title: Inclusion of Vpr accessory gene in a plasmid vaccine cocktail markedly reduces Nef vaccine effectiveness in vivo resulting in CD4 cell loss and increased viral loads in rhesus macaques.
abstract: We compared the immunogenicity of plasmid vaccines containing multiple human immunodeficiency virus (HIV) antigens and found that covaccination with plasmids expressing HIV-1 14 kDa vpr gene product profoundly reduces antigen-specific CD8-mediated cytotoxic T-cell activity (CTL). Interestingly, Th1 type responses against codelivered antigens (pGag-Pol, pNef, etc.) encoded by the plasmid vaccines were suppressed. This suggested that vpr might compromise CD8 T-cell immunity in vivo during infection. A pilot primate vaccine study was designed to test the hypothesis to compare the following groups: unvaccinated controls, animals vaccinated without simean immunodeficiency virus (SIV)-Nef antigen plasmid, and animals covaccinated with the identical plasmid antigen and a plasmid construct encoding SIV Vpr/Vpx. Animals were subsequently challenged intrarectally with pathogenic SIVmac251 after the final vaccination of a multiple immunization protocol. Control animals were all infected and exhibited high viral loads and rapid CD4+ T-cell loss. In contrast, the Nef plasmid-vaccinated animals were also infected but exhibited preservation of CD4+ T-cells and a multilog reduction in viral load compared with controls. Animals covaccinated multiple times with the Nef vaccine and pVpr/Vpx plasmid suffered rapid and profound loss of CD4+ T-cells. These results have important implications for the design of multicomponent and particle vaccines for HIV-1 as well as for our understanding of HIV/SIV pathogenesis in vivo.
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: K
authors.initials: K
authors.lastname: Muthumani
authors.forename: M
authors.initials: M
authors.lastname: Bagarazzi
authors.forename: D
authors.initials: D
authors.lastname: Conway
authors.forename: D S
authors.initials: DS
authors.lastname: Hwang
authors.forename: V
authors.initials: V
authors.lastname: Ayyavoo
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Manson
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Boyer
authors.forename: D B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology*; D016336:Gene Products, vpr / Q000235:genetics / Q000276:immunology*; D016015:Logistic Models; D008213:Lymphocyte Activation; D008253:Macaca mulatta / Q000276:immunology* / Q000821:virology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000235:genetics; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D018449:SAIDS Vaccines / Q000235:genetics* / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D013997:Time Factors; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology; D019562:Viral Load
chemical_list: D015693:Gene Products, nef; D016336:Gene Products, vpr; D012367:RNA, Viral; D018449:SAIDS Vaccines; D019444:Vaccines, DNA