Genetic variation in  CCR2  and  CXCL12  genes impacts on CD4 restoration in patients initiating cART with advanced immunesupression

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Abstract

Objective

We investigated the association of genetic polymorphisms in chemokine and chemokine receptor genes with poor immunological recovery in HIV patients starting combined antiretroviral therapy (cART) with low CD4 T-cell counts.

Methods

A case-control study was conducted in 412 HIV-infected patients starting cART with CD4 T-cell count <200 cells/μL and successful viral control for two years. CD4 count increase below 200 cells/μL after two years on cART was used to define INR (immunological non-responder) patients. Polymorphisms in CXCL12, CCL5 and CCR2 genes were genotyped using sequenom’s MassARRAY platform.

Results

Thirty two percent (134/412) of patients were classified as INR. After adjusting by age, route of HIV infection, length of infection before cART and viral hepatitis coinfection, CCR2 rs1799864-AG genotype was significantly associated with INR status (OR [95% CI]: 1.80 [1.04–3.11]; p = 0.04), and CXCL12 rs1801157-TT genotype showed a trend (OR [95% CI]: 2.47 [0.96–6.35]; p = 0.06).

Conclusions

CCR2 rs1799864-AG or CXCL12 rs1801157-TT genotypes influence on the probability of poor CD4 recovery in the population of HIV patients starting cART with low CD4 counts. Genotyping of these polymorphisms could be used to estimate the risk of poor CD4 restoration, mainly in patients who are diagnosed late in the course of infection.

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Most cited references 35

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The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1.

E. Oberlin, A. Amara, F Bachelerie … (1996)

A putative chemokine receptor that we previously cloned and termed LESTR has recently been shown to function as a co-receptor (termed fusin) for lymphocyte-tropic HIV-1 strains. Cells expressing CD4 became permissive to infection with T-cell-line-adapted HIV-1 strains of the syncytium-inducing phenotype after transfection with LESTR/fusin complementary DNA. We report here the indentification of a human chemokine of the CXC type, stromal cell-derived factor 1 (SDF-1), as the natural ligand for LESTR/fusin, and we propose the term CXCR-4 for this receptor, in keeping with the new chemokine-receptor nomenclature. SDF-1 activates Chinese hamster ovary (CHO) cells transfected with CXCR-4 cDNA as well as blood leukocytes and lymphocytes. In cell lines expressing CXCR-4 and CD4, and in blood lymphocytes, SDF-1 is a powerful inhibitor of infection by lymphocyte-tropic HIV-1 strains, whereas the CC chemokines RANTES, MIP-1 alpha and MIP-1 beta, which were shown previously to prevent infection with primary, monocyte-tropic viruses, are inactive. In combination with CC chemokines, which block the infection with monocyte/macrophage-tropic viruses, SDF-1 could help to decrease virus load and prevent the emergence of the syncytium-inducing viruses which are characteristic of the late stages of AIDS.

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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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CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression.

Robert Moore, Jeanne Keruly (2007)

Sustained suppression of the human immunodeficiency virus (HIV) type 1 RNA load with the use of highly active antiretroviral therapy (HAART) results in immunologic improvement, but it is not clear whether the CD4(+) cell count increases to normal levels or whether it reaches a less-than-normal plateau. We characterized the increase in the CD4(+) cell count in patients in clinical practice who maintained sustained viral suppression for up to 6 years. All patients were from the Johns Hopkins HIV Clinical Cohort, a longitudinal observational study of patients receiving primary HIV care in Baltimore, Maryland, who were observed for >1 year while receiving HAART and who had sustained suppression of the HIV RNA load at 350 cells/microL, and we assessed the development of clinical events (death and new acquired immunodeficiency syndrome-defining illness) by Kaplan-Meier analysis. A total of 655 patients were observed for a median of 46 months (range, 13-72 months). The median change from baseline to most recent CD4(+) cell count was +274 cells/microL, with 92% of patients having an increase in CD4(+) cell count. By 6 years, the median CD4(+) cell count was 493 cells/microL among patients with baseline CD4(+) cell counts 350 cells/microL. In addition to baseline CD4(+) cell count, injection drug use and older age were associated with a lesser CD4(+) cell count response, and duration of therapy was associated with a greater CD4(+) cell count response. Only patients with baseline CD4(+) cell counts >350 cells/microL returned to nearly normal CD4(+) cell counts after 6 years of follow-up. Significant increases were observed in all CD4(+) cell count strata during the first year, but there was a lower plateau CD4(+) cell count at lower baseline CD4(+) cell strata. These data suggest that waiting to start HAART at lower CD4(+) cell counts will result in the CD4(+) cell count not returning to normal levels.

