Recent efforts toward an HIV vaccine focus on inducing broadly neutralizing antibodies, but eliciting both neutralizing antibodies (nAbs) and cellular responses may be superior. Here, we immunized macaques with an HIV envelope trimer, either alone to induce nAbs, or together with a heterologous viral vector regimen to elicit nAbs and cellular immunity, including CD8+ tissue-resident memory T cells. After ten vaginal challenges with autologous virus, protection was observed in both vaccine groups at 53.3% and 66.7%, respectively. A nAb titer >300 was generally associated with protection but in the heterologous viral vector + nAb group, titers <300 were sufficient. In this group, protection was durable as the animals resisted six more challenges 5 months later. Antigen stimulation of T cells in ex vivo vaginal tissue cultures triggered antiviral responses in myeloid and CD4+ T cells. We propose that cellular immune responses reduce the threshold of nAbs required to confer superior and durable protection.
Bibliographical noteFunding Information:
We thank all animal staff at the Yerkes National Primate Research Center at Emory University for help with the macaque study and B. Wehrle and Z. S. Momin for technical assistance in processing samples. We thank J. Yewdell and D. Barouch for providing VV-Gag and Ad5-Gag viral vectors, respectively. We thank A. Dey of the International AIDS Vaccine Initiative for providing us with BG505 SOSIP.664 for vaccinations. We thank CFAR Immunology/Emory Vaccine Center Flow Cytometry Core, especially K. Gill and Stanford Shared FACS Facility, especially M. Rieck, for the support with flow cytometry. We thank S. Liang and S. Wang at the CFAR Immunology Core for viral load assays. We thank the Genome Sequencing Service Center by the Stanford Center for Genomics and Personalized Medicine, especially K. Garam, for gene expression library preparation and sequencing. We thank Y. Rosenberg at the Human Immune Monitoring Center for the Luminex assay. We thank S. de Jong, Pulendran laboratory, for critical reading of the first draft of the manuscript. TZM-bl cells were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: TZM-bl cells (cat. no. 8129) from J. C. Kappes and X. Wu. We acknowledge the NIH AIDS Reagent Program for Gag and Env peptide pool reagents. This work was supported by NIH grants UM1 AI124436 (Emory Consortium for Innovative AIDS Research in Nonhuman Primates, Principal Investigators E.H. and R.R.A.), NIAID UM1AI100663 (Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery to B.P. (Principal Investigator of the program, D. Burton) and the Bill and Melinda Gates Foundation Center for AIDS Vaccine Discovery (to B.P.) and HIVRAD P01 AI 110657 (to J.P.M.). This project was funded in part by the Yerkes National Primate Research Center Grant No. ORIP/OD P51OD011132, supported by the NIH, Office of Research Infrastructure Programs. We thank W. Ding for preparation of the SHIV.BG505 challenge stock.
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