期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：2
页码：518-523
DOI：10.1073/pnas.1407466112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceA major obstacle to developing an effective T-cell-based AIDS vaccine is that the immunization may activate CD4+ T cells, possibly making them more susceptible to infection by HIV. We tested several vaccine candidates and their effects on mucosal CD4+ T cells in a simian model of HIV infection [i.e., Simian immunodeficiency virus (SIV) infection of rhesus macaques]. We find that the immunizations did not protect the animals against infection; however, a lower set-point viral load was observed in the vaccinated animals. Importantly, this study showed that the presence of higher levels of activated CD4+ T cells in mucosal tissues is associated with increased risk of breakthrough SIV infection in vaccinated animals. 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/-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.
