title: Codelivery of Envelope Protein in Alum with MVA Vaccine Induces CXCR3-Biased CXCR5+ and CXCR5- CD4 T Cell Responses in Rhesus Macaques.
abstract: The goal of an HIV vaccine is to generate robust and durable protective Ab. Vital to this goal is the induction of CD4(+) T follicular helper (TFH) cells. However, very little is known about the TFH response to HIV vaccination and its relative contribution to magnitude and quality of vaccine-elicited Ab titers. In this study, we investigated these questions in the context of a DNA/modified vaccinia virus Ankara SIV vaccine with and without gp140 boost in aluminum hydroxide in rhesus macaques. In addition, we determined the frequency of vaccine-induced CD4(+) T cells coexpressing chemokine receptor, CXCR5 (facilitates migration to B cell follicles) in blood and whether these responses were representative of lymph node TFH responses. We show that booster modified vaccinia virus Ankara immunization induced a distinct and transient accumulation of proliferating CXCR5(+) and CXCR5(-) CD4 T cells in blood at day 7 postimmunization, and the frequency of the former but not the latter correlated with TFH and B cell responses in germinal centers of the lymph node. Interestingly, gp140 boost induced a skewing toward CXCR3 expression on germinal center TFH cells, which was strongly associated with longevity, avidity, and neutralization potential of vaccine-elicited Ab response. However, CXCR3(+) cells preferentially expressed the HIV coreceptor CCR5, and vaccine-induced CXCR3(+)CXCR5(+) cells showed a moderate positive association with peak viremia following SIV251 infection. Taken together, our findings demonstrate that vaccine regimens that elicit CXCR3-biased TFH cell responses favor Ab persistence and avidity but may predispose to higher acute viremia in the event of breakthrough infections.
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Smita S
authors.initials: SS
authors.lastname: Iyer
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Sailaja
authors.initials: S
authors.lastname: Gangadhara
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Blandine
authors.initials: B
authors.lastname: Victor
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Rosy
authors.initials: R
authors.lastname: Gomez
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Rahul
authors.initials: R
authors.lastname: Basu
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Jung Joo
authors.initials: JJ
authors.lastname: Hong
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27705;
authors.forename: Celia
authors.initials: C
authors.lastname: Labranche
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27705;
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Bernard
authors.initials: B
authors.lastname: Moss
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; Department of Microbiology and Immunology, Emory University, Atlanta, GA 30329 ramara@emory.edu.
authors.forename: Rama Rao
authors.initials: RR
authors.lastname: Amara
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D006023:Glycoproteins / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D019713:Receptors, CCR5 / Q000096:biosynthesis; D054367:Receptors, CXCR3 / Q000096:biosynthesis; D054380:Receptors, CXCR5 / Q000096:biosynthesis; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014611:Vaccination / Q000662:veterinary; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins / Q000276:immunology*; D019562:Viral Load / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*; D014766:Viremia / Q000276:immunology* / Q000821:virology
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000914:Antibodies, Viral; C033904:GP 140; D006023:Glycoproteins; D060889:Inducible T-Cell Co-Stimulator Protein; C560489:MVA vaccine; D061026:Programmed Cell Death 1 Receptor; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D054380:Receptors, CXCR5; D018449:SAIDS Vaccines; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; C041524:aluminum sulfate