TY - JOUR
T1 - Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies
AU - Petrovas, Constantinos
AU - Ferrando-Martinez, Sara
AU - Gerner, Michael Y.
AU - Casazza, Joseph P.
AU - Pegu, Amarendra
AU - Deleage, Claire
AU - Cooper, Arik
AU - Hataye, Jason
AU - Andrews, Sarah
AU - Ambrozak, David
AU - Del Río Estrada, Perla M.
AU - Boritz, Eli
AU - Paris, Robert
AU - Moysi, Eirini
AU - Boswell, Kristin L.
AU - Ruiz-Mateos, Ezequiel
AU - Vagios, Ilias
AU - Leal, Manuel
AU - Ablanedo-Terrazas, Yuria
AU - Rivero, Amaranta
AU - Gonzalez-Hernandez, Luz Alicia
AU - McDermott, Adrian B.
AU - Moir, Susan
AU - Reyes-Terán, Gustavo
AU - Docobo, Fernando
AU - Pantaleo, Giuseppe
AU - Douek, Daniel C.
AU - Betts, Michael R.
AU - Estes, Jacob D.
AU - Germain, Ronald N.
AU - Mascola, John R.
AU - Koup, Richard A.
N1 - Funding Information:
We thank the personnel of the Flow Cytometry Core at the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), NIH, the Children's National Medical Center (for providing tonsil tissues), and the personnel of HUVR working with LN biopsies. We are grateful to J. Hu (Human Immunology Section, VRC, NIH) for providing critical help with the transcriptome analysis. Funding: This research was supported by the Intramural Research Program of the VRC, NIAID, NIH, and CAVD grant (#OPP1032325) from the Bill and Melinda Gates Foundation (R.A.K.). This project was funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Part of the research was also supported by Redes Telem?ticas de Investigaci?n Cooperativa en Salud (RETICS; Red de SIDA, RD12/0017/0029) and Fondo de Investigacion Sanitaria (grants PI12/02283 and PI13/01912). E.R.-M. was supported by Fondo de Investigacion Sanitaria (grants CP08/00172 and CPII14/00025)
Publisher Copyright:
© 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2017/1/18
Y1 - 2017/1/18
N2 - Cytolytic CD8 T cells play a crucial role in the control and elimination of virus-infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals. This profile was associated with persistent local immune activation but did not appear to be directly related to local viral replication. Follicular CD8 (fCD8) T cells, despite compromised cytokine polyfunctionality, showed good cytolytic potential characterized by high ex vivo expression of granzyme B and perforin. We used an anti-HIV/anti-CD3 bispecific antibody in a redirected killing assay and found that fCD8 T cells had better killing activity than did non-fCD8 T cells. Our results indicate that CD8 T cells with potent cytolytic activity are recruited to GCs during HIV infection and, if appropriately redirected to kill HIV-infected cells, could be an effective component of an HIV cure strategy.
AB - Cytolytic CD8 T cells play a crucial role in the control and elimination of virus-infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals. This profile was associated with persistent local immune activation but did not appear to be directly related to local viral replication. Follicular CD8 (fCD8) T cells, despite compromised cytokine polyfunctionality, showed good cytolytic potential characterized by high ex vivo expression of granzyme B and perforin. We used an anti-HIV/anti-CD3 bispecific antibody in a redirected killing assay and found that fCD8 T cells had better killing activity than did non-fCD8 T cells. Our results indicate that CD8 T cells with potent cytolytic activity are recruited to GCs during HIV infection and, if appropriately redirected to kill HIV-infected cells, could be an effective component of an HIV cure strategy.
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UR - http://www.scopus.com/inward/citedby.url?scp=85010304642&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aag2285
DO - 10.1126/scitranslmed.aag2285
M3 - Article
C2 - 28100833
AN - SCOPUS:85010304642
VL - 9
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 373
M1 - eaag2285
ER -