Human immunodeficiency virus type 1 (HIV-1) emerged as a major human disease approximately 30 years ago, with roughly 70% of the current cases in sub-Saharan Africa and little hope for an efficacious vaccine in the near future. Alternative strategies to inhibit HIV-1 replication or purge viral resen/oirs are tremendously desirable. Several new and innovative strategies are proposed here and center on delivering small non-coding RNAs and an RNA targeted humanized protein complex capable of targeting the excision of integrated forms of HIV-1 or CCRS to specific cells. We hypothesize that it is possible to specifically target HIV-1 infected or relevant cell types in vivo and stably silence or excise HIV-1 or CCRS from these cells. The result of this targeted suppression/excision is a loss of HIV-1 fidelity and a functional cure. We will test our hypothesis using the recently developed and well-validated Rag2-/- yc-/- (RAG-hu) mouse model. We propose 3 aims which will test our hypothesis;
aim 1 contrast the various conditionally replicating vector systems for suppression and/or excision of HIV-1 and CCRS in the RAG-hu mouse model, aim 2 determine the ability of aptamer targeted minigenes or siRNAs to suppress and/or target the excision of HIV-1 or CCRS in vivo, and in aim 3 we will determine the ability of nanoparticle targeted minigenes and the Pddlp excision complex to suppress and target the excision of HlV-1 or CCRS in vivo. We envision one of these three different delivery platforms to prove efficacious at targeting HlV-1 or CCRS in target cells and significantly affecting viral replication and evolution, leading ultimately to functional cure (a state where viral replication and mutation is inhibited). Notably, data generated from the in vivo core can be translated efficiently into human based trials depending on the resultant findings.
This project will determine ability of three different cell targeted delivery strategies to selectively inhibit HIV-1 or CCRS expression in vivo and specifically affect the pathogenicity and infectivity of HIV-1.
|Johnsson, Per; Lipovich, Leonard; Grander, Dan et al. (2014) Evolutionary conservation of long non-coding RNAs; sequence, structure, function. Biochim Biophys Acta 1840:1063-71|
|Damski, Caio; Morris, Kevin V (2014) Targeted small noncoding RNA-directed gene activation in human cells. Methods Mol Biol 1173:1-10|
|Zhou, Jiehua; Rossi, John (2014) Cell-type-specific aptamer and aptamer-small interfering RNA conjugates for targeted human immunodeficiency virus type 1 therapy. J Investig Med 62:914-9|
|Saayman, Sheena; Ackley, Amanda; Turner, Anne-Marie W et al. (2014) An HIV-encoded antisense long noncoding RNA epigenetically regulates viral transcription. Mol Ther 22:1164-75|
|Groen, Jessica N; Capraro, David; Morris, Kevin V (2014) The emerging role of pseudogene expressed non-coding RNAs in cellular functions. Int J Biochem Cell Biol 54:350-5|
|Johnsson, Per; Morris, Kevin V; Grandér, Dan (2014) Pseudogenes: a novel source of trans-acting antisense RNAs. Methods Mol Biol 1167:213-26|
|Morris, Kevin V; Mattick, John S (2014) The rise of regulatory RNA. Nat Rev Genet 15:423-37|
|Roberts, Thomas C; Morris, Kevin V; Weinberg, Marc S (2014) Perspectives on the mechanism of transcriptional regulation by long non-coding RNAs. Epigenetics 9:13-20|
|Groen, Jessica N; Morris, Kevin V (2013) Chromatin, non-coding RNAs, and the expression of HIV. Viruses 5:1633-45|
|Akkina, Ramesh (2013) Human immune responses and potential for vaccine assessment in humanized mice. Curr Opin Immunol 25:403-9|
Showing the most recent 10 out of 15 publications