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ABSTRACT: Candidate vaccine ChimeriVax viruses are attenuated, efficacious, safe, and highly unlikely to be transmitted by arthropod vectors. Nevertheless, concerns have been raised about the use of these vaccines because of the potential for recombination between vaccine and wild-type (WT) strains. To evaluate the vertebrate pathogenicity of such a worst-case recombinant, ChimeriVax-dengue (DEN) 4 virus was chimerized with the WT Asibi yellow fever virus. In this worst-case scenario, chimeric viruses remained fully attenuated in nonhuman primates. We therefore conclude that, even in the highly unlikely event of "virulent" backbone reversion, the safety of ChimeriVax-DEN vaccines would not be compromised.
The Journal of Infectious Diseases 04/2008; 197(5):693-7. · 6.41 Impact Factor
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ABSTRACT: Highly active antiretroviral therapy (HAART) against human immunodeficiency virus type 1 (HIV-1) infection dramatically suppresses viral load, leading to marked reductions in HIV-1 associated morbidity and mortality. However, infected cell reservoirs and low-level replication persist in the face of suppressive HAART, leading invariably to viral rebound upon cessation of treatment. Toxins engineered to target the Env glycoprotein on the surface of productively infected cells represent a complementary strategy to deplete these reservoirs. We described previously highly selective killing of Env-expressing cell lines by CD4(178)-PE40 and 3B3(Fv)-PE38, recombinant derivatives of Pseudomonas aeruginosa exotoxin A containing distinct targeting moieties against gp120. In the present report, we compare the in vitro potency and breadth of these chimeric toxins against multiple clinical HIV-1 isolates, replicating in biologically relevant primary human target cell types. In PBMCs, 3B3(Fv)-PE38 blocked spreading infection by all isolates examined, with greater potency than CD4(178)-PE40. 3B3(Fv)-PE38 also potently inhibited spreading HIV-1 infection in primary macrophages. Control experiments demonstrated that in both target cell types, most of the 3B3(Fv)-PE38 activity was due to selective killing of infected cells, and not merely to neutralization by the antibody moiety of the chimeric toxin. High-dose treatment of rhesus macaques with 3B3(Fv)-PE38 did not induce liver toxicity, whereas equivalent dosage of CD4(178)-PE40 induced mild hepatotoxicity. These findings highlight the potential use of 3B3(Fv)-PE38 for depleting HIV-infected cell reservoirs persisting in the face of HAART.
Journal of Leukocyte Biology 12/2006; 80(5):1175-82. · 4.99 Impact Factor
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Julianna Lisziewicz,
Jeffrey Trocio,
Jianqing Xu,
Lucia Whitman,
Amy Ryder,
Nyasha Bakare,
Mark G Lewis, Wendeline Wagner,
Angela Pistorio,
Suresh Arya,
Franco Lori
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ABSTRACT: To reconstitute immune responses capable of eliminating infected cells and suppressing viral load during chronic retroviral infection.
: A topical, DNA-based therapeutic immunization (DermaVir) was designed to express most of the regulatory and structural viral genes in dendritic cells.
DermaVir alone and in combination with antiretroviral drugs was tested in chronically SIV-infected macaques.
DermaVir provided virological, immunological and clinical benefit for SIV-infected macaques during chronic infection and AIDS. In combination with antiretroviral drugs, DermaVir augmented SIV-specific T-cell responses and enhanced control of viral load rebound during treatment interruptions.
The results indicate the feasibility of therapeutic immunization even in immune compromised hosts, and suggest that DermaVir can complement antiretroviral drugs to sustain suppression of HIV-1 replication.
AIDS 02/2005; 19(1):35-43. · 6.24 Impact Factor
