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Recombinant influenza virus expressing HIV-1 p24 capsid protein induces mucosal HIV-specific CD8 T-cell responses
Affiliation:1. Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria 3010, Australia;2. School of Medicine, Deakin University, Geelong, Victoria, Australia;3. CSIRO Animal Health Laboratories, Geelong, Victoria, Australia;4. Melbourne Sexual Health Centre, Alfred Hospital, Monash University Central Clinical School, Victoria, Australia;5. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Melbourne, Victoria, Australia;6. Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, United States;1. Centre for Biomedical Research, Burnet Institute, 85 Commercial Road, Melbourne 3004, VIC, Australia;2. School of Applied Sciences, RMIT University, Plenty Road, Bundoora 3083, VIC, Australia;3. Influenza Research and Development, bioCSL Limited, 63 Poplar Road, Parkville 3052, VIC, Australia;1. Division of Biological Standards and Quality Control, Office of Compliance and Biologic Quality, CBER, FDA, New Hampshire Avenue, Silver Spring, MD 10903, USA;2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;3. Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 33 North Dr, Bethesda, MD, USA;1. Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA;2. University of Pennsylvania Perelman School of Medicine Institute for Immunology, Philadelphia, PA 19104, USA;1. Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, Zhejiang Province, China;2. Chun’an County Center for Disease Control and Prevention, Hangzhou 311700, Zhejiang Province, China;3. Changchun BCHT Biotechnology Co., Changchun 130012, Jilin Province, China;4. Xiuzhou District Center for Disease Control and Prevention, Jiaxing 314031, Zhejiang Province, China
Abstract:Influenza viruses are promising mucosal vaccine vectors for HIV but their use has been limited by difficulties in engineering the expression of large amounts of foreign protein. We developed recombinant influenza viruses incorporating the HIV-1 p24 gag capsid into the NS-segment of PR8 (H1N1) and X31 (H3N2) influenza viruses with the use of multiple 2A ribosomal skip sequences. Despite the insertion of a sizable HIV-1 gene into the influenza genome, recombinant viruses were readily rescued to high titers. Intracellular expression of p24 capsid was confirmed by in vitro infection assays. The recombinant influenza viruses were subsequently tested as mucosal vaccines in BALB/c mice. Recombinant viruses were attenuated and safe in immunized mice. Systemic and mucosal HIV-specific CD8 T-cell responses were elicited in mice that were immunized via intranasal route with a prime-boost regimen. Isolated HIV-specific CD8 T-cells displayed polyfunctional cytokine and degranulation profiles. Mice boosted via intravaginal route induced recall responses from the distal lung mucosa and developed heightened HIV-specific CD8 T-cell responses in the vaginal mucosa. These findings demonstrate the potential utility of recombinant influenza viruses as vaccines for mucosal immunity against HIV-1 infection.
Keywords:Vaccine  Influenza  HIV  Mucosal immunity  CD8 T-cell  Prime-boost
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