Activated CD4(+)CCR5(+) T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

• Type of Material: Article
• Authors: Diane G. Carnathan, Emory University; Katherine S. Wetzel, Emory University; Joana Yu, Emory University; S. Thera Lee, Emory University; Brent A. Johnson, University of Rochester; Mirko Paiardini, Emory University; Jian Yan, Inovio Pharmaceut; Matthew P. Morrow, Inovio Pharmaceut; Niranjan Y. Sardesai, Inovio Pharmaceut; David B. Weiner, University of Pennsylvania; Hildegund C. J. Ertl, Wistar Institute; Guido Silvestri, Emory University
• Language: English
• Date: 2015-01-13
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: National Academy of Sceinces
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1407466112
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 112
• Issue: 2
• Start Page: 518
• End Page: 523
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH) Grant HIVRAD P01 A080082 (to H.C.J.E. and G.S.) and by NIH/National Center for Research Resources Grant P51RR000165 and currently is supported by the Office of Research Infrastructure Programs Grant OD P51OD011132 to the Yerkes National Primate Research Center. N.Y.S., J. Yan, and M.P.M. were supported in part by NIH/National Institute of Allergy and Infection Diseases/Division of AIDS Grant HHSN272200800063C for HIV vaccine development.; D.B.W. has grant funding, participates in industry collaborations, has received speaking honoraria, and fees for consulting.
• Keywords: ADENOVIRUS; VIREMIA; Science & Technology - Other Topics; HIV; INFECTION; REPLICATION; vaccination; SIV; IMMUNODEFICIENCY VIRUS CHALLENGE; Science & Technology; SOOTY MANGABEYS; HIV-1 VACCINE; CD4; CELLULAR IMMUNE-RESPONSES; EFFICACY; Multidisciplinary Sciences; DOUBLE-BLIND
• Research Categories: Health Sciences, Immunology; Biology, Virology

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 (SIVmac239Gag/Tat). Five groups of six rhesus macaques (RMs) each were vaccinated with DNA/EP-AdC6-AdC7, VV-AdC6-AdC7, DNA/-EPVV- 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 SIVspecific 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.