Abstract
Abstract Development of an effective HIV vaccine is dependent on the quantity and quality of HIV Envelope specific antibody at the mucosal sites. Priming of the oral mucosa is a promising approach to generate mucosal antibody at HIV entry sites. Our recent work in mice has demonstrated the ability of IL-9 and IL-33, known regulators of mucosal immunity, to promote robust development of HIV Env-specific IgG; in addition they increase the breadth, magnitude, and durability of the Env-specific IgG response when combined with the DNA/protein HIV Env immunogen platform VC10014, which elicits Tier 2 neutralizing antibody in rhesus macaques. We hypothesized that conditioning the tonsil microenvironment with IL-9 or IL-33 would enable the rapid induction of durable and effective mucosal humoral immunity by the VC10014 DNA/protein HIV vaccine platform. Rhesus macaques were primed with VC10014 gp160 DNA plasmids in the absence or presence of IL-9 or IL-33 intra-tonsillar (IT), followed by intramuscular (IM) boosting with the DNA/protein HIV vaccine regimen. IT immunization with IL-9 or IL33 induced plasma Env-specific IgG that was present as early as week 6, mucosal Env-specific IgG and heterologous plasma neutralizing antibody. IL-33 treated animals exhibited the greatest number of germinal centers (GCs) and largest GCs following the first IM boost whereas IL-9 treated animals showed the greatest number of GCs following the second IM boost in the draining lymph nodes. The difference in kinetics, with IL-33 promoting an earlier B cell response, and IL-9 promoting greater magnitude later, may suggest that IL-9 and IL-33 promote the development of qualitatively different B cells subsets and may have synergistic potential in HIV vaccine development. Supported by a grant from NIH (R01DE027245).
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