Impact of T(h)1 CD4 Follicular Helper T Cell Skewing on Antibody Responses to an HIV-1 Vaccine in Rhesus Macaques

• Type of Material: Article
• Authors: Anil Verma, University of California Davis; Brian A. Schmidt, University of California Davis; Sonny R. Elizaldi, University of California Davis; Nancy K. Nguyen, University of California Davis; Korey A. Walter, Louisiana State University; Zoltan Beck, Henry M. Jackson Foundation for the Advancement of Military Medicine; Hung Trinh, Henry M. Jackson Foundation for the Advancement of Military Medicine; Ashok R. Dinasarapu, Emory University; Yashavanth Lakshmanappa, University of California Davis; Niharika N. Rane, University of California Davis; Gary R. Matyas, Walter Reed Army Institute of Research; Mangala Rao, Walter Reed Army Institute of Research; Xiaoying Shen, Duke University; Georgia D. Tomaras, Duke University; Celia C. LaBranche, Duke University; Keith A. Reimann, University of Massachusetts; David H. Foehl, University of Massachusetts; Johannes S. Gach, University of California Irvine; Donald N. Forthal, University of California Irvine; Pamela A. Kozlowski, Louisiana State University; Rama Amara, Emory University; Smita S. Iyer, University of California Davis
• Language: English
• Date: 2020-03-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Verma et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01737-19
• Title of Journal or Parent Work: Journal of Virology
• Volume: 94
• Issue: 6
• Grant/Funding Information: This work was partially supported by a cooperative agreement (W81XWH-18-2-0040) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DoD).
• Keywords: Differentiation; vaccine; TFH Cells; Infected cells; Nonhuman primates; Envelope protein; adjuvant; Simian immunodeficiency virus (SIV); Virology; DNA prime; CD4; Life Sciences & Biomedicine; Immune responses; antibody; Science & Technology; IL-1 Acts; T-fh; TH17 Cells
• Research Categories: Biology, Virology; Health Sciences, Immunology; Biology, Cell; Biology, Genetics

Abstract

Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T (Tfh) cells with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing costimulatory and cytokinedependent Tfh help to B cells. However, the question remains as to whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced antienvelope (anti-Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferoninduced protein 10 (IP-10)-adjuvanted HIV-1 DNA prime followed by a monophosphoryl lipid A and QS-21 (MPLA+QS-21)-adjuvanted Env protein boost (DIP-10 PALFQ) in macaques, we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity for V1V2, and effector functions than in macaques primed with DNA lacking IP-10 and boosted with MPLA-plus-alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibody levels in serum, showing for the first time that adjuvants can dramatically impact the IgG subclass profile in macaques. The DIP-10 PALFQ regimen also increased vaginal and rectal IgA antibodies to a greater extent. Within lymph nodes, we observed augmented GC B cell responses and the promotion of Th1 gene expression profiles in GC Tfh cells. The frequency of GC Tfh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of Th1-Tfh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody responses. IMPORTANCE The results of the RV144 trial demonstrated that vaccination could prevent HIV transmission in humans and that longevity of anti-Env antibodies may be key to this protection. Efforts to improve upon the prime-boost vaccine regimen used in RV144 have indicated that booster immunizations can increase serum anti-Env antibody titers but only transiently. Poor antibody durability hampers efforts to develop an effective HIV-1 vaccine. This study was designed to identify the specific elements involved in the immunological mechanism necessary to produce robust HIV-1-specific antibodies in rhesus macaques. By clearly defining immune-mediated pathways that improve the magnitude and functionality of the anti-HIV-1 antibody response, we will have the foundation necessary for the rational development of an HIV-1 vaccine.