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BMC Medicine
Published in: BMC Medicine 1/2018

Open Access 01-12-2018 | Research article

Class-modeling analysis reveals T-cell homeostasis disturbances involved in loss of immune control in elite controllers

Authors: José M. Benito, María C. Ortiz, Agathe León, Luis A. Sarabia, José M. Ligos, María Montoya, Marcial Garcia, Ezequiel Ruiz-Mateos, Rosario Palacios, Alfonso Cabello, Clara Restrepo, Carmen Rodriguez, Jorge del Romero, Manuel Leal, María A. Muñoz-Fernández, José Alcamí, Felipe García, Miguel Górgolas, Norma Rallón, On behalf of ECRIS integrated in the Spanish AIDS Research Network

Published in: BMC Medicine | Issue 1/2018

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Abstract

Background

Despite long-lasting HIV replication control, a significant proportion of elite controller (EC) patients may experience CD4 T-cell loss. Discovering perturbations in immunological parameters could help our understanding of the mechanisms that may be operating in those patients experiencing loss of immunological control.

Methods

A case–control study was performed to evaluate if alterations in different T-cell homeostatic parameters can predict CD4 T-cell loss in ECs by comparing data from EC patients showing significant CD4 decline (cases) and EC patients showing stable CD4 counts (controls). The partial least-squares–class modeling (PLS-CM) statistical methodology was employed to discriminate between the two groups of patients, and as a predictive model.

Results

Herein, we show that among T-cell homeostatic alterations, lower levels of naïve and recent thymic emigrant subsets of CD8 cells and higher levels of effector and senescent subsets of CD8 cells as well as higher levels of exhaustion of CD4 cells, measured prior to CD4 T-cell loss, predict the loss of immunological control.

