Co-delivery of mucosa-associated epithelial chemokine (MEC/CCL28) enhances anti-HIV-1 mucosal responses through CCR10 in the context of DNA vaccination

Abstract Mucosal antibody plays a vital role in protection against HIV transmission. Mucosa-associated epithelial chemokine (CCL28) is secreted by mucosal epithelial cells following commensal colonization, and binds CC-chemokine receptor 10 (CCR10), expressed on IgA+ plasma cells. Deletion of CCR10 impairs mucosal IgA production and memory responses. Thus, the CCL28/CCR10 axis is critical for regulating mucosal IgA production and memory immunity. Mice were vaccinated twice with consensus HIV-1 gp160 DNA alone (antigen-only), or antigen and plasmid-encoded CCL28 (pCCL28) via intramuscular injection and in vivo electroporation (EP). pCCL28 increased antigen-specific IgA in fecal extracts (average 36.7ng/ml IgA in the antigen only group compared with 90.9ng/ml in the pCCL28 group). The intestinal compartment from animals co-immunized with pCCL28 harbored a higher frequency of HIV-specific, IgA+ B cells compared to the antigen-alone group (13.1% compared to 5.7%, respectively), and these cells expressed significantly-higher levels of CCR10 than those from mice in the non-adjuvanted group (MFI 413 compared to 181, respectively). Colonization with commensals induces CCL28 secretion by intestinal epithelial cells. Indeed, In vitro experiments with human colonic epithelial cell lines indicate that these organisms increased expression of CCL28 at the transcript and protein level. These studies suggest that electroporated delivery of the mucosal chemokine CCL28, can enhance antigen-specific anti-HIV immunity in the mucosa. Ongoing studies will determine if supplementation of commensal flora during vaccination can enhance CCL28 secretion in vivo and promote retention of vaccine-induced IgA+ B cells at mucosal surfaces.