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<p>Abstract</p> <p>Background</p> <p>The possibility that a sub domain of a C clade HIV-1 gp120 could act as an effective immunogen was investigated. To do this, the outer domain (OD) of gp120_CN54was expressed and characterized in a construct marked by a re-introduced conformational epitope for MAb 2G12. The expressed sequence showed efficient epitope retention on the isolated OD_CN54suggesting authentic folding. To facilitate purification and subsequent immunogenicity OD_CN54was fused to the Fc domain of human IgG1. Mice were immunised with the resulting fusion proteins and also with gp120_CN54-Fc and gp120 alone.</p> <p>Results</p> <p>Fusion to Fc was found to stimulate antibody titre and Fc tagged OD_CN54was substantially more immunogenic than non-tagged gp120. Immunogenicity appeared the result of Fc facilitated antigen processing as immunisation with an Fc domain mutant that reduced binding to the FcR lead to a reduction in antibody titre when compared to the parental sequence. The breadth of the antibody response was assessed by serum reaction with five overlapping fragments of gp120_CN54expressed as GST fusion proteins in bacteria. A predominant anti-inner domain and anti-V3C3 response was observed following immunisation with gp120_CN54-Fc and an anti-V3C3 response to the OD_CN54-Fc fusion.</p> <p>Conclusion</p> <p>The outer domain of gp120_CN54is correctly folded following expression as a C terminal fusion protein. Immunogenicity is substantial when targeted to antigen presenting cells but shows V3 dominance in the polyvalent response. The gp120 outer domain has potential as a candidate vaccine component.</p>