Our proposal will address the need for a safe and effective HIV vaccine using next generation adenovirus (Ad) - based vectors. A variety of viral vectors have been employed to accomplish gene-based vaccination. One particularly promising approach is based upon genetic transduction via replication-incompetent adenoviral vectors (Ad). This utility has predicated the application of Ad-based vectors for a wide range of vaccine approaches, including recent studies demonstrating utility for Malaria, Ebola, SARS, Pseudomonas, and HIV. However, the recent findings of the STEP HIV vaccine clinical trial failed to reproduce promising findings seen in animal model systems. In this regard, this trial, which used a Ad5-based vaccine, failed to protect Ad5-seronegative individuals against infection and may even have enhanced infection in vaccinees with prior immunity to adenoviruses. In the aggregate, the general agreement is that efforts to reduce vector immunogenicity with respect to pre-existing Ad5 immunity will be required to generate a safer and effective Ad- based vector as an HIV vaccine. Therefore, our proposal will address these key points by engineering multiple genetic alterations as follows: (1) To evade humoral responses to the Ad5 vector, the major capsid protein hexon will be exchanged for the hexon of Ad3, a less prevalent serotype. Human immune responses largely focus on epitopes present in the hypervariable regions (HVR) of the Ad capsid hexon;therefore, a chimeric Ad5H3 capsid will evade recognition by preimmune Abs to Ad5 hexon (2) To induce HIV specific immune responses we will employ HIV capsid incorporation of antigen. We hypothesize that these Ad vectors can circumvent Ad5 immunity and provide HIV-specific immunity. The full merit of the promising adenovirus-based approach for vaccination is currently limited by host related immunity toward the vector. Accomplishing the goals of this proposal will expand our current understanding of host-vector interactions that will be critical for advancing the Ad vector platform as a viable approach for developing effective HIV vaccines. .
In this proposal, we seek to address the need for a safe and effective HIV vaccine using next generation adenovirus-based vectors. These studies will be carried out in an in vitro context as well as a well-established rodent model system. These findings have the potential for translation into a human/clinical setting.
|Crenshaw, Brennetta J; Gu, Linlin; Sims, Brian et al. (2018) Exosome Biogenesis and Biological Function in Response to Viral Infections. Open Virol J 12:134-148|
|Gu, Linlin; Sims, Brian; Krendelchtchikov, Alexandre et al. (2017) Differential binding of the HIV-1 envelope to phosphatidylserine receptors. Biochim Biophys Acta Biomembr 1859:1962-1966|
|Gu, Linlin; Icyuz, Mert; Krendelchtchikova, Valentina et al. (2016) Development of an Ad5H3 Chimera Using the ""Antigen Capsid-Incorporation"" Strategy for an Alternative Vaccination Approach. Open Virol J 10:10-20|
|Gu, Linlin; Krendelchtchikova, Valentina; Krendelchtchikov, Alexandre et al. (2016) Adenoviral vectors elicit humoral immunity against variable loop 2 of clade C HIV-1 gp120 via ""Antigen Capsid-Incorporation"" strategy. Virology 487:75-84|
|Matthews, Qiana L; Farrow, Anitra L; Rachakonda, Girish et al. (2016) Epitope Capsid-Incorporation: New Effective Approach for Vaccine Development for Chagas Disease. Pathog Immun 1:214-233|
|Farrow, Anitra L; Peng, Binghao J; Gu, Linlin et al. (2016) A Novel Vaccine Approach for Chagas Disease Using Rare Adenovirus Serotype 48 Vectors. Viruses 8:78|
|Gu, Linlin; Farrow, Anitra L; Krendelchtchikov, Alexandre et al. (2015) Utilizing the antigen capsid-incorporation strategy for the development of adenovirus serotype 5-vectored vaccine approaches. J Vis Exp :e52655|
|Farrow, Anitra L; Rachakonda, Girish; Gu, Linlin et al. (2014) Immunization with Hexon modified adenoviral vectors integrated with gp83 epitope provides protection against Trypanosoma cruzi infection. PLoS Negl Trop Dis 8:e3089|
|Gu, Linlin; Krendelchtchikova, Valentina; Krendelchtchikov, Alexandre et al. (2014) A recombinant adenovirus-based vector elicits a specific humoral immune response against the V3 loop of HIV-1 gp120 in mice through the ""Antigen Capsid-Incorporation"" strategy. Virol J 11:112|
|Sims, Brian; Gu, Linlin; Krendelchtchikov, Alexandre et al. (2014) Neural stem cell-derived exosomes mediate viral entry. Int J Nanomedicine 9:4893-7|
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