TY - JOUR
T1 - Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8+ T cells
AU - Nguyen, Son
AU - Deleage, Claire
AU - Darko, Samuel
AU - Ransier, Amy
AU - Truong, Duc P.
AU - Agarwal, Divyansh
AU - Japp, Alberto Sada
AU - Wu, Vincent H.
AU - Kuri-Cervantes, Leticia
AU - Abdel-Mohsen, Mohamed
AU - Del Rio Estrada, Perla M.
AU - Ablanedo-Terrazas, Yuria
AU - Gostick, Emma
AU - Hoxie, James A.
AU - Zhang, Nancy R.
AU - Naji, Ali
AU - Reyes-Terán, Gustavo
AU - Estes, Jacob D.
AU - Price, David A.
AU - Douek, Daniel C.
AU - Deeks, Steven G.
AU - Buggert, Marcus
AU - Betts, Michael R.
N1 - Funding Information:
We thank the Virus and Reservoirs Core at the Penn Center for AIDS Research for assistance with viral quantification, the Pathology Core at the Hospital of the University of Pennsylvania for access to biopsy materials, K. Noyan-Gertler for assistance with viral suppression assays, and M. Li and Y. Che for initial contributions to the scRNAseq analyses. This study was funded, in part, by the Oregon National Primate Research Center NIH grant P51OD011092 and by federal funds from the NCI under contract HHSN261200800001E. S.D., A.R., and D.C.D. were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the NIH. M.A.-M., J.A.H., and M.R.B. were supported by the Penn Center for AIDS Research (P30 AI045008). M.A.-M. was further supported by the NIH R21 grant AI129636, the Campbell Foundation, and a grant from the W.W. Smith Charitable Trust (A1701). M.R.B. was further supported by the NIH R01 grants AI076066 and AI118694 and the BEAT-HIV Delaney Collaboratory (UM1AI126620). D.A.P. was supported by a Wellcome Trust Senior Investigator Award (100326/Z/12/Z). M.B. was supported through the Swedish Research Council (VR), Karolinska Institutet, Swedish Society for Medical Research (SSMF), Jeansson Stiftelser, Ake Wibergs Stiftelse, The Swedish Society of Medicine (SLS), Magnus Bergvalls Stiftelse, Lars Hiertas Stiftelse. The SCOPE cohort was supported by the University of California, San Francisco (UCSF)–Gladstone Institute of Virology and Immunology Center for AIDS Research (P30 AI027763), the Delaney AIDS Research Enterprise (AI127966), and the amfAR Institute for HIV Cure Research (109301). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services (DHHS) nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Publisher Copyright:
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2019/12/18
Y1 - 2019/12/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85079527146&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079527146&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aax4077
DO - 10.1126/scitranslmed.aax4077
M3 - Article
C2 - 31852798
AN - SCOPUS:85079527146
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 523
M1 - eaax4077
ER -