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Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission

Abstract

The vast majority of new HIV infections result from relatively inefficient transmission1,2 of the virus across mucosal surfaces during sexual intercourse3. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections4. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process5. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens6,7. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza8 and human papilloma virus9. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies10. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain11, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.

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Figure 1: VIP protects against CD4+ T cell depletion in humanized mice resulting from challenge with CCR5-tropic or transmitted founder HIV strains.
Figure 2: VIP prevents mucosal transmission of CCR5-tropic HIV after repetitive intravaginal challenge.
Figure 3: VIP prevents mucosal transmission of transmitted founder HIV after repetitive intravaginal challenge.

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Acknowledgements

We acknowledge G. Nabel (Sanofi-Pasteur) and J. Mascola (US National Institutes of Health (NIH) Vaccine Research Center) for VRC01, VRC-PG04, VRC07 and VRC07G54W expression plasmids and proteins, D. Burton (Scripps) for b12, PG9, PGT121 and PGT128 expression plasmids, M. Nussenzweig (Rockefeller) for 3BNC117 and 12A12 expression plasmids and P. Bjorkman (California Institute of Technology) for the NIH45-46W expression plasmid. We also thank the Caltech Protein Expression Center for providing purified antibodies. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), NIH: pYK-JRCSF from I.S.Y. Chen and Y. Koyanagi, pREJO.c/2864 from J. Kappes and C. Ochsenbauer and TZM-bl cells from J. Kappes and X. Wu. We thank J. Kim, D. Majumdar, M. Mann and A. So for their helpful comments and other members of the Baltimore lab, as well as R. Cortado and S. Shimizu in the An lab, for their assistance in carrying out this work. Preparation of human CD34+ cells, tissue procurement and BLT mice were supported by the UCLA Center for AIDS Research (CFAR) AI028697. A.B.B. is supported by the NIAID Career Transition Award 1K22AI102769. D.S.R. was a Sidney Kimmel Scholar supported by the Sidney Kimmel Foundation for Cancer Research (Translational Award SKF-11-013) and is supported by career development award 1K08CA133521 from the NIH. D.S.A. is supported by NIAID grant 1R01AI100652-01A1. This project was supported by the NIH (HHSN266200500035C) through a contract from the NIAID and by the Joint Center for Translational Medicine.

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A.B.B. and D.B. conceived the study. A.B.B. designed the experiments. D.S.A. offered suggestions for the experiments and provided the BLT humanized mice. A.B.B., Y.O., C.M.H., J.C. and S.M.N. carried out experiments. A.B.B., Y.O., C.M.H., J.C. and S.M.N. analyzed the data. D.S.R. performed immunohistochemistry and analysis. A.B.B. and D.B. wrote the paper with contributions from all authors.

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Correspondence to David Baltimore.

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Balazs, A., Ouyang, Y., Hong, C. et al. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nat Med 20, 296–300 (2014). https://doi.org/10.1038/nm.3471

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