Frontiers in Immunology (Oct 2022)
HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control
- Rabiah Fardoos,
- Rabiah Fardoos,
- Sarah K. Nyquist,
- Sarah K. Nyquist,
- Osaretin E. Asowata,
- Samuel W. Kazer,
- Alveera Singh,
- Abigail Ngoepe,
- Jennifer Giandhari,
- Ntombifuthi Mthabela,
- Dirhona Ramjit,
- Samita Singh,
- Farina Karim,
- Søren Buus,
- Frank Anderson,
- J. Zachary Porterfield,
- J. Zachary Porterfield,
- J. Zachary Porterfield,
- J. Zachary Porterfield,
- Andile L. Sibiya,
- Rishan Bipath,
- Kumeshan Moodley,
- Warren Kuhn,
- Warren Kuhn,
- Bonnie Berger,
- Son Nguyen,
- Tulio de Oliveira,
- Thumbi Ndung’u,
- Thumbi Ndung’u,
- Thumbi Ndung’u,
- Philip Goulder,
- Philip Goulder,
- Philip Goulder,
- Alex K. Shalek,
- Alex K. Shalek,
- Alex K. Shalek,
- Alasdair Leslie,
- Alasdair Leslie,
- Henrik N. Kløverpris,
- Henrik N. Kløverpris,
- Henrik N. Kløverpris
Affiliations
- Rabiah Fardoos
- Africa Health Research Institute (AHRI), Durban, South Africa
- Rabiah Fardoos
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
- Sarah K. Nyquist
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Sarah K. Nyquist
- Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, United States
- Osaretin E. Asowata
- Africa Health Research Institute (AHRI), Durban, South Africa
- Samuel W. Kazer
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Alveera Singh
- Africa Health Research Institute (AHRI), Durban, South Africa
- Abigail Ngoepe
- Africa Health Research Institute (AHRI), Durban, South Africa
- Jennifer Giandhari
- KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
- Ntombifuthi Mthabela
- Africa Health Research Institute (AHRI), Durban, South Africa
- Dirhona Ramjit
- Africa Health Research Institute (AHRI), Durban, South Africa
- Samita Singh
- Africa Health Research Institute (AHRI), Durban, South Africa
- Farina Karim
- Africa Health Research Institute (AHRI), Durban, South Africa
- Søren Buus
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
- Frank Anderson
- Discipline of General Surgery, Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South Africa
- J. Zachary Porterfield
- Africa Health Research Institute (AHRI), Durban, South Africa
- J. Zachary Porterfield
- Department of Otolaryngology-Head & Neck Surgery, Division of Infectious Diseases, University of Kentucky, Lexington, KY, United States
- J. Zachary Porterfield
- Department of Microbiology, Immunology and Molecular Genetics, - Division of Infectious Diseases, University of Kentucky, Lexington, KY, United States
- J. Zachary Porterfield
- Department of Internal Medicine - Division of Infectious Diseases, University of Kentucky, Lexington, KY, United States
- Andile L. Sibiya
- 0Department of Otorhinolaryngology & Head & Neck Surgery, Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South Africa
- Rishan Bipath
- 1Department of Otorhinolaryngology, King Edward VIII hospital, University of KwaZulu-Natal, Durban, South Africa
- Kumeshan Moodley
- 2Department of Ear Nose and Throat, General Justice Gizenga Mpanza Regional Hospital (Stanger Hospital), University of KwaZulu-Natal, Durban, South Africa
- Warren Kuhn
- 0Department of Otorhinolaryngology & Head & Neck Surgery, Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South Africa
- Warren Kuhn
- 2Department of Ear Nose and Throat, General Justice Gizenga Mpanza Regional Hospital (Stanger Hospital), University of KwaZulu-Natal, Durban, South Africa
- Bonnie Berger
- 3Computer Science & Artificial Intelligence Lab and Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, United States
- Son Nguyen
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Tulio de Oliveira
- KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
- Thumbi Ndung’u
- Africa Health Research Institute (AHRI), Durban, South Africa
- Thumbi Ndung’u
- 4HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban, South Africa
- Thumbi Ndung’u
- 5University College London, Division of Infection and Immunity, London, United Kingdom
- Philip Goulder
- Africa Health Research Institute (AHRI), Durban, South Africa
- Philip Goulder
- 4HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban, South Africa
- Philip Goulder
- 6Department of Paediatrics, University of Oxford, Oxford, United Kingdom
- Alex K. Shalek
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Alex K. Shalek
- 7Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, United States
- Alex K. Shalek
- 8Ragon Institute of MGH, Harvard, Cambridge, MA, United States
- Alasdair Leslie
- Africa Health Research Institute (AHRI), Durban, South Africa
- Alasdair Leslie
- 5University College London, Division of Infection and Immunity, London, United Kingdom
- Henrik N. Kløverpris
- Africa Health Research Institute (AHRI), Durban, South Africa
- Henrik N. Kløverpris
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
- Henrik N. Kløverpris
- 5University College London, Division of Infection and Immunity, London, United Kingdom
- DOI
- https://doi.org/10.3389/fimmu.2022.912038
- Journal volume & issue
-
Vol. 13
Abstract
Lymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue-resident memory (TRM) CD8+ T-cells is of great interest, but limited data exist on TRM-like cells within lymph nodes of people living with HIV (PLWH). Here, we studied tonsil CD8+ T-cells obtained from PLWH and uninfected controls from South Africa. We show that these cells are preferentially located outside the germinal centers (GCs), the main reservoir site for HIV, and display a low cytolytic and a transcriptionally TRM-like profile distinct from blood CD8+ T-cells. In PLWH, CD8+ TRM-like cells are expanded and adopt a more cytolytic, activated, and exhausted phenotype not reversed by antiretroviral therapy (ART). This phenotype was enhanced in HIV-specific CD8+ T-cells from tonsils compared to matched blood suggesting a higher antigen burden in tonsils. Single-cell transcriptional and clonotype resolution showed that these HIV-specific CD8+ T-cells in the tonsils express heterogeneous signatures of T-cell activation, clonal expansion, and exhaustion ex-vivo. Interestingly, this signature was absent in a natural HIV controller, who expressed lower PD-1 and CXCR5 levels and reduced transcriptional evidence of T-cell activation, exhaustion, and cytolytic activity. These data provide important insights into lymphoid tissue-derived HIV-specific CD8+ TRM-like phenotypes in settings of HIV remission and highlight their potential for immunotherapy and targeting of the HIV reservoirs.
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