HIV-1 DNA vaccines

Abstract

HIV-1 was among the original DNA vaccine targets and HIV DNA vaccines are now in human trials. Lack of strong correlates of protective immunity makes vaccine design difficult; however, DNA vaccines have the potential to be an ideal vaccine and therapeutic approach against HIV-1. DNA vaccines induce conformational-dependent antibodies, mimic live vaccines but without the pathogenic potential, and can easily be made polyvalent. Genes which encode important CTL and antibody epitopes can be included while those that confer pathogenicity, virulence, antibody enhancement or represent non-conserved epitopes can be excluded. In our hands pre-treatment of muscles with bupivacaine or cardiotoxin did not offer any advantage over no muscle pre-treatment or gene gun inoculation of skin although gene gun immunization seem to favour a Th2 type response. As DNA vaccine candidates we have compared vaccines encoding native HIV MN gp160 with Rev-independent synthetic genes encoding MNgp160 and MNgp120 using mammalian high expression codons. In these experiments the gene encoding secreted gp120 gave highest antibody neutralizing titers. High and fast antibody responses could also be obtained by transferring the HIV-1 MN V3 loop to the secreted HBsAg as a fusion gene vaccine. Thus, in the case of HIV-1 MN genes encoding secreted surface glycoproteins may be preferred instead of membrane bound envelopes. CTL responses were induced in all cases. However, in order to meet the high diversity of HIV and HLA types our approach is to include many CTL epitopes in a multivalent minigene vaccine. We found that gene gun DNA vaccination with minimal epitopes could induce specific CTL. Flanking sequences influenced the CTL response but was not needed. DNA vaccines encoding known and computer predicted CTL epitopes are now being developed.