HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control

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  • Rabiah Fardoos
  • Sarah K. Nyquist
  • Osaretin E. Asowata
  • Samuel W. Kazer
  • Alveera Singh
  • Abigail Ngoepe
  • Jennifer Giandhari
  • Ntombifuthi Mthabela
  • Dirhona Ramjit
  • Samita Singh
  • Farina Karim
  • Frank Anderson
  • J. Zachary Porterfield
  • Andile L. Sibiya
  • Rishan Bipath
  • Kumeshan Moodley
  • Warren Kuhn
  • Bonnie Berger
  • Son Nguyen
  • Tulio de Oliveira
  • Thumbi Ndung’u
  • Philip Goulder
  • Alex K. Shalek
  • Alasdair Leslie

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.

TidsskriftFrontiers in Immunology
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
HK is supported by the Wellcome Trust (202485/Z/16/Z). AL is supported by the Wellcome Trust (210662/Z/18/Z). This work was supported through the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative (DEL-15-006). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science in Africa and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (107752/Z/15/Z) and the United Kingdom government. HNK and AS were supported by SANTHE. AKS was supported, in part, by the Searle Scholars Program, the Beckman Young Investigator Program, the NIH (5U24AI118672), a Sloan Fellowship in Chemistry, and the Bill and Melinda Gates Foundation. This research was funded in part by the Africa Health Research Institute through its Strategic Core Award by the Wellcome Trust (201433/A/16/A). This publication was supported by a Subagreement from the Johns Hopkins University with funds provided by Grant No. UM1AI164566 from the National Institute of Allergy and Infectious Diseases.

Publisher Copyright:
Copyright © 2022 Fardoos, Nyquist, Asowata, Kazer, Singh, Ngoepe, Giandhari, Mthabela, Ramjit, Singh, Karim, Buus, Anderson, Porterfield, Sibiya, Bipath, Moodley, Kuhn, Berger, Nguyen, de Oliveira, Ndung’u, Goulder, Shalek, Leslie and Kløverpris.

ID: 327473589