Expansion of CCR5+ CD4+ T-lymphocytes in the course of active pulmonary tuberculosis

Santucci, Marilina B.; Bocchino, Marialuisa; Garg, Sanjay; Marruchella, Almerico; Colizzi, Vittorio; Saltini, Cesare; Fraziano, Maurizio

doi:10.1183/09031936.04.000105403

Cited by 32 publications

(21 citation statements)

References 29 publications

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“…33 Our findings established CCR5-utilizing variants in both plasma and tissue in all but two sequences; this is consistent with previous studies of HIV-1 subtype C infections showing minimal corrector switch from CCR5 to CXCR4 even in the context of late stage AIDS and coinfections such as pulmonary TB. 28 Phenotypic studies may be warranted since genotype does not always accurately predict coreceptor utilization and subtle differences in usage of CD4 and coreceptors have been noted with CSF-derived and other viral isolates.…”

Section: Discussionsupporting

confidence: 80%

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

Danaviah

Oliveira

Gordon³

et al. 2016

AIDS Research and Human Retroviruses

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Extrapulmonary tuberculosis (TB) is a significant public health challenge in South Africa and worldwide, largely fuelled by the HIV epidemic. In spinal TB, Mycobacteria infect the spinal column without dissemination to the spinal cord. The immune microenvironment, target cell characteristics, and other evolutionary forces within granulomas during HIV/TB coinfection are poorly characterized. We investigated whether spinal TB granulomas represent a sequestered anatomical site where independent HIV evolution occurs, and assessed the role of macrophages as a target cell for both HIV and mycobacteria. RNA was extracted from plasma and granulomatous tissue from six antiretroviral-naive HIV-1/spinal TB-coinfected patients, RT-PCR amplified, and the C2-V5 env segment was cloned and sequenced. Analysis of genetic diversity, phylogeny and coalescence patterns was performed on clonal sequences. To investigate their role in HIV sequestration, macrophages and the HIV-1 p24 protein were immune localized and ultrastructural features were studied. Intercompartment diversity measurements and phylogenetic reconstruction revealed anatomically distinct monophyletic HIV-1 clusters in four of six patients. Genotypic CCR5-tropic variants were predominant (98.9%) with conservation of putative N-linked glycosylation sites in both compartments. CD68+ reactivity was associated with higher tissue viral load (r = 1.0; p < 0.01) but not greater intrapatient diversity (r = 0.60; p > 0.05). Ultrastructural imaging revealed the presence of bacterial and virus-like particles within membrane-bound intracellular compartments of macrophages. Spinal tuberculosis granulomas may form anatomically discreet sites of divergent viral evolution. Macrophages in these granulomas harbored both pathogens, suggesting that they may facilitate the process of viral sequestration within this compartment.

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Section: Discussionsupporting

confidence: 80%

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

Danaviah

Oliveira

Gordon³

et al. 2016

AIDS Research and Human Retroviruses

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“…There was also an increase in the proportion of CD4 + T cells co-expressing CCR5 + and CXCR3 + in the TB-IRIS group compared with the non-TB-IRIS group at the week 2 visit after ART initiation, but this did not persist. It has been previously shown that M. tuberculosis infection of monocyte-derived macrophages increases CCR5 + expression on T cells when compared with the CXCR3 + expression and that CCR5 + CD4 + T cells accumulate in the lung at higher rates during the course of active TB 37. Given the association of CCR5 + T cells with M. tuberculosis disease, and our finding of increased CCR5 + CD4 + T cells in TB-IRIS, we suggest that CCR5 inhibitor therapy should be considered as a therapeutic strategy to prevent TB-IRIS in HIV-infected patients with treated TB who commence ART.…”

Section: Discussionmentioning

confidence: 99%

TB-IRIS After Initiation of Antiretroviral Therapy Is Associated With Expansion of Preexistent Th1 Responses Against Mycobacterium tuberculosis Antigens

