Targeted transcriptional activation of HIV
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Principal Investigator: Kevin V Morris Organization: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE Fiscal Year: 2020 Award: $440,000 Funding agency: National Institute of Allergy and Infectious Diseases Project Summary Targeted transcriptional activation of HIV Human Immunodeficiency Virus type 1 (HIV-1) is a lentivirus that causes a persistent viral infection that results in the demise of immune regulatory cells. Clearance of HIV-1 infection by the immune system is inefficient, and integration of proviral DNA into the genome of host cells provides an efficient means for evasion and long-term persistence. This proviral integrant is potentially subjected to the regulatory control which ultimately leads to the orchestration of transcriptional shutdown and a latent state in resting CD4+ cells (reviewed in (1)). Viral latency is thought to be the result of the virus remaining quiescent and undetected in resting CD4+ T-cells (2). A methodology to reactivate latent virus is paramount to developing afunctional cure and purging reservoirs of viral infected T-cells. We have recently developed three recombinant proteins that can activate HIV directly or T-cells harboring latent provirus. We propose here to develop three aims to develop an HIV specific and general T-cell transcriptional activator to be used to purge reservoirs of latent virus, with the premise that it is possible to activate, and purge HIV from infected ART induced latent infected T-cells in vivo. In Aim 1, we will develop and contrast recombinant protein, exosome, or lipid nanoparticle delivered ZFP- 362-VPR for transcriptional activation of latent HIV while in Aim 2 we will we will Develop and test recombinant CD18 and truncated CD11b I-domain A proteins for targeted activation of HIV in ART induced latently infected CD4+ T-cells. AIM 3 will contrast ZFP-362-VPR, recombinant CD18, and truncated CD11b I-domain A in vivo for targeted activation of latent HIV. These Aims are designed to be complimentary used in conjunction with one another to stably activate and potentially purge HIV- 1 provirus from latently infected cells. Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Arts><Brain><Brain Nervous System><CD11b><CD18><CD34><CD34 gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CR3A><Cell Body><Cells><DNA><Deoxyribonucleic Acid><Encephalon><Gene Transcription><Genetic Transcription><Genome><HIV><HIV-1><HIV-I><HIV1><HPCA1><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><ITGAM><ITGAM gene><ITGB2><ITGB2 gene><Immune><Immune system><Immunes><Individual><Infection><LAV-HTLV-III><LCAMB><Lead><Lentivirinae><Lentivirus><Lymphadenopathy-Associated Virus><MAC1A><MF17><MO1A><Messenger RNA><Methodology><Methods><Modern Man><Patients><Pb element><Proteins><Proviruses><RNA Expression><Recombinant Proteins><Recombinants><Rest><Sampling><Subfamily lentivirinae><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Testing><Therapeutic><Transcription><Transcription Activation><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcriptional Activation><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Viral Diseases><Viral Latency><Viral reservoir><Virus><Virus Diseases><Virus Latency><Virus reservoir><Virus-HIV><Virus-Lenti><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><allergic/immunologic body system><allergic/immunologic organ system><design><designing><exosome><heavy metal Pb><heavy metal lead><in vivo><innovate><innovation><innovative><lipid nanoparticle><mRNA><mouse model><murine model><nano particle delivery><nanoparticle delivered><nanoparticle delivery><protein activation><purge><purges><purging><thymus derived lymphocyte><transcription co-activator><transcriptional co-activator><viral infection><virus infection><virus-induced disease>