application Abstract). Initial attempts to induce protective immunity to HIV have relied on the use of a single recombinant form of HIV gp120 as an immunogen. The success of these initial attempts to vaccinate against HIV may have been limited by the monomeric nature of gpl20 and that it was not representative of gpl20 from primary HIV isolates. The applicants propose that expression of HIV envelope derived from a primary isolate in human antigen-presenting cells may be more effective at inducing protective immunity to HIV infection. They propose to develop strategies that can deliver expression of native HIV envelope to human antigen presenting cells in vivo as a means to immunize individuals against HIV. They will compare immunity induced by in vivo gene delivery of env expression to conventional approaches that immunize with recombinant forms of HIV env. They also propose to test these vaccination strategies in a long-term model of the human lymph node, SCID-hu BTL. SCID-hu BTL mice possess human tissue grafts that provide for human hematopoiesis, human thymopoiesis and human secondary lymphoid tissue. BTL mice produce significant quantities of human IgM and IgG up to eight months after tissue transplantation. The applicants propose to use this in vivo model of the human immune system to study the use of recombinant pseudotyped lentiviral vectors to deliver HIV env sequences to human APC in vivo. Specifically they will, (1) Test whether vaccination with multiple forms of recombinant monomeric and oligomeric HIV gpl20 confers protective immunity to HIV, (2) Test whether pseudotyped lentiviral vectors can deliver expression of a gene to human antigen-presenting cells in vivo, (3) Test whether in vivo gene delivery of HIV env sequences by pseudotyped lentiviral vectors confers protective immunity to HIV.
