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Transient expansion of activated CD8(+) T cells characterizes tuberculosis-associated immune reconstitution inflammatory syndrome in patients with HIV: a case control study.

ABSTRACT: CD4(+) T cell activation indicators have been reported to be a common phenomenon underlying diverse manifestations of immune reconstitution inflammatory syndrome (IRIS). However, we have found that a high frequency of circulating CD8(+) T cells is a specific risk factor for mycobacterial IRIS. Therefore, we investigated whether CD8(+) T cells from patients who develop TB IRIS were specifically activated.We obtained PBMCs from HIV+?patients prior to and 4, 8, 12, 24, 52 and 104 weeks after initiating antiretroviral therapy. CD38 and HLADR expression on naive, central memory and effector memory CD8(+) and CD4(+) T cells were determined by flow cytometry. Absolute counts and frequencies of CD8(+) T cell subsets were compared between patients who developed TB IRIS, who developed other IRIS forms and who remained IRIS-free.TB IRIS patients showed significantly higher counts of naive CD8(+) T cells than the other groups at most time points, with a contraction of the effector memory subpopulation occurring later in the follow-up period. Activated (CD38(+) HLADR(+)) CD8(+) T cells from all groups decreased with treatment but transiently peaked in TB IRIS patients. This increase was due to an increase in activated naive CD8(+) T cell counts during IRIS. Additionally, the CD8(+) T cell subpopulations of TB IRIS patients expressed HLADR without CD38 more frequently and expressed CD38 without HLADR less frequently than cells from other groups.CD8(+) T cell activation is specifically relevant to TB IRIS. Different IRIS forms may involve different alterations in T cell subsets, suggesting different underlying inflammatory processes.

SUBMITTER: Espinosa E

PROVIDER: S-EPMC3679878 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Transient expansion of activated CD8(+) T cells characterizes tuberculosis-associated immune reconstitution inflammatory syndrome in patients with HIV: a case control study.

Espinosa Enrique E Romero-Rodríguez Dámaris P DP Cantoral-Díaz María-Teresa MT Reyes-Terán Gustavo G

Journal of inflammation (London, England) 20130520

<h4>Background</h4>CD4(+) T cell activation indicators have been reported to be a common phenomenon underlying diverse manifestations of immune reconstitution inflammatory syndrome (IRIS). However, we have found that a high frequency of circulating CD8(+) T cells is a specific risk factor for mycobacterial IRIS. Therefore, we investigated whether CD8(+) T cells from patients who develop TB IRIS were specifically activated.<h4>Methods</h4>We obtained PBMCs from HIV+ patients prior to and 4, 8, 12 ...[more]

PMID: 23688318

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Project description:BackgroundPatients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation.MethodsWe undertook this prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults (aged ≥21 years) with advanced HIV (CD4 cell counts ≤125 cells per μL) and pulmonary tuberculosis. We obtained data for clinical variables and for levels of 29 plasma biomarkers, quantified by Luminex assay. We classified patients as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 6 months after ART initiation. We used rank-sum or χ(2) tests, and logistic regression with odds ratios (OR) and 95% CIs, to assess the association between variables measured before and 4 weeks after ART initiation with death and tuberculosis-associated IRIS, compared with controls.FindingsBetween Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. 31 (15%) patients left the study before ART initiation, leaving 170 (85%) patients for analysis. Patients with tuberculosis-associated IRIS had reduced pre-ART concentrations of several pro-inflammatory biomarkers, including interleukin (IL)-6 (adjusted OR per 1 log10 increase 0·40 [95% CI 0·18-0·89]). However, patients with early death had increased pre-ART concentrations of inflammatory biomarkers, including monocyte chemoattractant protein-1 (adjusted OR 9·0 [95% CI 1·0-80·0]) and tumour necrosis factor (TNF)α (7·8 [1·1-55·2]). At week 4 after ART initation, tuberculosis-associated IRIS was independently associated with greater increases in several inflammatory biomarkers, including IL-6 (adjusted OR 1·7 [95% CI 1·2-2·5]) and TNFα (1·5 [1·0-2·2]), versus controls. Death was likewise associated with greater increases in systemic inflammatory markers, including granulocyte colony-stimulating factor (adjusted OR 2·8 [95% CI 1·3-6·1]), IL-12p40 (1·8 [1·0-3·4]), and IL-15 (2·0 [1·1-3·7]), versus controls. However, changes in CD4 cell count during ART, which were similar between controls and patients with tuberculosis-associated IRIS (p=0·45), were substantially lower in patients who died (p=0·006).InterpretationDistinct immunological profiles before and after ART initiation characterise patients with advanced HIV and tuberculosis who have tuberculosis-associated IRIS and death. Interventions that decrease inflammation while promoting cellular immune recovery during ART should be considered in patients co-infected with HIV and tuberculosis.FundingNational Institutes of Health and the Penn Center for AIDS Research.

Project description:BACKGROUND:Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwide. In some TB-HIV co-infected individuals treated for both diseases simultaneously, a pathological inflammatory reaction termed immune reconstitution inflammatory syndrome (IRIS) may occur. The risk factors for IRIS are not fully defined. We investigated the association of HLA-B, HLA-C, and KIR genotypes with TB, HIV-1 infection, and IRIS onset. METHODS:Patients were divided into four groups: Group 1- TB+/HIV+ (n?=?88; 11 of them with IRIS), Group 2- HIV+ (n?=?24), Group 3- TB+ (n?=?24) and Group 4- healthy volunteers (n?=?26). Patients were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. The HLA-B and HLA-C loci were typed using SBT, NGS, and KIR genes by PCR-SSP. Unconditional logistic regression models were performed for Protection/risk estimation. RESULTS:Among the individuals with TB as the outcome, KIR2DS2 was associated with increased risk for TB onset (aOR?=?2.39, P?=?0.04), whereas HLA-B*08 and female gender were associated with protection against TB onset (aOR?=?0.23, P?=?0.03, and aOR?=?0.33, P?=?0.01, respectively). Not carrying KIR2DL3 (aOR?=?0.18, P?=?0.03) and carrying HLA-C*07 (aOR?=?0.32, P?=?0.04) were associated with protection against TB onset among HIV-infected patients. An increased risk for IRIS onset was associated with having a CD8 count ?500 cells/mm3 (aOR?=?18.23, P?=?0.016); carrying the KIR2DS2 gene (aOR?=?27.22, P?=?0.032), the HLA-B*41 allele (aOR?=?68.84, P?=?0.033), the KIR2DS1?+?HLA-C2 pair (aOR?=?28.58, P?=?0.024); and not carrying the KIR2DL3?+?HLA-C1/C2 pair (aOR?=?43.04, P?=?0.034), and the KIR2DL1?+?HLA-C1/C2 pair (aOR?=?43.04, P?=?0.034), CONCLUSIONS: These results suggest the participation of these genes in the immunopathogenic mechanisms related to the conditions studied. This is the first study demonstrating an association of HLA-B*41, KIR2DS2, and KIR + HLA-C pairs with IRIS onset among TB-HIV co-infected individuals.

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Transient expansion of activated CD8(+) T cells characterizes tuberculosis-associated immune reconstitution inflammatory syndrome in patients with HIV: a case control study.

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Transient expansion of activated CD8(+) T cells characterizes tuberculosis-associated immune reconstitution inflammatory syndrome in patients with HIV: a case control study.

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