Epitopes that induce protective immunity against human immunodeficiency virus (HIV) have not yet been identified, nor have the immune effector mechanisms that can prevent or at least control initial infection. In view of these difficulties, an attractive strategy for HIV vaccine development is one that permits expression of multiple HIV proteins and elicits a multifaceted immune response. Easily engineered, deoxyribonucleic acid (DNA) virus vectors such as poxviruses (Buller laboratory) or herpesviruses (Morrison laboratory) fulfill these criteria and would be useful for vaccination of the young adult population, in whom vector-specific immunity is low. Poxvirus recombinants expressing a number of HIV-1 antigens have been shown to be safe in human clinical trials and to induce neutralizing antibody and cytotoxic T lymphocytes (CTL) specific for multiple HIV proteins. The applicants are constructing replication-defective herpesvirus and poxvirus vectors that encode HIV gp160 as well as factors that enhance replication and trafficking of dendritic cells (DC) and monocytes to augment immune response induction to gp160. An important aspect in refining these virus vectors will be maximization of immune responses to the vector-encoded HIV proteins, including improvement of the immunogenicity of the HIV envelope proteins by facilitating their secretion and targeted uptake by antigen presenting cells (APC). In this project, herpesvirus and poxvirus genes encoding proteins that interfere with induction of immune responses to virus-infected cells will be inactivated. Secondly, the investigators propose to engineer forms of the vectors that secrete herpes simplex virus (HSV) VP22-gp160 or Cd3-gpl60 fusion proteins. The applicants hypothesize that these fusion proteins will expand the APC pool by targeting uptake to neighboring cells (VP22 fusion) or specifically to DC and B cells (Cd3 fusion) attracted by vector-expressed immune enhancing molecules. Finally, the applicants' propose an immunization protocol that utilizes mucosal administration of the live virus vector, and sequential immunization with herpes and poxvirus vectors to minimize the dampening effect of vector-specific immunity. The long-range goal is the creation of virus vector-based vaccines against HIV that intensify and expand immune responses to HIV at mucosal surfaces. Investigation of replication-defective HSV as a vaccine vector for HIV also raises the intriguing possibility of a combinatorial vaccine against sexually transmitted diseases.
