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.
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|Shevchenko, Galina; Morris, Kevin V (2018) All I's on the RADAR: role of ADAR in gene regulation. FEBS Lett 592:2860-2873|
|Shrivastava, Surya; Charlins, Paige; Ackley, Amanda et al. (2018) Stable Transcriptional Repression and Parasitism of HIV-1. Mol Ther Nucleic Acids 12:12-18|
|Johnsson, Per; Lister, Nicholas; Shevchenko, Galina et al. (2017) Reply to Liu et al.: Yin and yang of PTEN regulation. Proc Natl Acad Sci U S A 114:E10512-E10513|
|Lister, Nicholas; Shevchenko, Galina; Walshe, James L et al. (2017) The molecular dynamics of long noncoding RNA control of transcription in PTEN and its pseudogene. Proc Natl Acad Sci U S A 114:9942-9947|
|Hewson, Chris; Morris, Kevin V (2016) Form and Function of Exosome-Associated Long Non-coding RNAs in Cancer. Curr Top Microbiol Immunol 394:41-56|
|Lazar, Daniel C; Morris, Kevin V; Saayman, Sheena M (2016) The emerging role of long non-coding RNAs in HIV infection. Virus Res 212:114-26|
|Saayman, Sheena M; Lazar, Daniel C; Scott, Tristan A et al. (2016) Potent and Targeted Activation of Latent HIV-1 Using the CRISPR/dCas9 Activator Complex. Mol Ther 24:488-98|
|Weinberg, Marc S; Morris, Kevin V (2016) Transcriptional gene silencing in humans. Nucleic Acids Res 44:6505-17|
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