Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.

Rafael Cubas (1) , Julien van Grevenynghe (2) , Saintedym Wills (3) , Lela Kardava (4) , Brian H Santich (4) , Clarisa M Buckner (4) , Roshell Muir (1) , Virginie Tardif (1) , Carmen Nichols (1) , Francesco Procopio (5) , Zhong He (1) , Talibah Metcalf (1) , Khader Ghneim (1) , Michela Locci (6) , Petronella Ancuta (7) , Jean-Pierre Routy (8) , Lydie Trautmann (1) , Yuxing Li (9) , Adrian B Mcdermott (10) , Rick A Koup (10) , Constantinos Petrovas (10) , Steven A Migueles (4, 10) , Mark Connors (4) , Georgia D Tomaras (3) , Susan Moir (4) , Shane Crotty (6) , Elias K Haddad (1)

1 USF - University of South Florida [Tampa]
2 INRS-IAF - Institut Armand Frappier
3 Department of Immunology and the Duke Human Vaccine Institute
4 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
5 CHUV - Centre Hospitalier Universitaire Vaudois [Lausanne]
6 La Jolla Institute for Immunology [La Jolla, CA, États-Unis]
7 Department of Medicine, University of Montreal
8 MUHC - McGill University Health Center [Montreal]
9 The Scripps Research Institute [La Jolla, San Diego]
10 Vaccine Research Center, National Institute for Allergy and Infectious Diseases

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.

Domains: Life Sciences [q-bio]

Rafael Cubas, Julien van Grevenynghe, Saintedym Wills, Lela Kardava, Brian H Santich, et al.. Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.. Journal of Immunology, 2015, 195 (12), pp.5625-36. ⟨10.4049/jimmunol.1501524⟩. ⟨pasteur-01351053⟩