title: Multispecific vaccine-induced mucosal cytotoxic T lymphocytes reduce acute-phase viral replication but fail in long-term control of simian immunodeficiency virus SIVmac239.
abstract: Given the current difficulties generating vaccine-induced neutralizing antibodies to human immunodeficiency virus (HIV), the focus of the vaccine community has shifted toward creating cytotoxic-T-lymphocyte (CTL)-based vaccines. Recent reports of CTL-based vaccine trials in macaques challenged with simian/human immunodeficiency virus SHIV-89.6P have supported the notion that such vaccines can ameliorate the course of disease. However, almost all of these studies included Env as an immunogen and since SHIV-89.6P is sensitive to neutralizing antibodies it is difficult to determine the mechanism(s) of protection. Consequently, SHIV-89.6P challenge of macaques may be a poor model for determining vaccine efficacy in humans. To ascertain the effect of vaccine-induced multispecific mucosal CTL, in the absence of Env-specific antibody, on the control of an immunodeficiency virus challenge, we vaccinated Mamu-A*01(+) macaques with constructs encoding a combination of CTL epitopes and full-length proteins (Tat, Rev, and Nef) by using a DNA prime/recombinant modified vaccinia virus Ankara (rMVA) boost regimen. The vaccination induced virus-specific CTL and CD4(+) helper T lymphocytes with CTL frequencies as high as 20,000/million peripheral blood mononuclear cells. The final rMVA vaccination, delivered intravenously, engendered long-lived mucosal CTL. At 16 weeks after the final rMVA vaccination, the vaccinees and naive, Mamu-A*01(+) controls were challenged intrarectally with SIVmac239. Massive early anamnestic cellular immune responses controlled acute-phase viral replication; however, the three vaccinees were unable to control virus replication in the chronic phase. The present study suggests that multispecific mucosal CTL, in the absence of neutralizing antibodies, can achieve a modicum of control over early viral replication but are unable to control chronic-phase viral replication after a high-dose mucosal challenge with a pathogenic simian immunodeficiency virus.
authors.affiliation: Wisconsin Primate Research Center. Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors.forename: Thorsten U
authors.initials: TU
authors.lastname: Vogel
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reynolds
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Fuller
authors.forename: Kathy
authors.initials: K
authors.lastname: Vielhuber
authors.forename: Tim
authors.initials: T
authors.lastname: Shipley
authors.forename: James T
authors.initials: JT
authors.lastname: Fuller
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Kunstman
authors.forename: Gerd
authors.initials: G
authors.lastname: Sutter
authors.forename: Marta L
authors.initials: ML
authors.lastname: Marthas
authors.forename: Volker
authors.initials: V
authors.lastname: Erfle
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: Chenxi
authors.initials: C
authors.lastname: Wang
authors.forename: David B
authors.initials: DB
authors.lastname: Allison
authors.forename: Erling W
authors.initials: EW
authors.lastname: Rud
authors.forename: Nancy
authors.initials: N
authors.lastname: Wilson
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.forename: John D
authors.initials: JD
authors.lastname: Altman
authors.forename: David I
authors.initials: DI
authors.lastname: Watkins
mesh_terms: D000208:Acute Disease; D000818:Animals; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D018928:Immunity, Mucosal; D007117:Immunization, Secondary; D008253:Macaca mulatta; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; C110764:Mamu-A 01 antigen; D018449:SAIDS Vaccines; D019444:Vaccines, DNA