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PD-1+ and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals

Nature Medicine volume 22, pages 754–761 (2016)Cite this article

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Abstract

The mechanisms responsible for the persistence of HIV-1 after many years of suppressive antiretroviral therapy (ART) have been only partially elucidated. Most of the studies investigating HIV-1 persistence have been performed with blood, although it is well known that germinal centers (GCs) within lymph nodes (LNs) serve as primary sites for HIV-1 replication. We sought to identify the memory CD4 T cell populations in blood and LNs that are responsible for the production of replication-competent and infectious HIV-1, as well as for active and persistent virus transcription in ART-treated (for 1.5–14.0 years), aviremic (<50 HIV RNA copies/ml) HIV-infected individuals. We demonstrate that LN CD4 T cells that express programmed cell death 1 (PDCD1; also known as PD-1), which are composed of about 65% T follicular helper cells as defined by the expression of the cell surface receptors CXCR5 and PD-1, are the major source of replication-competent HIV-1 and of infectious virus, as compared to any other (CXCR5−PD-1− and CXCR5+PD-1−) blood or LN memory CD4 T cell populations. LN PD-1+ cells accounted for 46% and 96% of the total pools of memory CD4 T cells containing inducible replication-competent or infectious virus, respectively. Notably, higher levels of cell-associated HIV-1 RNA were present in LN PD-1+ cells after long-term (up to 12 years) ART than in other memory CD4 T cell subpopulations. These results indicate that LN PD-1+ cells are the major CD4 T cell compartment in the blood and LNs for the production of replication-competent and infectious HIV-1, and for active and persistent virus transcription in long-term-ART-treated aviremic individuals. Thus, these cells may represent a major obstacle to finding a functional cure for HIV-1 infection.

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Figure 1: HIV replication and production of memory CD4 T cell populations in blood and LNs.
Figure 2: The levels of HIV-1 RNA and P24 from LN PD-1+/TFH cells inversely correlate with duration of treatment.
Figure 3: Detection of cell-associated HIV-1 RNA in LN PD-1+/TFH cells of long-term-ART-treated aviremic HIV-1-infected individuals.
Figure 4: Histopathological changes associated with long-term ART in LN tissues.
Figure 5: LN PD-1+ TFH cells of long-term-treated aviremic HIV-1-infected individuals are enriched for replication-competent and infectious virus.

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Acknowledgements

We are grateful to N. Grandchamp, P. Pochon, X. Bron, M. Graff, A. Crétignier, R. Mamin, F. Bellanger, L. Leuenberger and C. André for technical assistance, and to D. Alves and the study manager N. Rettby. This work was funded by an educational grant from Bristol-Myers Squibb (M.P.).

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Authors and Affiliations

  1. Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

    Riddhima Banga, Francesco Andrea Procopio, Alessandra Noto, Khalid Ohmiti, Giuseppe Pantaleo & Matthieu Perreau

  2. Department of Clinical Infection, Microbiology and Immunology (CIMI), Institute of Infection and Global Health (IGH), University of Liverpool, Liverpool, UK

    Georgios Pollakis

  3. Service of Infectious Diseases, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

    Matthias Cavassini

  4. Service of Vascular Surgery, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

    Jean-Marc Corpataux

  5. Institute of Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

    Laurence de Leval

  6. Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

    Giuseppe Pantaleo

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  1. Riddhima Banga
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  10. Matthieu Perreau
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Contributions

R.B., F.A.P. and A.N. performed the experiments; G. Pollakis performed and analyzed HIV sequencing; M.C. recruited patients; K.O. performed statistical analyses; J.-M.C. performed lymph node biopsies; L.d.L. was in charge of immunohistochemistry experiments; G. Pantaleo and M.P. conceived the study, designed the experiments and wrote the manuscript.

Corresponding authors

Correspondence to Giuseppe Pantaleo or Matthieu Perreau.

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The authors declare no competing financial interests.

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Banga, R., Procopio, F., Noto, A. et al. PD-1+ and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat Med 22, 754–761 (2016). https://doi.org/10.1038/nm.4113

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