title: Quality and quantity of TFH cells are critical for broad antibody development in SHIVAD8 infection.
abstract: Broadly neutralizing antibodies (bNAbs) protect against HIV-1 infection, yet how they are generated during chronic infection remains unclear. It is known that T follicular helper (TFH) cells are needed to promote affinity maturation of B cells during an immune response; however, the role of TFH during HIV-1 infection is undefined within lymph node germinal centers (GCs). We use nonhuman primates to investigate the relationship in the early stage of chronic SHIVAD8 (simian-human immunodeficiency virus AD8) infection between envelope (Env)-specific TFH cells, Env-specific B cells, virus, and the generation of bNAbs during later infection. We found that both the frequency and quality of Env-specific TFH cells were associated with an expansion of Env-specific immunoglobulin G-positive GC B cells and broader neutralization across HIV clades. We also found a correlation between breadth of neutralization and the degree of somatic hypermutation in Env-specific memory B cells. Finally, we observed high viral loads and greater diversity of Env sequences in rhesus macaques that developed cross-reactive neutralization as compared to those that did not. These studies highlight the importance of boosting high-quality TFH populations as part of a robust vaccine regimen aimed at eliciting bNabs.
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Humoral Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Lynch
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Gautam
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Matus-Nicodemos
authors.affiliation: Humoral Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Boswell
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Darko
authors.affiliation: Humoral Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wong
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Zizhang
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Petrovas
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Adrian B
authors.initials: AB
authors.lastname: McDermott
authors.affiliation: Cellular Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Humoral Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Martin
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA. rkoup@mail.nih.gov.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000032:analysis / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D011323:Primates; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing