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Transcriptional signature of resting-memory CD4 T cells differentiates spontaneous from treatment-induced HIV control

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Abstract

The HIV reservoir is the main barrier to eradicating HIV infection, and resting memory CD4 T (Trm) cells are one of the most relevant cellular component harboring latent proviruses. This is the first study analyzing the transcriptional profile of Trm cells, in two well-characterized groups of HIV patients with distinct mechanisms of viral replication control (spontaneous versus treatment-induced). We use a systems biology approach to unravel subtle but important differences in the molecular mechanisms operating at the cellular level that could be associated with the host’s ability to control virus replication and persistence. Despite the absence of significant differences in the transcriptome of Trm cells between Elite Controllers (ECs) and cART-treated (TX) patients at the single gene level, we found 353 gene ontology (GO) categories upregulated in EC compared with TX. Our results suggest the existence of mechanisms at two different levels: first boosting both adaptive and innate immune responses, and second promoting active viral replication and halting HIV latency in the Trm cell compartment of ECs as compared with TX patients. These differences in the transcriptional profile of Trm cells could be involved in the lower HIV reservoir observed in ECs compared with TX individuals, although mechanistic studies are needed to confirm this hypothesis. Combining transcriptome analysis and systems biology methods is likely to provide important findings to help us in the design of therapeutic strategies aimed at purging the HIV reservoir.

Key messages

  • HIV-elite controllers have the lowest HIV-DNA content in resting memory CD4 T cells.

  • HIV-ECs show a particular transcriptional profile in resting memory CD4 T cells.

  • Molecular mechanisms of enhanced adaptative and innate immune response in HIV-ECs.

  • High viral replication and low viral latency establishment associate to the EC status.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

cART:

Combination antiretroviral therapy

Ct:

Cycle threshold

ddPCR:

Digital droplet PCR

ECs:

Elite controllers

FDR:

False discovery rate

GO:

Gene ontology

GSE:

Gene set enrichment

HLA:

Human leukocyte antigen

HIV:

Human immunodeficiency virus

LRA:

Latency-reversing agent

LTNP:

Long-term nonprogressor

NK:

Natural killer

PBMC:

Peripheral blood mononuclear cell

PCA:

Principal component analysis

qRT-PCR:

Quantitative real-time PCR

Trm:

Resting memory CD4 T

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Acknowledgments

We would like to thank all participants and healthy donors who participated in the study.

Funding

This work was supported by projects CP14/00198, PI16/01769, and RD16/0025/0013, integrated into the State Plan for Scientific and Technical Research and Innovation from the General Sub-Directorate for research assessment and promotion, Spanish Carlos III Institute of Health (ISCIII) co-funded by the European Regional Development Fund (ERDF). Norma Rallón is a Miguel Servet II investigator from the ISCIII [grant CPII19/00025]. P Minguez is a Miguel Servet investigator [CP16/00116 grant]. S Morón-López was funded by a predoctoral fellowship from the Agència de Gestió d’Ajuts Universitaris i de Recerca [2013FI_B 00275]. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Clara Restrepo is funded by project RD16/0025/0013. Maria A Navarrete-Muñoz is funded by IND2018/BMD9651. M García was a predoctoral student co-funded by CP14/00198 project, and is currently co-funded by project RD16/0025/0013 and an Intramural Research Scholarship from IIS-FJD.

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Authors and Affiliations

  1. HIV and Viral Hepatitis Research Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), Av. Reyes Católicos, 2, 28040, Madrid, Spain

    Marcial García, Clara Restrepo, María A Navarrete-Muñoz, José M. Benito & Norma Rallón

  2. Hospital Universitario Rey Juan Carlos, Móstoles, Spain

    Marcial García, Clara Restrepo, María A Navarrete-Muñoz, José M. Benito & Norma Rallón

  3. Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

    Luis López-Fernández & María Isabel García

  4. Bioinformatics Unit, Genetics Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain

    Pablo Mínguez

  5. irsiCaixa AIDS Research Institute, Badalona, Spain

    Sara Morón-López & Javier Martínez-Picado

  6. Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Juan Carlos López-Bernaldo

  7. Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    Alberto Benguría

  8. Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain

    Alfonso Cabello, Manuel Fernández-Guerrero, Francisco Javier De la Hera & Miguel Górgolas

