Using adenoviral vectors to express broadly neutralizing anti-gp160 antibodies
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DESCRIPTION (provided by applicant): Recent estimates have suggested there are 1.1 million individuals living with human immunodeficiency virus (HIV) in the United States with over 56,000 new infections arising annually. Of these new infections, 12% are a direct result of intravenous drug use (IDU, sharing of contaminated needles) and 32% are due to IDU-associated behaviors (heterosexual and homosexual contact with an IDU individual). According to the Centers for Disease Control, IDU is considered the third most important risk factor for HIV infection, surpassed by the risk groups of men who have sex with men and individuals engaging in unprotected heterosexual contact. While drug use prevention and treatment can alleviate the incidence of HIV, this may not be currently achievable due to inadequate funding and access to resources given the number and socioeconomic status of IDU individuals; thus in the meantime treatment of the disease is key. For individuals in the US and developing world who live with HIV, highly active antiretroviral therapy (HAART) has become the mainstay of treatment. New developments in HAART have given rise to increasing numbers of patients with undetectable viremia, higher CD4+ T-cell counts, better quality of life, and overall improved survival. However, many issues remain by way of emergence of escape mutants, patient inaccessibility and non-adherence, adverse side effects and the need for ongoing treatment. Importantly, HAART does not affect cells that continue to produce virus. As a result, most patients on HAART have low-level viremia and must remain on treatment indefinitely to prevent viral rebound. To therapeutically address this issue, we propose the use of first generation and helper-dependent adenoviral vectors encoding broadly neutralizing antibodies (bnAbs) against HIV gp160. Such bnAbs can target antigen-expressing, infected cells for elimination by the host immune system, and the use of adenoviral vectors gives high efficiency transduction of diverse cell types for long-term transgene expression. First, well-characterized bnAbs will be encoded in the context of first generation and helper-dependent adenoviral systems. Second, we will produce and purify high-titer stocks of vector particles for in vitro characterization. Third, vectr particles will be tested in vivo with the use of a humanized mouse model of HIV infection to determine the effectiveness of the bnAbs in reducing viral replication. In this proposal vector-encoded bnAbs will be tested in parallel against purified recombinant bnAbs, and first generation adenoviruses compared with helper-dependent adenoviruses. Various combinations of encoded bnAbs will be tested to determine if targeting different epitopes improves efficacy. The completion of these objectives should provide insight into adenoviral-mediated vector delivery and host-neutralizing anti-HIV antibody responses, as well as offer the potential for new vector-mediated means of long-lasting therapy that may eventually reduce the frequency and duration of HAART required for infected individuals, including those who use substances.
