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    Vaccine protection against simian immunodeficiency virus in monkeys using recombinant gamma-2 herpesvirus

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    Authors
    Bilello, John P.
    Manrique, Julieta M.
    Shin, Young C.
    Lauer, William
    Li, Wenjun
    Lifson, Jeffrey D.
    Mansfield, Keith G.
    Johnson, R. Paul
    Desrosiers, Ronald C.
    UMass Chan Affiliations
    Department of Medicine, Division of Preventive and Behavioral Medicine
    Document Type
    Journal Article
    Publication Date
    2011-12-09
    Keywords
    Animals
    Antibodies, Viral
    Blotting, Western
    Enzyme-Linked Immunosorbent Assay
    Flow Cytometry
    Gammaherpesvirinae
    Gene Products, env
    Gene Products, gag
    Gene Products, nef
    Genetic Vectors
    Herpesviridae Infections
    Humans
    Immunity, Cellular
    Immunoenzyme Techniques
    Kidney
    Macaca mulatta
    Neutralization Tests
    Plasmids
    Recombination, Genetic
    SAIDS Vaccines
    Simian Acquired Immunodeficiency Syndrome
    control
    Simian immunodeficiency virus
    Vaccination
    Viral Load
    Virus Replication
    Immunology of Infectious Disease
    Immunoprophylaxis and Therapy
    Virology
    Virus Diseases
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    Abstract
    Recombinant strains of replication-competent rhesus monkey rhadinovirus (RRV) were constructed in which strong promoter/enhancer elements were used to drive expression of simian immunodeficiency virus (SIV) Env or Gag or a Rev-Tat-Nef fusion protein. Cultured rhesus monkey fibroblasts infected with each recombinant strain were shown to express the expected protein. Three RRV-negative and two RRV-positive rhesus monkeys were inoculated intravenously with a mixture of these three recombinant RRVs. Expression of SIV Gag was readily detected in lymph node biopsy specimens taken at 3 weeks postimmunization. Impressive anti-SIV cellular immune responses were elicited on the basis of major histocompatibility complex (MHC) tetramer staining and gamma interferon enzyme-linked immunospot (ELISPOT) assays. Responses were much greater in magnitude in the monkeys that were initially RRV negative but were still readily detected in the two monkeys that were naturally infected with RRV at the time of immunization. By 3 weeks postimmunization, responses measured by MHC tetramer staining in the two Mamu-A*01(+) RRV-negative monkeys reached 9.3% and 13.1% of all CD8(+) T cells in peripheral blood to the Gag CM9 epitope and 2.3% and 7.3% of all CD8(+) T cells in peripheral blood to the Tat SL8 epitope. Virus-specific CD8(+) T cell responses persisted at high levels up to the time of challenge at 18 weeks postimmunization, and responding cells maintained an effector memory phenotype. Despite the ability of the RRVenv recombinant to express high levels of Env in cultured cells, and despite the appearance of strong anti-RRV antibody responses in immunized monkeys, anti-Env antibody responses were below our ability to detect them. Immunized monkeys, together with three unimmunized controls, were challenged intravenously with 10 monkey infectious doses of SIVmac239. All five immunized monkeys and all three controls became infected with SIV, but peak viral loads were 1.2 to 3.0 log(10) units lower and chronic-phase viral loads were 1.0 to 3.0 log(10) units lower in immunized animals than the geometric mean of unimmunized controls. These differences were statistically significant. Anti-Env antibody responses following challenge indicated an anamnestic response in the vaccinated monkeys. These findings further demonstrate the potential of recombinant herpesviruses as preventive vaccines for AIDS. We hypothesize that this live, replication-competent, persistent herpesvirus vector could match, or come close to matching, live attenuated strains of SIV in the degree of protection if the difficulty with elicitation of anti-Env antibody responses can be overcome.
    Source
    Bilello JP, Manrique JM, Shin YC, Lauer W, Li W, Lifson JD, Mansfield KG, Johnson RP, Desrosiers RC. Vaccine protection against simian immunodeficiency virus in monkeys using recombinant gamma-2 herpesvirus. J Virol. 2011 Dec;85(23):12708-20. doi: 10.1128/JVI.00865-11. Link to article on publisher's site
    DOI
    10.1128/JVI.00865-11
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/44862
    PubMed ID
    21900170
    Related Resources
    Link to Article in PubMed
    Rights
    Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
    ae974a485f413a2113503eed53cd6c53
    10.1128/JVI.00865-11
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