132 Argotom-VAX: A Proposed Investigational HIV DNA Vaccine Composed Of Selected Sequences Of Clade B Gag, Pol, Nef, Tat, Vif, And Env Linked To Lysosomal Membrane Associated Protein (LAMP)

Abstract

HIV infection results in a progressive loss of CD4+ cells and the immune response of the host. The aim of immune intervention in the chronic stage is to restore immunological competence of infected individuals, reduce viral load, and retard CD4 cell loss. It has been shown by extensive animal and human studies that the immunogenicity of the protein antigen can be enhanced by targeting the antigen as a lysosome associated membrane protein (LAMP) chimera to the major histocompatibility complex type 2 (MHC II) processing compartment of professional antigen presenting cells for enhanced presentation to CD4 cells. Each of the three plasmids of the vaccine product will contain three distinct domains of LAMP: (1) the highly glycosylated luminal domain with an N-terminal endoplasmic reticulum translocation signal; (2) the transmembrane domain, and (3) the cytoplasmic domain at the C-terminal. The antigen sequences are inserted between the luminal and transmembrane domains. Studies of HIV-1 DNA immunogen formulations have described an HIV-1 p55Gag DNA construct with strong, broad and poly-functional cellular and humoral immune responses in immunized mice when the Gag sequence was incorporated into the complete LAMP cDNA sequence. The LAMP/Gag chimera with the complete LAMP protein co-localized with the MHC II of transfected cells and elicited strong cellular and humoral responses in immunized mice compared to DNA-encoding native Gag, with a 4-to 5-fold increase in CD8+ T-cell response and antibody titers of >100,000. The proposed investigational vaccine, Argotom-VAX, is composed of three closed, circular supercoiled DNA plasmids containing the 8L-pCMV vector with three characterized nucleotide sequences that encode HIV antigens: LAMP/gag, LAMP/pol, and LAMP/NTVE. The complete LAMP protein will be used in each chimeric construct, designed for optimum protein expression and targeting to the major histocompatibility II (MHC II) compartment of selected sequences of HIV-1 Clade B proteins, p55 gag, pol, and a fusion of Nef-Tat-Vif-Env (gp41).