Disrupted Homeostatic Cytokines Expression in Secondary Lymph Organs during HIV Infection

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Abstract

Research has firmly established that infection by human immunodeficiency virus (HIV) leads to structural disruption in secondary lymph organs (SLOs) and that IL-7 expression by SLOs is downregulated in simian immunodeficiency virus (SIV)-infected rhesus macaques. However, the foregoing has not been demonstrated in HIV-infected patients. As well, SLO-produced chemokines and cytokines, other than IL-7, have not been tested. In this study, SLOs in HIV-infected patients exhibit decreased levels of lymphoid cytokines, such as IL-7 and C–C motif chemokine ligand 21 (CCL21), due to lower expression of lymphotoxin (LT)-β. Previous research has shown that LT-β is produced mainly by CD4 ⁺T cells in rhesus macaques, while our study found the same level of LT-β expressed by CD4 ⁺T and CD8 ⁺T cells in humans. CD8 ⁺T cells substitute for depleted CD4 ⁺T cells LT-β production. Only the total number of CD3 ⁺T cells can account for the majority of LT-β in human SLOs. This study indicates a possible mechanism and a potential target for improvement of SLO function in HIV-infected patients, a novel adjuvant therapy for AIDS.

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Most cited references 25

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Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes.

Marc Bajénoff, Jackson G Egen, Lily Y. Koo … (2006)

After entry into lymph nodes (LNs), B cells migrate to follicles, whereas T cells remain in the paracortex, with each lymphocyte type showing apparently random migration within these distinct areas. Other than chemokines, the factors contributing to this spatial segregation and to the observed patterns of lymphocyte movement are poorly characterized. By combining confocal, electron, and intravital microscopy, we showed that the fibroblastic reticular cell network regulated naive T cell access to the paracortex and also supported and defined the limits of T cell movement within this domain, whereas a distinct follicular dendritic cell network similarly served as the substratum for movement of follicular B cells. These results highlight the central role of stromal microanatomy in orchestrating cell migration within the LN.

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Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment.

Colleen Kelley, Christina Kitchen, Peter W. Hunt … (2009)

Although antiretroviral therapy has the ability to fully restore a normal CD4(+) cell count (>500 cells/mm(3)) in most patients, it is not yet clear whether all patients can achieve normalization of their CD4(+) cell count, in part because no study has followed up patients for >7 years. Three hundred sixty-six patients from 5 clinical cohorts who maintained a plasma human immunodeficiency virus (HIV) RNA level 1000 copies/mL for at least 4 years after initiation of antiretroviral therapy were included. Changes in CD4(+) cell count were evaluated using mixed-effects modeling, spline-smoothing regression, and Kaplan-Meier techniques. The majority (83%) of the patients were men. The median CD4(+) cell count at the time of therapy initiation was 201 cells/mm(3) (interquartile range, 72-344 cells/mm(3)), and the median age was 47 years. The median follow-up period was 7.5 years (interquartile range, 5.5-9.7 years). CD4(+) cell counts continued to increase throughout the follow-up period, albeit slowly after year 4. Although almost all patients (95%) who started therapy with a CD4(+) cell count 300 cells/mm(3) were able to attain a CD4(+) cell count 500 cells/mm(3), 44% of patients who started therapy with a CD4(+) cell count 500 cells/mm(3) over a mean duration of follow-up of 7.5 years; many did not reach this threshold by year 10. Twenty-four percent of individuals with a CD4(+) cell count <500 cells/mm(3) at year 4 had evidence of a CD4(+) cell count plateau after year 4. The frequency of detectable viremia ("blips") after year 4 was not associated with the magnitude of the CD4(+) cell count change. A substantial proportion of patients who delay therapy until their CD4(+) cell count decreases to <200 cells/mm(3) do not achieve a normal CD4(+) cell count, even after a decade of otherwise effective antiretroviral therapy. Although the majority of patients have evidence of slow increases in their CD4(+) cell count over time, many do not. These individuals may have an elevated risk of non-AIDS-related morbidity and mortality.

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The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance.

Terry Fry, Crystal Mackall (2005)

IL-7 is well known as a lymphopoietic cytokine, but recent studies have also identified a critical role for IL-7 in peripheral T cell homeostasis. IL-7 is well poised to serve as a homeostatic cytokine because it is produced by resting stromal cells, the IL-7R is present on most T cells, and IL-7 down-regulates its own receptor. These features allow IL-7 to signal large numbers of resting T cells and to be efficiently used when supplies are limiting. Consistent with this, in normal hosts, IL-7 is required for survival of naive T cell populations, and IL-7 contributes to homeostatic cycling of naive and memory cells. In addition, lymphopenic hosts accumulate increased levels of IL-7, and the supranormal levels are largely responsible for inducing homeostatic peripheral expansion in response to lymphopenia. Thus, IL-7 plays critical and nonredundant roles in both T cell lymphopoiesis and in maintaining and restoring peripheral T cell homeostasis.

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Author and article information

Contributors

Susanna Esposito: Role: Academic Editor

Tatsuo Kanda: Role: Academic Editor

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 22 March 2016

Publication date Collection: March 2016

Volume: 17

Issue: 3

Electronic Location Identifier: 413

Affiliations

[1 ]Department of Oncology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; chaoren72@ 123456126.com (L.Z.); nwgjb@ 123456163.com (J.G.); lln372@ 123456126.com (L.L.); yangoncology@ 123456163.com (Y.Y.)

[2 ]Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; xili72@ 123456163.com

[3 ]Department of Pathogenic Biology, Third Military Medical University, Chongqing 400037, China

Author notes

[* ]Correspondence: guobomail@ 123456gmail.com (B.G.); bo.zhu@ 123456tmmu.edu.cn (B.Z.); Tel.: +86-23-68755626 (B.G. & B.Z.)

[†]

These authors contributed equally to this work.

Article

Publisher ID: ijms-17-00413

DOI: 10.3390/ijms17030413

PMC ID: 4813265

PubMed ID: 27011165

SO-VID: 8c4e6dad-8bfb-4cde-b959-6d45ad3f27a3

License:

This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

Disrupted Homeostatic Cytokines Expression in Secondary Lymph Organs during HIV Infection

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Abstract

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Decoding Infection and Transmission

Most cited references 25

Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes.

Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment.

The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance.

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