Codelivery of Envelope Protein in Alum with MVA Vaccine Induces CXCR3-Biased CXCR5+ and CXCR5- CD4 T Cell Responses in Rhesus Macaques

• Published in: The Journal of immunology (1950) Vol. 195; no. 3; pp. 994 - 1005
• Main Authors: Iyer, Smita S, Gangadhara, Sailaja, Victor, Blandine, Gomez, Rosy, Basu, Rahul, Hong, Jung Joo, Labranche, Celia, Montefiori, David C, Villinger, Francois, Moss, Bernard, Amara, Rama Rao
• Format: Journal Article
• Language: English
• Published: United States 01.08.2015
• Subjects: Adjuvants, Immunologic - administration & dosage; Alum Compounds - administration & dosage; Animals; Antibodies, Viral - blood; Glycoproteins - immunology; Human immunodeficiency virus; Inducible T-Cell Co-Stimulator Protein - biosynthesis; Lymph Nodes - cytology; Lymph Nodes - immunology; Macaca mulatta; Male; Programmed Cell Death 1 Receptor - biosynthesis; Receptors, CCR5 - biosynthesis; Receptors, CXCR3 - biosynthesis; Receptors, CXCR5 - biosynthesis; SAIDS Vaccines - immunology; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - virology; Simian immunodeficiency virus; Swine influenza virus; T-Lymphocytes, Helper-Inducer - immunology; Vaccination - veterinary; Vaccinia virus; Viral Envelope Proteins - immunology; Viral Load - immunology; Viral Vaccines - immunology; Viremia - immunology; Viremia - virology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1500083

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.