HIV-1 remains a constant threat to global health through its ability to integrate and persist in the genome of infected cells. Current therapeutic strategies effectively reduce HIV-1 replication and improve quality of life, however, existence of viral variants allows for the persistence and eventual recovery of pathogenic variants. These variants are the inevitable outcome of the stable integration of HIV-1, which allows for the natural selection and evolution of drug resistant strains. Interestingly, integrated HIV can provide an ideal environment for the propagation and dissemination of conditionally replicating vectors. We have found that when conditionally replicating vectors contain antiviral genes expressing small non-coding RNAs targeted to transcriptionally active regions of the LTR, an added long-term epigenetic mediated selective pressure is placed on the virus. The observed selective pressure correlates with both the persistence of the vector and significant transcriptional suppression of the virus resulting in reduced viral fitness. Moreover, we will utilize these validated small non-coding RNAs and a recently developed small RNA targeted gene excision complex to excise fragments of HIV-1 or CCR5 from human cells in an effort to permanently alter viral and OCRS co-receptor expression. In this project we will develop conditionally replicating vectors that can both target HIV-1 or CCR5 for suppression and/or excision while simultaneously hijacking the viral machinery to spread the anti-HIV-1 vector to other cells being infected with HIV-1. In essence we wish to place a prisoners dilemma on HIV-1 and modulate viral fitness (Morris 2004;Morris and Looney 2005). We hypothesize that the observed long-term suppression of HIV-1 can be directly regulated by such selective pressures and propose to test this hypothesis by (1) utilizing selectable conditionally replicating HIV-2 vectors, (2) determining the best suppressive vector and whether the number of small RNAs targeted to HIV or CCR5 and/or the targeted loci is important and (3) characterizing the respective long-term suppressive and/or excision properties of the best candidate vectors in human T cells and macrophages.

National Institute of Health (NIH)
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Scripps Research Institute
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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

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