Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses

A Corrigendum to this article was published on 29 June 2017

Abstract

The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV1,2,3. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells. Notably, productive HIV-1 infection of T-cell-receptor-stimulated CD4 T cells is not associated with CD32a expression, suggesting that a quiescence-dependent mechanism is required for its induction. Using blood samples from HIV-1-positive participants receiving suppressive antiretroviral therapy, we identify a subpopulation of 0.012% of CD4 T cells that express CD32a and host up to three copies of HIV DNA per cell. This CD32a+ reservoir was highly enriched in inducible replication-competent proviruses and can be predominant in some participants. Our discovery that CD32a+ lymphocytes represent the elusive HIV-1 reservoir may lead to insights that will facilitate the specific targeting and elimination of this reservoir.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The gene expression signature of latently HIV-1-infected quiescent CD4 T cells.
Figure 2: CD32a is specifically induced at the surface of HIV-infected quiescent CD4 T lymphocytes.
Figure 3: CD32a identifies CD4 T-cell reservoir harbouring inducible replication-competent HIV-1 in ART-treated participants

References

  1. 1

    Chun, T. W. et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 94, 13193–13197 (1997)

    CAS  Article  ADS  Google Scholar 

  2. 2

    Chun, T. W., Davey, R. T., Jr, Engel, D., Lane, H. C. & Fauci, A. S. Re-emergence of HIV after stopping therapy. Nature 401, 874–875 (1999)

    CAS  Article  ADS  Google Scholar 

  3. 3

    Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997)

    CAS  Article  ADS  Google Scholar 

  4. 4

    Zack, J. A. et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 61, 213–222 (1990)

    CAS  Article  Google Scholar 

  5. 5

    Stevenson, M., Stanwick, T. L., Dempsey, M. P. & Lamonica, C. A. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J . 9, 1551–1560 (1990)

    CAS  Article  Google Scholar 

  6. 6

    Chomont, N. et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat. Med . 15, 893–900 (2009)

    CAS  Article  Google Scholar 

  7. 7

    Laguette, N. et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474, 654–657 (2011)

    CAS  Article  Google Scholar 

  8. 8

    Berger, A. et al. SAMHD1-deficient CD14+ cells from individuals with Aicardi-Goutières syndrome are highly susceptible to HIV-1 infection. PLoS Pathog . 7, e1002425 (2011)

    CAS  Article  Google Scholar 

  9. 9

    Hrecka, K. et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474, 658–661 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Descours, B. et al. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4+ T-cells. Retrovirology 9, 87 (2012)

    CAS  Article  Google Scholar 

  11. 11

    Baldauf, H. M. et al. SAMHD1 restricts HIV-1 infection in resting CD4+ T cells. Nat. Med . 18, 1682–1687 (2012)

    CAS  Article  Google Scholar 

  12. 12

    Cribier, A., Descours, B., Valadão, A. L., Laguette, N. & Benkirane, M. Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1. Cell Reports 3, 1036–1043 (2013)

    CAS  Article  Google Scholar 

  13. 13

    Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol . 8, 34–47 (2008)

    CAS  Article  Google Scholar 

  14. 14

    Guilliams, M., Bruhns, P., Saeys, Y., Hammad, H. & Lambrecht, B. N. The function of Fcγ receptors in dendritic cells and macrophages. Nat. Rev. Immunol . 14, 94–108 (2014)

    CAS  Article  Google Scholar 

  15. 15

    Laird, G. M. et al. Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. PLoS Pathog . 9, e1003398 (2013)

    CAS  Article  Google Scholar 

  16. 16

    Ho, Y. C. et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155, 540–551 (2013)

    CAS  Article  Google Scholar 

  17. 17

    Cohn, L. B. et al. HIV-1 integration landscape during latent and active infection. Cell 160, 420–432 (2015)

    CAS  Article  Google Scholar 

  18. 18

    Bournazos, S. et al. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158, 1243–1253 (2014)

    CAS  Article  Google Scholar 

  19. 19

    Bruel, T. et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat. Commun . 7, 10844 (2016)

    CAS  Article  ADS  Google Scholar 

  20. 20

    Horwitz, J. A. et al. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc. Natl Acad. Sci. USA 110, 16538–16543 (2013)

    CAS  Article  ADS  Google Scholar 

  21. 21

    Avettand-Fènoël, V. et al. LTR real-time PCR for HIV-1 DNA quantitation in blood cells for early diagnosis in infants born to seropositive mothers treated in HAART area (ANRS CO 01). J. Med. Virol. 81, 217–223 (2009)

    Article  Google Scholar 

  22. 22

    Pereira Bittencourt Passaes, C . et al. Ultrasensitive HIV-1 p24 detects single infected cells and differences in reservoir induction by latency-reversal agents. J. Virol. 91, e.02296-16 (2017)

  23. 23

    Rosenbloom, D. I . et al. Designing and interpreting limiting dilution assays: general principles and applications to the latent reservoir for Human Immunodeficiency Virus-1. Open Forum Infect. Dis. 2, ofv123 (2015)

    Article  Google Scholar 

Download references

Acknowledgements

We thank the participants enrolled in this study. We thank members of the Molecular Virology laboratory for critical reading of the manuscript, J. Venables for editing the manuscript, MRI platform for FACSAria cell sorting. We are grateful to J.-F. Delfraissy and F. Barré-Sinoussi for their continuous support. This work was supported by grants from the European FP7 contract 305762, MSDAvenir, ANRS and FRM ‘équipe labéllisée’ and Labex EpiGenMed to M.B. G.P was supported by FRM fellowships; B.D. and R.R. by ANRS fellowships. T.B. was supported by a Vaccine Research Institute (VRI) fellowship. O.S was supported by grants from ANRS, VRI, Labex IBEID, Sidaction, European FP7 contract 305762 and Institut Pasteur.

Author information

Affiliations

Authors

Contributions

M.B. conceived the study. M.B., G.P. and B.D. designed experiments, interpreted data and wrote the paper. R.R. analysed the RNA-seq data. T.B. and O.S. performed highly sensitive p24 assays. J.D.L., J.-L.L.-Z., C.L., C.P., J.R. and Y.L. recruited participants and collected blood samples. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Benjamin Descours, Gaël Petitjean or Monsef Benkirane.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reviewer Information Nature thanks N. Chomont, F. Nimmerjahn, D. Richman, G. Silvestri and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Figure 1 Cellular pathways significantly modulated in latently infected quiescent CD4 T cells compared to bystanders and non-infected cells.

a, b, Biological pathway analysis using REACTOME (a) or STRING (b) databases for the 103 genes differentially expressed in XH+ compared to XH and non-infected cells.

Source data

Extended Data Figure 2 Flow cytometry dot plots and gating strategy for cell sorting of CD32ahi, CD32aint and CD32a CD4 T lymphocytes subsets from 10 HIV-1 infected participants.

When available similar number of events were displayed in CD32a staining than in isotype control. Note that for patient 566, the cell-sorting strategy was designed by selecting a threshold on CD3 positivity.

Extended Data Figure 3 Contribution of CD32a+ CD4 T cells to the inducible viral reservoir contained in total CD4 T cells.

qVOA was performed using CD32a and total CD4 T cell isolated from participant 769.

Source data

Related audio

Supplementary information

Supplementary Data

This file contains Supplementary Table 1. (XLSX 4517 kb)

Supplementary Data

This file contains Supplementary Table 2. (XLSX 16 kb)

Supplementary Data

This file contains Supplementary Tables 3 and 4. (PDF 166 kb)

PowerPoint slides

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Descours, B., Petitjean, G., López-Zaragoza, JL. et al. CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses. Nature 543, 564–567 (2017). https://doi.org/10.1038/nature21710

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing