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- This comprehensive longitudinal study is the first to document that clinically-relevant HIV-1-specific T cell responses can be induced by rapid prime (recombinant Gag polyprotein adsorbed to PLGA microspheres) with boost (Gag-expressing HSV-1) immunization in 31 BLT humanized mice, each generated from 1/4 individual donors with distinct human HLA alleles, during the first 12 weeks of HIV-1JR-CSF infection. Gag-immunized BLT humanized mice were capable of mounting strong and broadly directed HIV-1 specific IFNγ+ T cell responses that drive CTL epitope viral evolution and enhance Gag-specific post-challenge responses while also associating with significant, yet modest, reductions in early HIV-1 viremia.
- No pre-challenge Gag-specific responses were detected and impact on early HIV-1 viremia was only transient. Authors suggest that improvements in immunization strategy and/or additional maturation of recapitulated human immune system may be beneficial for further vaccine studies.
- Origination and increasing frequency of epitope variants were generally observed in individual BLT humanized mice infected with HIV-1JR-CSF. At 12 weeks post infection, complete or nearly complete escape (<10% of inoculum sequence) was observed in 1 CTL epitope in 11/25 mice, 2 CTL epitopes in 6/25 mice and 3 CTL epitopes in 5/25 mice.
- At 12 weeks post HIV-1JR-CSF-infection, 11/17 BLT humanized mice with donor tissue expressing HLA-I alleles B0702/B5801 displayed evolution of epitope Vpu VW10, predicted to bind to B*57. Within a single mouse, the frequency of an individual variant was up to 76% while the frequency of HIV-1JR-CSF VW10 sequence VAGIIAIIVW was 17-78% in these 11 mice. B*57 HLA-I alleles and B5801 are categorized into HLA supertype B58 [Sydney, et al. BMC Immunol, 9(1). PMID: 18211710].
Daniel T. Claiborne, Timothy E. Dudek, Colby R. Maldini, Karen A. Power, Musie Ghebremichael, Edward Seung, Elizabeth F. Mellors, Vladimir D. Vrbanac, Katharine Krupp, Abigail Bisesi, Andrew M. Tager, David M. Knipe, Christian L. Boutwell, and Todd M. Allen. Immunization of BLT Humanized Mice Redirects T Cell Responses to Gag and Reduces Acute HIV-1 Viremia. J. Virol., 93(20), 15 Oct 2019. PubMed ID: 31375576.
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