A High Frequency of HIV-Specific Circulating Follicular Helper T Cells Is Associated with Preserved Memory B Cell Responses in HIV Controllers M. Claireaux, a,b M. Galperin, a,b D. Benati, a,b * A. Nouël, a,b M. Mukhopadhyay, a,b J. Klingler, c P. de Truchis, d D. Zucman, e S. Hendou, f F. Boufassa, f C. Moog, c O. Lambotte, g,h,i,j L. A. Chakrabarti a,b a Pasteur Institute, Viral Pathogenesis Unit, Paris, France b INSERM U1108, Paris, France c INSERM UMR_S1109, Center for Research in Immunology and Hematology, Medicine Faculty, Strasbourg Translational Medicine Federation (FMTS), Strasbourg University, Strasbourg, France d AP-HP, Infectious and Tropical Diseases Department, Raymond Poincaré Hospital, Garches, France e HIV Unit, Foch Hospital, Suresnes, France f INSERM U1018, Center for Research in Epidemiology and Population Health (CESP), Le Kremlin-Bicêtre, France g INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin-Bicêtre, France h AP-HP, Department of Internal Medicine and Clinical Immunology, University Hospital Paris Sud, Le Kremlin- Bicêtre, France i Université Paris Sud, UMR1184, Le Kremlin-Bicêtre, France j CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Fontenay-aux-Roses, France ABSTRACT Follicular helper T cells (Tfh) play an essential role in the affinity matu- ration of the antibody response by providing help to B cells. To determine whether this CD4  T cell subset may contribute to the spontaneous control of HIV infection, we analyzed the phenotype and function of circulating Tfh (cTfh) in patients from the ANRS CO21 CODEX cohort who naturally controlled HIV-1 replication to unde- tectable levels and compared them to treated patients with similarly low viral loads. HIV-specific cTfh (Tet  ), detected by Gag-major histocompatibility complex class II (MHC-II) tetramer labeling in the CD45RA  CXCR5  CD4  T cell population, proved more frequent in the controller group (P  0.002). The frequency of PD-1 expression in Tet  cTfh was increased in both groups (median, 75%) compared to total cTfh (30%), but the intensity of PD-1 expression per cell remained higher in the treated patient group (P  0.02), pointing to the persistence of abnormal immune activation in treated patients. The function of cTfh, analyzed by the capacity to promote IgG secretion in cocultures with autologous memory B cells, did not show major differ- ences between groups in terms of total IgG production but proved significantly more efficient in the controller group when measuring HIV-specific IgG production. The frequency of Tet  cTfh correlated with HIV-specific IgG production (R  0.71 for Gag-specific and R  0.79 for Env-specific IgG, respectively). Taken together, our findings indicate that key cTfh-B cell interactions are preserved in controlled HIV in- fection, resulting in potent memory B cell responses that may play an underappreci- ated role in HIV control. IMPORTANCE The rare patients who spontaneously control HIV replication in the absence of therapy provide a unique model to identify determinants of an effective anti-HIV immune response. HIV controllers show signs of particularly efficient antivi- ral T cell responses, while their humoral response was until recently considered to play only a minor role in viral control. However, emerging evidence suggests that HIV controllers maintain a significant but “silent” antiviral memory B cell population that can be reactivated upon antigenic stimulation. We report that cTfh help likely Received 7 February 2018 Accepted 16 April 2018 Published 8 May 2018 Citation Claireaux M, Galperin M, Benati D, Nouël A, Mukhopadhyay M, Klingler J, de Truchis P, Zucman D, Hendou S, Boufassa F, Moog C, Lambotte O, Chakrabarti LA. 2018. A high frequency of HIV-specific circulating follicular helper T cells is associated with preserved memory B cell responses in HIV controllers. mBio 9:e00317-18. https://doi.org/ 10.1128/mBio.00317-18. Invited Editor Viviana Simon, Icahn School of Medicine at Mount Sinai Editor Peter Palese, Icahn School of Medicine at Mount Sinai Copyright © 2018 Claireaux et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to L. A. Chakrabarti, chakra@pasteur.fr. * Present address: D. Benati, Center for Regenerative Medicine Stephano Ferrari, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. RESEARCH ARTICLE crossm May/June 2018 Volume 9 Issue 3 e00317-18 ® mbio.asm.org 1 on June 18, 2020 by guest http://mbio.asm.org/ Downloaded from