Work

586. Anti-HIV-1 Neutralizing Antibody Gene Delivery to Rhesus Macaques and Rodents: A Novel Vaccination Approach

Year: 2006

Type: article

Abstract: We are continuing to develop a novel vaccination approach that is predicated on providing protective anti-HIV-1 humoral immune responses through antibody gene transfer. Our strategy is to utilize rAAV mediated antibody gene transfer to skeletal muscle to supply the host with a renewable source of anti-HIV-1 antibodies in their systemic circulation. The genes encode several rare, but broadly neutralizing scFv HIV-1 antibodies (X5, 3B3, and 3B3-hCC). One potential challenge to this approach is whether therapeutic levels of NAbs are achievable. Data from previous passive immunization protection studies in primates indicate that protective levels may be achieved with serum concentrations of potent NAbs in the range of 50 -100 ug/ml. To address this issue, we have optimized several variables for efficient antibody gene delivery and expression; these include rAAV serotype, antibody genetic fusions for increased half- life, and inclusion of cis sequences for maximal expression. This has resulted in increased antibody levels by greater than 100-fold over our initial efforts. Significantly, optimization of delivery and expression parameters has yielded NAb levels exceeding 500 ug/ml in mice and up to 43 ug/ml in primates - levels which approach or exceed the predicted therapeutic range. Consistent with their broad neutralization activity, animal sera containing X5 and 3B3-hCC from rAAV vaccinated mice and primates possess potent in vitro neutralization activity against TCLA and primary HIV-1 single- cycle HIV-1 pseudoviruses as measured by reduction of luciferase reporter gene activity in TZM-BL cells. These data now set the stage for future challenge experiments to determine whether the in vivo levels observed to date provide protection (reduction in viral load) upon a virulent SHIV challenge.

Source: Molecular Therapy

DOI: 10.1016/j.ymthe.2006.08.660

Authors: K. Reed Clark, Jianchao Zhang, David C. Montefiori, Philip R. Johnson

Institutions: Duke Medical Center, Abigail Wexner Research Institute, The Ohio State University, Children's Hospital of Philadelphia

Language: English

Topic: HIV Research and Treatment

Subfield: Virology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500