4>Prior to ART, TB-IRIS patients had higher percentages of CD8hi T cells that are KLRG1+PD-1+ compared to each control group (p?0.034). Though PD-1 expression decreased during ART in all groups (p?0.026), the percentage KLRG1+PD-1+CD8hi T cells remained higher in TB-IRIS patients after 3 months of ART (p?0.013). Though these patterns were less pronounced in CD3-CD8lo lymphocytes, the percentage of KLRG1+ cells was higher in TB-IRIS patients prior to ART (p?0.043). In contrast, no clear differences could be observed for CD4+ T cells or monocytes.<h4>Conclusion</h4>TB-IRIS is preceded by a high level of exhausted (KLRG1+PD-1+) CD8hi T cells, which persists during 3 months of ART. This trait is potentially mirrored in a subpopulation of NK cells, but not CD4+ T cells. Since a dysfunctional CD8+ lymphocyte compartment could predispose patients to TB-IRIS, the functional role of these cells prior to TB-IRIS development should be further explored.

			Action	DRS
	E-MEXP-3618.README.txt	Txt
	E-MEXP-3618.idf.txt	Idf
	E-MEXP-3618.processed.1.zip	Processed
	E-MEXP-3618.raw.1.zip	Raw
	E-MEXP-3618.sdrf.txt	Txt

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Transcription profiling by array of human monocytes to study their involement in HIV-Tuberculosis associated Immune Reconstitution Inflammatory Syndrome at the initiation of combined antiretroviral therapy

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