Production of HIV-1 Env-specific antibodies mediating innate immune functions depends on cognate IL-21- secreting CD4+ T cells

Jernej Pušnik; Stephanie Fischinger; Ulf Dittmer; Stefan Esser; Marit J van Gils; Rogier W Sanders; Galit Alter; Hendrik Streeck

doi:10.1128/JVI.02097-20

Production of HIV-1 Env-specific antibodies mediating innate immune functions depends on cognate IL-21- secreting CD4+ T cells

J Virol. 2021 Mar 25;95(8):e02097-20. doi: 10.1128/JVI.02097-20. Epub 2021 Jan 27.

Authors

Jernej Pušnik^{1

2}, Stephanie Fischinger³, Ulf Dittmer⁴, Stefan Esser⁵, Marit J van Gils⁶, Rogier W Sanders⁶, Galit Alter³, Hendrik Streeck^{7

2}

Affiliations

¹ Institute of Virology, University Hospital, University of Bonn, Germany, and German Center for Infection Research (DZIF), partner site Bonn-Cologne, Germany.
² Institute for HIV Research, University Hospital, University Duisburg-Essen, Essen, Germany.
³ Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁴ Institute for Virology, University Hospital, University Duisburg-Essen, Essen, Germany.
⁵ Center for HIV, AIDS and Venereal Diseases, Clinic for Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
⁶ Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands.
⁷ Institute of Virology, University Hospital, University of Bonn, Germany, and German Center for Infection Research (DZIF), partner site Bonn-Cologne, Germany hstreeck@uni-bonn.de.

Abstract

Antibodies with a functional Fc region were previously associated with protection from HIV-1 acquisition and spontaneous suppression of viral replication. Unlike broadly neutralizing antibodies, they are not restricted to neutralizing epitopes and do not require unconventional structural traits to exert their antiviral activity. They, therefore, develop earlier after infection and can be detected in the majority of cases. The conditions under which these antibodies are generated, however, remain largely unknown. Here we demonstrate that the generation of HIV-1 Env-specific antibodies facilitating Fc-dependent innate immune responses, including neutrophil phagocytosis (ADNP), complement deposition (ADCD), and NK cell activation, likely depends on help provided by CD4+ T and peripheral T follicular helper (pTfh) cells secreting IL-21. Other proteins, including CD40L, IFNγ, and IL-4/13, involved in crosstalk between B and T cells were linked to the production of antibodies with functional Fc region but only when co-expressed with IL-21. As a potential source of these antibodies, we identified a subset of Env-specific memory B cells known to be expanded in chronic HIV-1 infection. The frequency and level of Blimp-1 expression in Env-specific tissue-like memory B cells (TLM) correlated with the functional CD4+ T cell subsets associated with robust antibody-dependent innate responses. Thus, our data suggest a mechanism responsible for the generation of antibodies with functional Fc region in chronically HIV-1 infected individuals that is based on CD4+ T cell-induced activation of memory B cells.Importance To develop a vaccine or immunotherapy that would cure the HIV-1 infection it is important to identify helper T cells able to mount an efficient antibody response. Here, we demonstrate that the generation of HIV-1 Env-specific antibodies facilitating antibody-dependent innate immune responses likely depends on Env-specific IL-21-secreting CD4+ T and peripheral T follicular helper cells.