Conclusions

These data indicate that the parameters of T-cell homeostasis may identify those EC patients with a higher proclivity to CD4 T-cell loss. Our results may open new avenues for understanding the mechanisms underlying immunological progression despite HIV replication control, and eventually, for finding a functional cure through immune-based clinical trials.
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Literature
1.
Sajadi MM, Constantine NT, Mann DL, Charurat M, Dadzan E, Kadlecik P, et al. Epidemiologic characteristics and natural history of HIV-1 natural viral suppressors. J Acquir Immune Defic Syndr. 2009;50:403–8.CrossRefPubMedPubMedCentral
2.
Autran B, Descours B, Avettand-Fenoel V, Rouzioux C. Elite controllers as a model of functional cure. Curr Opin HIV and AIDS. 2011;6:181–7.CrossRefPubMed
3.
Cockerham LR, Hatano H. Elite control of HIV: is this the right model for a functional cure? Trends Microbiol. 2015;23:71–5.CrossRefPubMed
4.
Shasha D, Walker BD. Lessons to be learned from natural control of HIV—future directions, therapeutic, and preventive implications. Front Immunol. 2013;4:1–8.CrossRef
5.
Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity. 2007;27:406–16.CrossRefPubMed
6.
Pereyra F, Addo M, Kaufmann DE, Liu Y, Miura T, Rathod A, et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis. 2008;197:563–71.CrossRefPubMed
7.
Walker BD, Yu XG. Unravelling the mechanisms of durable control of HIV-1. Nat Rev Immunol. 2013;13:487–98.CrossRefPubMed
8.
Madec Y, Boufassa F, Porter K, Meyer L. CASCADE collaboration. Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters. AIDS. 2005;19:2001–7.CrossRefPubMed
9.
Boufassa F, Saez-Cirión A, Lechenadec J, Zucman D, Avettand-Fenoel V, Venet A, et al. CD4 dynamics over a 15 year-period among HIV controllers enrolled in the ANRS French observatory. PLoS One. 2011;6:e18726.CrossRefPubMedPubMedCentral
10.
Noel N, Lerolle N, Lecuroux C, Goujard C, Venet A, Saez-Cirión A, et al. Immunologic and virologic progression in HIV controllers: the role of viral blips and immune activation in the ANRS CO21 CODEX study. PLoS One. 2015;10:e0131922.CrossRefPubMedPubMedCentral
11.
Leon A, Perez I, Ruiz-Mateos E, Benito JM, Leal M, Lopez-Galindez C, et al. Rate and predictors of progression in elite and viremic HIV-1 controllers. AIDS. 2016;30:1209–20.CrossRefPubMed
12.
13.
14.
15.
Hunt PW, Brenchey J, Sinclair E, McCune JM, Roland M, Page-Shafer K, et al. Relationship between T cell activation and CD4 T cell count in VIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008;197:126–33.CrossRefPubMedPubMedCentral
16.
López M, Soriano V, Peris-Pertusa A, Rallón N, Benito JM. Elite controllers display higher activation on central memory CD8 T cells than HIV patients successfully on HAART. AIDS Res Hum Retrovir. 2011;27:157–65.CrossRefPubMed
17.
Yang Y, Al-Mozaini M, Buzón MJ, Beamon J, Ferrando-Martínez S, Ruiz-Mateos E, et al. CD4 T cell regeneration in HIV-1 elite controllers. AIDS. 2012;26:701–6.CrossRefPubMedPubMedCentral
18.
Sajadi MM, Pulijala R, Redfield RR, Talwani R. Chronic immune activation and decreased CD4 counts associated with hepatitis C infection in HIV-1 natural viral suppressors. AIDS. 2012;26:1879–84.CrossRefPubMedPubMedCentral
19.
Sajadi MM, Redfield RR, Talwani R. Altered T-cell subsets in HIV-1 natural viral suppressors (elite controllers) with hepatitis C infection. AIDS. 2013;27:1989–95.CrossRefPubMedPubMedCentral
20.
Ramirez CM, Sinclair E, Epling L, Lee SA, Jain V, Hsue PY, et al. Immunologic profiles distinguish aviremic HIV-infected adults. AIDS. 2016;30:1553–62.CrossRefPubMedPubMedCentral
21.
Sobrino-Vegas P, Gutiérrez F, Berenguer J, Labarga P, et al. [The Cohort of the Spanish HIV Research Network (CoRIS) and its associated biobank; organizational issues, main findings and losses to follow-up.] In Spanish. Enferm Infecc Microbiol Clin. 2011;29:645–53.CrossRefPubMed
22.
García-Merino I, de Las CN, Jiménez JL, Gallego J, Gómez C, Prieto C, et al. Spanish HIV BioBank. The Spanish HIV BioBank: a model of cooperative HIV research. Retrovirology. 2009;6:27.CrossRefPubMedPubMedCentral
23.
Krishnan S, Wilson EM, Sheikh V, Rupert A, Mendoza D, Yang J, et al. Evidence for innate immune system activation in HIV type-1 elite controllers. J Infect Dis. 2014;209:931–9.CrossRefPubMed
24.
Pereyra F, Lo J, Triant V, Wei A, Buzon M, Fitch K, et al. Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers. AIDS. 2012;26:2409–12.CrossRefPubMedPubMedCentral
25.