Vignesh

Kumarasamy

Lim

et al. 2013

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background The role of T-cell responses against Mycobacterium tuberculosis antigens in tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is unclear. Methods Peripheral blood mononuclear cells from 45 HIV patients with treated TB, of whom 12 developed TB-IRIS, were collected at weeks 0, 2, and 6 of antiretroviral therapy (ART). Production of interferon-γ (IFN-[γ]) and interleukin-2 by T cells after stimulation with purified protein derivative (PPD) or early secretory antigenic target-6 (ESAT-6) and T-cell expressions of CCR5 and CXCR3 were assessed by flow cytometry. IFN-γ and CXCL10 were assayed by enzyme-linked immunosorbent assay. Results TB-IRIS patients had higher proportions of PPD- and ESAT-6–reactive IFN-γ+CD4+ and CD3+CD4- T cells at weeks 0, 2, and 6. IFN-γ levels were also higher in peripheral blood mononuclear cell culture supernatants at all times with PPD but only at weeks 2 and 6 with ESAT-6. There were few differences for interleukin-2. CXCL10 levels in supernatants after PPD and ESAT-6 stimulation were only higher at week 6. CXCR3+/CCR5+CD4+ T cells were higher at week 2, and CCR5+CD4+ T cells were higher at week 6. Conclusions TB-IRIS is associated with Th1 responses against M. tuberculosis antigens by CD4+ and CD3+CD4- T cells that are present before ART and amplified afterward. It is unclear if these cause immunopathology or reflect a high pathogen load.

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“…It is expressed on granulocytes, dendritic cells, macrophages, CD8 + cells, memory CD4 + cells, and stromal cells and at high levels on Th1 lymphocytes (29)(30)(31)(32)(33). CCR5 plays a critical role in Th1 inflammation and immunity, where it is required for the successful control of a variety of infectious agents, including tuberculosis, cryptococcus, and toxoplasma (29,31,(34)(35)(36) and is expressed in exaggerated quantities in Tc1-dominated responses, including those in tuberculosis, sarcoidosis, Wegner granulomatosis, rheumatoid arthritis, periodontitis, and acute and chronic transplant rejection (7,31,34,(37)(38)(39)(40)(41). In these responses, CCR5 plays an important role in the pathogenesis of tissue inflammation, protease production, tissue remodeling (41), and local cell death responses (42,43).…”

Section: Introductionmentioning

confidence: 99%

Role of CCR5 in IFN- -induced and cigarette smoke-induced emphysema

Kang²,

Lee³

et al. 2005

Journal of Clinical Investigation

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Th1 inflammation and remodeling characterized by tissue destruction frequently coexist in human diseases.To further understand the mechanisms of these responses, we defined the role(s) of CCR5 in the pathogenesis of IFN-g-induced inflammation and remodeling in a murine emphysema model. IFN-g was a potent stimulator of the CCR5 ligands macrophage inflammatory protein-1α/CCL-3 (MIP-1α/CCL-3), MIP-1β/CCL-4, and RANTES/CCL-5, among others. Antibody neutralization or null mutation of CCR5 decreased IFN-g-induced inflammation, DNA injury, apoptosis, and alveolar remodeling. These interventions decreased the expression of select chemokines, including CCR5 ligands and MMP-9, and increased levels of secretory leukocyte protease inhibitor. They also decreased the expression and/or activation of Fas, FasL, TNF, caspase-3, -8, and -9, Bid, and Bax. In accordance with these findings, cigarette smoke induced pulmonary inflammation, DNA injury, apoptosis, and emphysema via an IFN-g-dependent pathway(s), and a null mutation of CCR5 decreased these responses. These studies demonstrate that IFN-g is a potent stimulator of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-g-induced and cigarette smoke-induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN-g stimulation of its own ligands, other chemokines, MMPs, caspases, and cell death regulators and the inhibition of antiproteases.

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Expansion of CCR5+ CD4+ T-lymphocytes in the course of active pulmonary tuberculosis

Cited by 32 publications

References 29 publications

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

TB-IRIS After Initiation of Antiretroviral Therapy Is Associated With Expansion of Preexistent Th1 Responses Against Mycobacterium tuberculosis Antigens

Role of CCR5 in IFN- -induced and cigarette smoke-induced emphysema

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