title: Activated CD4+CCR5+ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques.
abstract: An effective T-cell-based AIDS vaccine should induce strong HIV-specific CD8(+) T cells in mucosal tissues without increasing the availability of target cells for the virus. Here, we evaluated five immunization strategies that include Human adenovirus-5 (AdHu5), Chimpanzee adenovirus-6 (AdC6) or -7 (AdC7), Vaccinia virus (VV), and DNA given by electroporation (DNA/EP), all expressing Simian immunodeficiency virus group specific antigen/transactivator of transcription (SIV(mac239Gag/Tat)). Five groups of six rhesus macaques (RMs) each were vaccinated with DNA/EP-AdC6-AdC7, VV-AdC6-AdC7, DNA/-EP-VV-AdC6, DNA/EP-VV-AdC7, or AdHu5-AdHu5-AdHu5 and were challenged repeatedly with low-dose intrarectal SIVmac239. Upon challenge, there were no significant differences among study groups in terms of virus acquisition or viral load after infection. When taken together, the immunization regimens did not protect against SIV acquisition compared with controls but did result in an ∼ 1.6-log decline in set-point viremia. Although all immunized RMs had detectable SIV-specific CD8(+) T cells in blood and rectal mucosa, we found no correlation between the number or function of these SIV-specific CD8(+) T cells and protection against SIV acquisition. Interestingly, RMs experiencing breakthrough infection showed significantly higher prechallenge levels of CD4(+)C-C chemokine receptor type 5 (CCR5)(+)HLA-DR(+) T cells in the rectal biopsies (RB) than animals that remained uninfected. In addition, among the infected RMs, the percentage of CD4(+)CCR5(+)Ki-67(+) T cells in RBs prechallenge correlated with higher early viremia. Overall, these data suggest that the levels of activated CD4(+)CCR5(+) target T cells in the rectal mucosa may predict the risk of SIV acquisition in RMs vaccinated with vectors that express SIVGag/Tat.
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Diane G
authors.initials: DG
authors.lastname: Carnathan
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Wetzel
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Joana
authors.initials: J
authors.lastname: Yu
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: S Thera
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY 14642;
authors.forename: Brent A
authors.initials: BA
authors.lastname: Johnson
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
authors.forename: Mirko
authors.initials: M
authors.lastname: Paiardini
authors.affiliation: Inovio Pharmaceuticals, Plymouth Meeting, PA 19462;
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Inovio Pharmaceuticals, Plymouth Meeting, PA 19462;
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Morrow
authors.affiliation: Inovio Pharmaceuticals, Plymouth Meeting, PA 19462;
authors.forename: Niranjan Y
authors.initials: NY
authors.lastname: Sardesai
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
authors.affiliation: Wistar Institute, Philadelphia, PA 19104.
authors.forename: Hildegund C J
authors.initials: HC
authors.lastname: Ertl
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; gsilves@emory.edu.
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D015683:Gene Products, gag / Q000276:immunology; D015696:Gene Products, tat / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D018928:Immunity, Mucosal; D008213:Lymphocyte Activation; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D019713:Receptors, CCR5 / Q000378:metabolism; D012007:Rectum / Q000276:immunology / Q000821:virology; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000472:pathogenicity; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology*; D014611:Vaccination / Q000379:methods; D014766:Viremia / Q000276:immunology / Q000517:prevention & control
chemical_list: D015683:Gene Products, gag; D015696:Gene Products, tat; D019713:Receptors, CCR5; D018449:SAIDS Vaccines
keywords: CD4; HIV; SIV; vaccination