Hsue PY, Hunt PW, Schnell A, Kalapus SC, Hoh R, Ganz P, et al. Role of viral replication, antiretroviral therapy and immunodeficiency in HIV-associated atherosclerosis. AIDS. 2009;23:1059–67.CrossRefPubMedPubMedCentral
26.
Crowell TA, Gebo KA, Blankson JN, Korthuis PT, Yehia BR, Rutsein RM, et al. Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection. J Infect Dis. 2012;211:1692–702.CrossRef
27.
Ruiz-Mateos E, Ferrando-Martínez S, Machmach K, Viciana P, Pacheco YM, Nogales N, et al. High levels of CD57+CD28- T-cells, low T-cell proliferation and preferential expansion of terminally differentiated CD4+ T-cells in HIV-elite controllers. Curr HIV Res. 2010;8:471–81.CrossRefPubMed
28.
Hunt PW, Landay AL, Sinclair E, Martinson JA, Hatano H, Emu B, et al. A low regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. PLoS One. 2011;6:e15924.CrossRefPubMedPubMedCentral
29.
Gattinoni L, Speiser DE, Lichterfeld M, Bonini C. T memory cells in health and disease. Nat Med. 2017;23:18–27.CrossRefPubMed
30.
31.
Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigkey MF, et al. A human memory T cell subset with stem cell-like properties. Nat Med. 2011;17:1290–7.CrossRefPubMedPubMedCentral
32.
Sanchez JL, Hunt PW, Reilly CS, Hatano H, Beilman GJ, Khoruts A, et al. Lymphoid fibrosis occurs in long-term nonprogressors and persists with antiretroviral therapy but may be reversible with curative interventions. J Infect Dis. 2015;211:1068–75.CrossRefPubMed
33.
Dominguez-Molina B, Tarancón-Diez L, Hua S, Abad-Molina C, Rodriguez-Gallego E, Machmach K, et al. HLA-B*57 and IFNL4-related polymorphisms are associated with protection against HIV-1 disease progression in controllers. Clin Infect Dis. 2017;64:321–8.
34.
Westrop SJ, Cocker ATH, Boasso A, Sullivan AK, Nelson MR, Imami N. Enrichment of HLA types and single-nucleotide polymorphism associated with non-progression in a strictly defined cohort of HIV-1 controllers. Front Immunol. 2017;8:746.CrossRefPubMedPubMedCentral
35.
Li JZ, Arnold KB, Lo J, Dugast AS, Plants J, Ribaudo HJ, et al. Differential levels of soluble inflammatory markers by human immunodeficiency virus controller status and demographics. Open Forum Infect Dis. 2015;2:ofu117.CrossRefPubMed
36.
Bansal A, Sterret S, Erdman N, Westfall AO, Dionne-Odom J, Overton ET, et al. Normal T-cell activation in elite controllers with preserved CD4+ T-cell counts. AIDS. 2015;29:2245–54.CrossRefPubMedPubMedCentral
37.
Kamya P, Tsoukas CM, Boulet S, Routy JP, Thomas R, Côte P, et al. T cell activation does not drive CD4 decline in longitudinally followed HIV-infected elite controllers. AIDS Res Ther. 2011;8:20–6.CrossRefPubMedPubMedCentral
38.
Pereyra F, Palmer S, Miura T, Block BL, Wiegand A, Rothchild AC, et al. Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters. J Infect Dis. 2009;200:984–90.CrossRefPubMedPubMedCentral
39.
Dock J, Effros RB. Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence. Aging Dis. 2011;2:382–97.PubMedPubMedCentral
40.
Dagarag M, Ng H, Lubong R, Effros RB, Yang OO. Differential impairment of lytic and cytokine functions in senescent human immunodeficiency virus type 1-specific cytotoxic T lymphocytes. J Virol. 2003;77:3077–83.CrossRefPubMedPubMedCentral
41.
Yang OO, Lin H, Dagarag M, Ng HL, Effros RB, Uittenbogaart CH. Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes. Virology. 2005;332:16–9.CrossRefPubMed
42.
Grabmeier-Pfistershammer K, Steinberger P, Rieger A, Leitner J, Kohrgruber N. Identification of PD-1 as a unique marker for failing immune reconstitution in HIV-1-infected patients on treatment. J Acquir Immune Defic Syndr. 2011;56:118–24.CrossRefPubMed
43.
Nakanjako D, Ssewanyana I, Mayanja-Kizza H, Kiragga A, Colebunders R, Manabe YC, et al. High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort. BMC Infect Dis. 2011;11:43.CrossRefPubMedPubMedCentral
Metadata
Title
Class-modeling analysis reveals T-cell homeostasis disturbances involved in loss of immune control in elite controllers
Authors
José M. Benito
María C. Ortiz
Agathe León
Luis A. Sarabia
José M. Ligos
María Montoya
Marcial Garcia
Ezequiel Ruiz-Mateos
Rosario Palacios
Alfonso Cabello
Clara Restrepo
Carmen Rodriguez
Jorge del Romero
Manuel Leal
María A. Muñoz-Fernández
José Alcamí
Felipe García
Miguel Górgolas
Norma Rallón
On behalf of ECRIS integrated in the Spanish AIDS Research Network
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2018
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-018-1026-6

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