AAV vector has recently been used to deliver single chain Fv immunoadhesin (scFVI) versions of rhesus monkey antibodies with neutralizing activity against SIV. High, persisting levels of scFVI were achieved in 6 of 9 rhesus monkeys and these six exhibited a sterilizing barrier against SIV challenge. Three of the nine monkeys developed antibody responses to the scFVI that they received and these three were not protected against SIV challenge. Two different approaches will be compared for AAV vector delivery of the authentic IgG verison of these scFVIs. We will determine whether delivery of authentic IgG decreases the frequency with which anti-anti responses are observed. We will determine whether AAV vector can be used to deliver dimeric secretory IgA and whether secretory IgA provides a more effective barrier to SIV infection by the mucosal route. Finally, we will determine whether antibody-dependent cellular cytotoxicity is important for the protective effects of the IgG versions of 4L6 and 5L7. Results from these experiments in rhesus monkeys will inform and guide development of analogous vectors for the prevention of HIV-1 infection in humans.
Successful strategies have not been devised for the elicitation of antibodies with potent broadly-neutralizing activity against field strains of HIV-1. Use of AAV vector to deliver predefined antibodies with potent, broadly-neutralizing activity is a novel promising strategy for creating a sterilizing barrier to HIV-1 infection. Results from the proposed experiments in rhesus monkeys will uniform and guide development of such vectors for the prevention of HIV-1 infection in humans.
|Stephenson, Kathryn E; Neubauer, George H; Reimer, Ulf et al. (2015) Quantification of the epitope diversity of HIV-1-specific binding antibodies by peptide microarrays for global HIV-1 vaccine development. J Immunol Methods 416:105-23|
|Barouch, Dan H; Picker, Louis J (2014) Novel vaccine vectors for HIV-1. Nat Rev Microbiol 12:765-71|
|Dugast, Anne-Sophie; Chan, Ying; Hoffner, Michelle et al. (2014) Lack of protection following passive transfer of polyclonal highly functional low-dose non-neutralizing antibodies. PLoS One 9:e97229|
|Balandya, Emmanuel; Miller, Andrew D; Beck, Matthew et al. (2014) Adenovirus serotype 26 and 35 vectors induce simian immunodeficiency virus-specific T lymphocyte responses in foreskin in rhesus monkeys. J Virol 88:3756-65|
|Barouch, Dan H; Michael, Nelson L (2014) Accelerating HIV-1 Vaccine Efficacy Trials. Cell 159:969-72|
|Li, Qingsheng; Zeng, Ming; Duan, Lijie et al. (2014) Live simian immunodeficiency virus vaccine correlate of protection: local antibody production and concentration on the path of virus entry. J Immunol 193:3113-25|
|Whitney, James B; Hill, Alison L; Sanisetty, Srisowmya et al. (2014) Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature 512:74-7|
|Teigler, Jeffrey E; Phogat, Sanjay; Franchini, Genoveffa et al. (2014) The canarypox virus vector ALVAC induces distinct cytokine responses compared to the vaccinia virus-based vectors MVA and NYVAC in rhesus monkeys. J Virol 88:1809-14|
|Shang, Liang; Smith, Anthony J; Duan, Lijie et al. (2014) NK cell responses to simian immunodeficiency virus vaginal exposure in naive and vaccinated rhesus macaques. J Immunol 193:277-84|
|Barouch, Dan H; Deeks, Steven G (2014) Immunologic strategies for HIV-1 remission and eradication. Science 345:169-74|
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