  9. Hospital Universitario Clínico San Carlos, Madrid, Spain

    Vicente Estrada

  10. Hospital Universitario de Móstoles, Móstoles, Spain

    Carlos Barros

  11. University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain

    Javier Martínez-Picado

  12. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

    Javier Martínez-Picado

Authors
  1. Marcial García
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  2. Luis López-Fernández
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  3. Pablo Mínguez
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  4. Sara Morón-López
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  5. Clara Restrepo
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  6. María A Navarrete-Muñoz
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  7. Juan Carlos López-Bernaldo
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  8. Alberto Benguría
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  9. María Isabel García
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  10. Alfonso Cabello
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  11. Manuel Fernández-Guerrero
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  12. Francisco Javier De la Hera
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  13. Vicente Estrada
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  14. Carlos Barros
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  15. Javier Martínez-Picado
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  16. Miguel Górgolas
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  17. José M. Benito
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  18. Norma Rallón
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Contributions

Conceptualization, JMB and NR. Data curation, JCLB, AC, MFG, FJDH, VE, CB, and MGo. Formal analysis, MG, LLF, PM, SML, JMP, JMB, and NR. Funding acquisition, JMB and NR. Investigation, MG, SML, AB, CR, MANM, and MIG. Methodology, LLF, JMP, JMB, and NR. Project administration, JMB and NR. Resources, JCLB, AC, MFG, FJDH, VE, CB, and MGo. Software, MG, LLF, PM, JMB, and NR. Supervision, JMB and NR. Validation, JMB and NR. Visualization, JMB and NR. Writing the original draft, MG, LLF, PM, SML, JMP, JMB, and NR. Writing, review, and editing, JMB and NR.

Corresponding authors

Correspondence to José M. Benito or Norma Rallón.

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The authors declare that they have no competing interests.

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Clinical perspectives

• Background

The HIV reservoir is the main barrier to eradicate HIV infection, being resting memory CD4 T (Trm) cells one of the most relevant cellular component harboring latent proviruses. Previous studies have reported a smaller HIV reservoir size in the special group of HIV-infected individuals able to spontaneously control viral replication (elite controllers (EC)) compared with well-suppressed HIV individuals on cART and viremic progressors. However, the specific intrinsic mechanisms of the EC subjects intervening in the viral reservoir control have not been evaluated in these Trm cells.

• Results

Our results show a particular transcriptional profile with specific biological pathways in the Trm cells of the EC subjects, different to that associated to individuals with antiretroviral treatment-induced control. Our data suggest that molecular mechanisms involving enhanced adaptative and innate immune response, high viral genome replication, and low viral latency establishment could promote the EC status and could be related to the reduced HIV reservoir size observed in these individuals.

•Potential significance of the results to human health and disease: These findings highlight the relevance of combining transcriptome analysis and systems biology methods to provide important findings to help us in the design of therapeutic strategies aimed at purging the HIV reservoir and achieve HIV remission.

Electronic supplementary materials

ESM 1

Representative flow cytometry of immuno-magnetic purification of Trm cells (defined as CD4+CD45RO+CD69-CD25-HLADR- cells). The gating strategy and percentages of different T cell populations are shown (PNG 4948 kb)

High Resolution Image (TIF 144 kb)

ESM 2

The characteristics of HIV-infected individuals included in the study (DOCX 14 kb)

ESM 3

List of GO biological processes upregulated in EC compared with TX individuals. Processes are ordered by GO code (DOCX 332 kb)

ESM 4

List of GO biological processes upregulated in TX compared with EC individuals. Processes are ordered by GO code (DOCX 220 kb)

ESM 5

List of GO biological processes upregulated in ECs compared with HC subjects. Processes are ordered by GO code (DOCX 299 kb)

ESM 6

List of GO biological processes upregulated in TX individuals compared with HC subjects. Processes are ordered by GO code (DOCX 176 kb)

ESM 7

GO biological processes related to the immune system are overrepresented in EC individuals compared with HC subjects. a Proportions of the immune system and non-immune system GO biological processes upregulated in Trm cells of EC versus HC (gray-toned left graph) and categories of immune system GO processes (color-coded right graph). b Proportions of the immune system and non-immune system GO biological processes upregulated in Trm cells of TX individuals versus HC (gray-toned left graph) and categories of immune system GO processes (color-coded right graph). EC, elite controllers; TX, cART-suppressed non-controllers; HC, healthy controls (PNG 4948 kb)

High Resolution Image (TIF 4392 kb)

ESM 8

List of GO biological processes upregulated in EC compared with TP individuals. Processes are ordered by GO code (DOCX 185 kb)

ESM 9

List of GO biological processes upregulated in TX compared with TP individuals. Processes are ordered by GO code (DOCX 166 kb)

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García, M., López-Fernández, L., Mínguez, P. et al. Transcriptional signature of resting-memory CD4 T cells differentiates spontaneous from treatment-induced HIV control. J Mol Med 98, 1093–1105 (2020). https://doi.org/10.1007/s00109-020-01930-x

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  • DOI: https://doi.org/10.1007/s00109-020-01930-x

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