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Author and article information

Contributors

Clara Restrepo: Role: Writing – original draft

Mónica Gutierrez-Rivas: Role: Methodology

Yolanda M. Pacheco: Role: Conceptualization

Marcial García: Role: Methodology

Julià Blanco: Role: Conceptualization

Luz M. Medrano: Role: Methodology

María A. Navarrete-Muñoz: Role: Methodology

Félix Gutiérrez: Role: Data curationRole: Resources

Pilar Miralles: Role: Data curationRole: Resources

David Dalmau: Role: Data curationRole: Resources

Juan Luis Gómez: Role: Data curationRole: Resources

Miguel Górgolas: Role: Data curationRole: Resources

Alfonso Cabello: Role: Data curationRole: Resources

Salvador Resino:

ORCID: http://orcid.org/0000-0001-8783-0450

Role: ConceptualizationRole: Formal analysis

José M. Benito:

ORCID: http://orcid.org/0000-0002-7172-049X

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Norma Rallón: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Golo Ahlenstiel: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 28 March 2019

Publication date Collection: 2019

Volume: 14

Issue: 3

Electronic Location Identifier: e0214421

Affiliations

[1 ] HIV and Viral Hepatitis Research Laboratory, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain

[2 ] Hospital Universitario Rey Juan Carlos, Móstoles (Madrid), Spain

[3 ] Instituto de Salud Carlos III, Madrid, Spain

[4 ] Laboratory of Immunology, Instituto de Biomedicina de Sevilla (IBiS)/UGC Clinical Laboratories, Hospital Universitario Virgen del Rocío, Sevilla, Spain

[5 ] IrsiCaixa AIDS Research Institute, Badalona, Spain

[6 ] Hospital General Universitario de Elche & University Miguel Hernández, Alicante, Spain

[7 ] Hospital General Universitario Gregorio Marañón, Madrid, Spain

[8 ] Hospital Universitari Mutua Terrasa, Terrasa, Spain

[9 ] Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain

[10 ] Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain

Western Sydney University, AUSTRALIA

Author notes

Competing Interests: The authors have declared that no competing interests exist.

‡ These authors also contributed equally to this work.

¶ The clinical centers and research groups that contribute to CoRIS and HIV Biobank are shown in S1 Text. Lead author for this group: MA Muñoz-Fernández, Laboratory of Molecular Immuno-Biology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. e-mail: mmunoz.hgugm@ 123456gmail.com

* E-mail: jbenito1@ 123456hotmail.com , jose.benito@ 123456fjd.es (JMB); Sresino@ 123456isciii.es (SR)

Author information

Salvador Resino http://orcid.org/0000-0001-8783-0450

José M. Benito http://orcid.org/0000-0002-7172-049X

Article

Publisher ID: PONE-D-18-36250

DOI: 10.1371/journal.pone.0214421

PMC ID: 6438540

PubMed ID: 30921390

SO-VID: 98ff1a42-7fa3-4ee0-825e-0ebb3d32471b

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 19 December 2018

Date accepted : 12 March 2019

Page count

Figures: 1, Tables: 3, Pages: 13

Funding

This work has been (partially) funded by the Spanish AIDS Research Network RD12/0017/0031, RD16/0025/0013, RD16CIII/0002/0002, and PI14CIII/00011 projects as part of the Health Research and Development Strategy, State Plan for Scientific and Technical Research and Innovation (2008-2011, 2013-2016) and co-financed by Institute of Health Carlos III, ISCIII-Sub-Directorate General for Research Assessment and Promotion and European Regional Development Fund (ERDF). M Gutierrez-Rivas is funded by project RD16CIII/0002/0002. LM Medrano is supported by IISCIII, grant CD14/00002. F. Gutiérrez is supported by ISCIII, grants PI08/893, PI13/02256 and PI16/01740; FISABIO, grants UGP-14-197 and UGP-15-232, and RD16/0025/0038. N Rallón is a Miguel Servet investigator from the ISCIII (grant CP14/00198), Madrid, Spain. MA Navarrete-Muñoz is co-funded by RD16/0025/0013 project and Intramural Research Scholarship from IIS-FJD. M García is co-funded by CP14/00198 project and Intramural Research Scholarship from IIS-FJD. C Restrepo was funded by project RD12/0017/0031 and currently is funded by project RD16/0025/0013.

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Data Availability All relevant data are within the manuscript and its Supporting Information files.

Genetic variation in CCR2 and CXCL12 genes impacts on CD4 restoration in patients initiating cART with advanced immunesupression

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Abstract

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Conclusions

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Most cited references 35

The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1.

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

CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression.

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