title: HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4+ T Cell Responses.
abstract: Antigen-specific CD4(+) T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4(+) T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4(+) T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4(+) T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4(+) T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4(+) T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4(+) T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4(+) T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4(+) T cells and, to a lesser extent, gp41-specific CD4(+) T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.
  
  
  OBJECTIVE
  One of the earliest discoveries related to CD4(+) T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4(+) T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4(+) T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4(+) T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4(+) T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4(+) T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA sranasinghe@mgh.harvard.edu fporichis@mgh.harvard.edu.
authors.forename: Srinika
authors.initials: S
authors.lastname: Ranasinghe
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: Damien Z
authors.initials: DZ
authors.lastname: Soghoian
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: Madelene
authors.initials: M
authors.lastname: Lindqvist
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: Musie
authors.initials: M
authors.lastname: Ghebremichael
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: Faith
authors.initials: F
authors.lastname: Donaghey
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA Cancer and Inflammation Program, HLA Immunogenetics Section, Leidos Biomedical Research, Inc., National Cancer Institute, Frederick, Maryland, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA sranasinghe@mgh.harvard.edu fporichis@mgh.harvard.edu.
authors.forename: Filippos
authors.initials: F
authors.lastname: Porichis
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000097:blood*; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D054301:gag Gene Products, Human Immunodeficiency Virus; C514787:gp41 protein, Human immunodeficiency virus 1