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.
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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.
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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.
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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.
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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.
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.
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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
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DOI: https://doi.org/10.1038/nature21710
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