Human immunodeficiency viruses have the same general structural and functional characteristics as lentiviruses. Lentiviruses cause slow debilitating disease in animals and humans and in many cases there a striking inability of the immune system to provide effective immunity despite a notable host immune ponse. The latency period, the chronic course of disease and the failure of the immune response to control infection may be related to the complex genetic structure of the virus. Knowledge of factors which ntribute to the complex state of natural infection is important for an understanding of disease rogression and pathogenesis. In addition to the HIV/SIV regulatory genes, tat and rev, and the major ral structural genes, gag, pol and env, the HIV/SIV group of viruses contain genes of accessory function ch are not essential for virus replication in vitro. Of the accessory gene, vpx and vpr are assembled and packaged with the virus particle, are expressed both in vitro and in vivo and have been shown to augment rus replication. Nevertheless, the function of vpx and vpr in the virus life cycle and their importance n the pathobiology of HIV infection is unknown. This project will elucidate, in vitro, the function of the vpx and vpr genes in the life cycle of HIV as well as the relevance of their presence in the virus particle with respect to function and virion architecture. Specifically: (a) CDNA libraries will be constructed and analyzed to determine whether berrant splicing, common among HIV central region genes, occurs within vpx and vpr and if so whether roteins are encoded which are of biological significance; (b) the mechanism by which vpx augments fectivity of the virus particle will be defined more precisely by comparing vpx-deficient and wild-type ruses with respect to gpl2O-CD4 binding affinities, virus binding, reverse transcription and transctivational properties; (c) the importance of vpr for virus replication and the events in the virus life cycle for which it is important will be determined; (d) the mechanism by which vpx and vpr are assembled at the 11 membrane and their requirements for packaged into the virus particle will be studied; (e) and finally, functional, intramolecular protein domains of vpx and vpr will be identified allowing further delineation of the mechanism of protein function. These investigations are expected to provide new and important formation regarding the biology of HIV-2 as well as providing a sound basis from which it will be possible to evaluate, in vivo, the relevance of vpx and vpr in virus induced pathogenesis.
