CD8⁺CD28^?CD127^loCD39⁺ regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection? - 06/06/18

Doi : 10.1016/j.jaci.2017.08.021

Daniela Fenoglio, PhD ^a,^b,^c,^{^{∗
These authors contributed equally to this work.}}, Chiara Dentone, MD ^a,^d,^{^{∗
These authors contributed equally to this work.}}, Alessio Signori, PhD ^e, Antonio Di Biagio, MD ^f, Alessia Parodi, PhD ^a, Francesca Kalli, PhD ^a, Giorgia Nasi, PhD ^a, Monica Curto, PhD ^a, Giovanni Cenderello, MD ^g, Pasqualina De Leo, MD ^h, Valentina Bartolacci, MD ⁱ, Giancarlo Orofino, MD ^j, Laura Ambra Nicolini, MD ^e,^f, Lucia Taramasso, MD ^f, Edoardo Fiorillo, PhD ^k, Valeria Orrù, PhD ^k, Paolo Traverso, MD ^a,^c,^l, Bianca Bruzzone, MD ^m, Federico Ivaldi, PhD ^a, Eugenio Mantia, MD ⁿ, Michele Guerra, MD ^o, Simone Negrini, MD ^a,^b,^c, Mauro Giacomini ^a,^p, Sanjay Bhagani, MD, FRCP ^q, Gilberto Filaci, MD ^a,^b,^c,^⁎
^a Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
^b Department of Internal Medicine, University of Genoa, Genoa, Italy
^e Department of Health Sciences, University of Genoa, Genoa, Italy
^l Department of Surgical Science and Integrated Diagnostics, University of Genoa, Genoa, Italy
^p Department of Informatics, Bioengineering, Robotic and System Engineering, University of Genoa, Genoa, Italy
^c IRCCS Azienda Ospedaliero Universitaria San Martino, IST–Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
^f Infectious Disease Unit, IRCCS Azienda Ospedaliero Universitaria San Martino, IST–Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
^m Hygiene Unit, Infectious Disease Unit, IRCCS Azienda Ospedaliero Universitaria San Martino, IST–Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
^d Infectious Diseases Department, Sanremo Hospital, Imperia, Italy
^g Infectious Diseases Department, Galliera Hospital, Genoa, Italy
^h Infectious Diseases Department, San Paolo Hospital, Savona, Italy
ⁱ S.M. Misericordia Hospital, Albenga, Italy
^j Infectious Diseases Department, Amedeo di Savoia Hospital, Turin, Italy
^k Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Sede Secondaria IRGB, Lanusei, Italy
ⁿ Infectious Diseases Department, SS Antonio, Biagio, Cesare Arrigo Hospital, Alessandria, Italy
^o Infectious Diseases Department, Sant'Andrea Hospital, La Spezia, Italy
^q Department of Infectious Diseases/HIV Medicine, Royal Free Hospital, National Health Service, London, United Kingdom

^∗Corresponding author: Gilberto Filaci, MD, Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV no. 7, 16132 Genoa, Italy.Centre of Excellence for Biomedical Research (CEBR)University of GenoaViale Benedetto XV no. 7Genoa16132Italy

Abstract

Background

HIV-associated immunodeficiency is related to loss of CD4⁺ T cells. This mechanism does not explain certain manifestations of HIV disease, such as immunodeficiency events in patients with greater than 500 CD4⁺ T cells/μL. CD8⁺CD28⁻CD127^loCD39⁺ T cells are regulatory T (Treg) lymphocytes that are highly concentrated within the tumor microenvironment and never analyzed in the circulation of HIV-infected patients.

Objectives

We sought to analyze the frequency of CD8⁺CD28⁻CD127^loCD39⁺ Treg cells in the circulation of HIV-infected patients.

Methods

The frequency of circulating CD8⁺CD28⁻CD127^loCD39⁺ Treg cells was analyzed and correlated with viral load and CD4⁺ T-cell counts/percentages in 93 HIV-1–infected patients subdivided as follows: naive (n = 63), elite controllers (n = 19), long-term nonprogressors (n = 7), and HIV-infected patients affected by tumor (n = 4). The same analyses were performed in HIV-negative patients with cancer (n = 53), hepatitis C virus–infected patients (n = 17), and healthy donors (n = 173).

Results

HIV-infected patients had increased circulating levels of functional CD8⁺CD28⁻CD127^loCD39⁺ Treg cells. These cells showed antigen specificity against HIV proteins. Their frequency after antiretroviral therapy (ART) correlated with HIV viremia, CD4⁺ T-cell counts, and immune activation markers, suggesting their pathogenic involvement in AIDS- or non–AIDS-related complications. Their increase after initiation of ART heralded a lack of virologic or clinical response, and hence their monitoring is clinically relevant.

Conclusion

HIV infection induces remarkable expansion of CD8⁺CD28⁻CD127^loCD39⁺ Treg cells, the frequency of which correlates with both clinical disease and signs of chronic immune cell activation. Monitoring their frequency in the circulation is a new marker of response to ART when effects on viremia and clinical response are not met.

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Graphical abstract

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Key words : HIV, CD8⁺CD28⁻CD127^loCD39⁺ regulatory T cell, antiretroviral therapy

Abbreviations used : APC, ART, BV, EC, FITC, HCV, LTNP, PE, PerCP-Cy5.5, Treg

Plan

Methods

Patients

Measurement of plasma viral load in HIV-infected patients

Purification of PBMCs and tumor lymphocyte infiltrates

mAbs and immunofluorescence analyses

Evaluation of HLA-A2–positive patients

Frequency of gag-specific CD8⁺ T lymphocytes

Sorting of CD8⁺CD28⁻CD127^loCD39⁺ Treg cells

Proliferation suppression assay

Statistical analyses

Results

Increased CD8⁺CD28⁻CD127^loCD39⁺ Treg cell frequencies in the circulation of chronically HIV-infected patients with viremia controlled by therapy

Induction of CD8⁺CD28⁻CD127^loCD39⁺ Treg cells is HIV related

CD8⁺CD28⁻CD127^loCD39⁺ Treg cell frequency is a possible biomarker of HIV infection

Correlation between CD8⁺CD28⁻CD127^loCD39⁺ Treg cell frequency and immune activation

Discussion

	Supported by a grant from Ministero dell'Istruzione, dell'Università e della Ricerca, PRIN no. 2008WXF7KK entitled “Immunoterapia anti-tumorale operata attraverso l'inibizione dei circuiti regolatori citochino-dipendenti.”
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 141 - N° 6

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CD8⁺CD28^?CD127^loCD39⁺ regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection? - 06/06/18

Abstract

Background

Objectives

Methods

Results

Conclusion

Graphical abstract

Plan

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