Elite Control of HIV Is Associated With Distinct Functional and Transcriptional Signatures in Lymphoid Tissue CD8 + T Cells

Son Nguyen1, Claire Deleage2, Samuel Darko3, Amy Ransier3, Duc P Truong4, Divyansh Agarwal5, Alberto Sada Japp1, Vincent H Wu1, Leticia Kuri-Cervantes1, Mohamed Abdel-Mohsen6, Perla M Del Rio Estrada7, Yuria Ablanedo-Terrazas7, Emma Gostick8, James A Hoxie9, Nancy R Zhang5, Ali Naji10, Gustavo Reyes-Terán7, Jacob D Estes11,12, David A Price8, Daniel C Douek3, Steven G Deeks13, Marcus Buggert14, Michael R Betts15

  1. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  2. AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
  3. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  4. Department of Mathematics, Southern Methodist University, Dallas, TX 75205, USA.
  5. Department of Statistics, University of Pennsylvania, Philadelphia, PA 19104, USA.
  6. The Wistar Institute, Philadelphia, PA 19104, USA.
  7. Departamento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City 14080, Mexico.
  8. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
  9. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  10. Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  11. Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR 97239, USA.
  12. Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University, Portland, OR 97239, USA.
  13. Department of Medicine, University of California, San Francisco General Hospital, San Francisco, CA 94110, USA.
  14. Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
  15. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. betts@pennmedicine.upenn.edu.

Abstract

The functional properties of circulating CD8+ T cells have been associated with immune control of HIV. However, viral replication occurs predominantly in secondary lymphoid tissues, such as lymph nodes (LNs). We used an integrated single-cell approach to characterize effective HIV-specific CD8+ T cell responses in the LNs of elite controllers (ECs), defined as individuals who suppress viral replication in the absence of antiretroviral therapy (ART). Higher frequencies of total memory and follicle-homing HIV-specific CD8+ T cells were detected in the LNs of ECs compared with the LNs of chronic progressors (CPs) who were not receiving ART. Moreover, HIV-specific CD8+ T cells potently suppressed viral replication without demonstrable cytolytic activity in the LNs of ECs, which harbored substantially lower amounts of CD4+ T cell-associated HIV DNA and RNA compared with the LNs of CPs. Single-cell RNA sequencing analyses further revealed a distinct transcriptional signature among HIV-specific CD8+ T cells from the LNs of ECs, typified by the down-regulation of inhibitory receptors and cytolytic molecules and the up-regulation of multiple cytokines, predicted secreted factors, and components of the protein translation machinery. Collectively, these results provide a mechanistic framework to expedite the identification of novel antiviral factors, highlighting a potential role for the localized deployment of noncytolytic functions as a determinant of immune efficacy against HIV.

Presented By Son Nguyen

Immunology & Microbiology, MedicineNicholas Liao2019-12 (Dec)