| Neutralizing antibodies directed to the HIV Envelope are capable of preventing HIV infection, but the high degree of Envelope variation has rendered difficult the design of immunogens capable of eliciting neutralizing antibodies that recognize diverse isolates. Current vaccine approaches to overcome this hurdle emphasize the need for Envelope immunogens to elicit antibodies against epitopes that are conserved among diverse HIV isolates. In this dissertation, I have sought to define the effects of modifying the Envelope variable regions on the immunogenicities of soluble Envelope-derived vaccine constructs in macaque and mouse models. In parallel, I have monitored the development of neutralizing antibodies in macaques infected with a simian/human immunodeficiency virus (SHIV) which expresses the same Envelope expressed by the immunogens. The antibody responses elicited during immunization and infection differed significantly, both as it concerns the breadth and potency of the neutralizing antibodies elicited, as well as their epitope specificity. A narrow neutralizing response, directed primarily to the V1 and V3 variable loops, was elicited during immunization while a much broader neutralizing response, of as yet undefined epitope specificity, was elicited during infection. My studies advance our understanding of how various epitopes are presented on current HIV Envelope immunogens and suggest that modifications may improve the immunogenicity of conserved epitopes and thus augment the ability of future Envelope-derived immunogens to elicit broadly reactive neutralizing antibodies. These studies also highlight the utility of the SHIV/macaque animal model for addressing factors that contribute to the development of broadly reactive neutralizing antibodies and for identifying the epitope specificities of those antibodies. |
