The Protective HIV-1 Envelope gp41 Antigen P1 Acts as a Mucosal Adjuvant Stimulating the Innate Immunity

Abstract

Mucosal nasal vaccine development, although ideal to protect from pathogens invading mucosally, is limited by the lack of specific adjuvant. We recently used P1, a conserved region of HIV-1 gp41-envelope glycoprotein, as efficient antigen in a prophylactic HIV-1 mucosal vaccine applied nasally. Herein, P1 immunomodulation properties were assessed on human nasal mucosal models by measuring induction of cytokine and chemokine production, intracellular signaling pathways, mucosal dendritic cell (DC) activation, and T cell proliferation. P1 adjuvant properties were evaluated by quantification of antigen-specific B cell responses against a model antigen in an in vitro immunization model. We now demonstrated that P1 has additional immunological properties. P1 initiates immune responses by inducing nasal epithelial cells to secrete the Th2-cytokine thymic stromal lymphopoietin (TSLP), a described mucosal adjuvant. Secreted TSLP activates, in turn, intracellular calcium flux and PAR-2-associated NFAT signaling pathway regulated by microRNA-4485. Thereafter, P1 induces mucosal dendritic cell maturation, secretion of TSLP in a TSLP-receptor (R)-dependent autocrine loop, but also IL-6, IL-10, IL-8, CCL20, CCL22, and MMP-9, and proliferation of CD4+ T cells. Finally, P1 acts as an adjuvant to stimulate antigen-specific B cell responses in vitro. Overall, P1 is a multi-functional domain with various immuno-modulatory properties. In addition to being a protective vaccine antigen for HIV prevention, P1 acts as adjuvant for other mucosal vaccines able to stimulate humoral and cellular antigen-specific responses.

The initial interplay between HIV and mucosal innate immunity

“…Immunological containment of HIV infection in the mucosa would represent a strategic choice to effectively block viral replication and prevent its peripheral spread and systemic dissemination. Further studies are needed to assess whether a systemic immune response is an appropriate objective, or whether predominantly mucosal or both mucosal and systemic immunity would be more effective (258)(259)(260)(261).…”

Cooperation Between Systemic and Mucosal Antibodies Induced by Virosomal Vaccines Targeting HIV-1 Env: Protection of Indian Rhesus Macaques Against Low-Dose Intravaginal SHIV Challenges

“…The virosomal platform by itself has self-adjuvanticity mostly due to the influenza virus-derived HA antigens. In addition, a new function for peptide P1 has recently been discovered: its ability to act as a mucosal adjuvant for unrelated antigens ( 66 ). Given the sudden loss of protection when the SHIV challenge dose was changed at the start of Challenge Phase II, adding additional viral antigens could be considered to increase the number of viral targets and thus overall immunogenicity.…”

The use of RNA-based treatments in the field of cancer immunotherapy

“…This characteristic of mRNA might either be helpful or detrimental to therapeutic endeavors, depending on the circumstances [89]. Because it may increase DC maturation, which in turn enhances T and B cell immunological responses, it has the potential to be effective as an adjuvant for vaccination [90]. On the other hand, the reduction of antigen expression could be a collateral consequence of the innate immune system detecting mRNA [91].…”