Evaluation of novel therapeutics for HIV prevention and treatment in a humanized mouse model
Date
2011
Authors
Neff, Charles Preston Tagg, author
Akkina, Ramesh, advisor
Aboellail, Tawfik, committee member
Callahan, Gerald, committee member
Chen, Chaoping, committee member
Garrity, Deborah, committee member
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Abstract
In the absence of an effective HIV-1 vaccine finding alternative therapeutics and preventative methods has become essential. In this regard preventative approaches such as pre-exposure chemo-prophylaxis that employ either topical applied microbicides or systemically administered anti-retroviral drugs show great promise. In these studies, we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically and topically applied pre-exposure chemo-prophylaxis. Additionally, therapeutic strategies designed to combat HIV/AIDS using siRNAs show considerable promise. However, targeted delivery of these synthetic molecules into infected cells in vivo has been a formidable challenge. In addressing this need we sought to evaluate the efficacy of a chimeric construct consisting of an HIV-1 gp120 specific aptamer with viral neutralization capacity fused to a siRNA with proven efficacy against tat/rev viral transcripts. We also sought to evaluate the efficacy of structurally flexible, cationic PAMAM dendrimers as a siRNA delivery system. For these novel therapeutic strategies to succeed it is important to evaluate them in both in vitro and in vivo. The rhesus macaque has been a valuable research tool for comparative HIV-1 studies. However, aspects of this model render its usefulness limited considering its expensive nature and not utilizing HIV-1 itself. In this regard the recently developed humanized mouse model that permits multi-lineage human hematopoiesis is an excellent alternative to the non human primate model. To generate humanized mice, neonatal Rag2-/-yc-/- or Rag1-/-yc-/- mice were xenografted with human CD34+ hematopoietic stem cells, resulting in a model that can permit HIV-1 infection. Upon infection by HIV-1 chronic viremia develops with a subsequent loss of CD4 T cells. These mice also successfully mimic the predominant mode of HIV-1 transmission via the sexual vaginal route which also results in chronic viremia and helper T cell loss. Thus this small animal model permits the rapid preclinical evaluation of potential candidates for pre-exposure prophylactic (PrEP) efficacy as well as novel RNA-based therapeutics. Here we utilize these humanized mouse models to evaluate the PrEP efficacies of the drugs named above as well as the in vivo efficacy of siRNAs delivered by utilizing a chimeric aptamer construct or a PAMAM dendrimer. Our results showed that both of these approaches using either a chimeric aptamer or a PAMAM dendrimer resulted in suppression of viral loads in vivo and most importantly also resulted in protection from T-cell depletion, making these compounds attractive therapeutic candidates for the treatment of HIV-1 infection. Lastly, using the same humanized mouse model we also successfully tested a gene therapy strategy employing lentiviral vectors having RNA-based anti-HIV-1 constructs convey intracellular immunization against HIV-1 in vivo.
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Subject
novel
therapeutics
humanized
prevention
HIV
mice