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Principal Investigator: David T Evans
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $847,878
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
A reservoir of latently infected cells persists in various anatomical sites in people living with HIV (PLWH),
despite effective virological control by antiretroviral therapy (ART). The majority of virally suppressed individuals
experience rapid viral rebound upon ART interruption, providing a strong rationale for the development of cure
strategies. Even in an ART-suppressed HIV infection, chronic inflammation and immune activation are observed,
along with limited CD4+T cell reconstitution, mucosal immune dysfunction, co-morbidities, and accelerated
ageing. Low-grade persistent transcription and trickling production of viral proteins from the pool of integrated
proviruses are believed to be partly responsible for these conditions. HIV eradication strategies such as shock-
and-kill have not been successful so far, and the pursuit of a functional cure or HIV remission has been thought
as an alternative worth exploring. A functional cure entails long-term, durable control of viral expression in the
absence of therapy, preventing disease progression and transmission, despite the presence of detectable
integrated proviruses. Our group has been at the forefront of developing one such strategy, labeled the block-
and-lock approach. The premise of this approach is that transcriptional inhibitors can mediate epigenetic
silencing of proviral expression, locking the virus in a profound state of latency from which reactivation is very
unlikely to occur upon ART discontinuation. We have demonstrated this principle using the small molecule
didehydro-Cortistatin A (dCA) inhibitor of Tat, the key regulator of HIV transcriptional amplification. In in vitro and
in humanized mouse models of HIV latency, dCA inhibition of HIV transcription over time drives the viral promoter
into deep transcriptional inhibition, limiting viral reactivation upon treatment interruption or with latency
reactivating agents (LRAs)1–8.
We believe that HIV transcriptional inhibitors, in general, have the potential to transform the way we treat HIV-
1 infections. Here we propose to investigate the potential of adding the transcriptional inhibitor dCA to an ART
regimen in the rhesus macaque (RhM) model of SHIV infection. Not only is dCA a new molecule that inhibits the
activity of a viral target not yet clinically explored, but it also opens the possibility for exploration of novel
approaches to fight HIV. Here we propose to: 1) determine the safety and pharmacokinetics of dCA in ART-
treated RhMs; 2) understand the relationship between dCA treatment and reduction in viral RNA in tissues, with
the time to viral rebound upon treatment interruption; and 3) study the impact of dCA as front-line therapy on the
size of the established viral reservoir.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Anatomic Sites><Anatomic structures><Anatomy><Anti-Retroviral Agents><Assay><Bioassay><Biological Assay><Biopsy><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Serum><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cancers><Cell Body><Cells><Chemistry><Chronic><Circulatory Collapse><Clinic><Clinical><Colon><Complete Blood Count><DNA><Deoxyribonucleic Acid><Development><Disease Progression><Disease remission><Dose><Drug Kinetics><Drug or chemical Tissue Distribution><Drugs><Endocrine Gland Secretion><Evaluation><Gene Transcription><Genetic Transcription><Goals><HIV><HIV Infections><HIV-1><HIV-I><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Hormones><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Immune Cell Activation><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><In Vitro><Individual><Infection><Inflammation><Injections><Interruption><LAV-HTLV-III><Label><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Malignant Neoplasms><Malignant Tumor><Measurement><Measures><Mediating><Medication><Modeling><Monitor><Mucosa><Mucosal Tissue><Mucous Membrane><Non-Polyadenylated RNA><PBMC><Peripheral Blood Mononuclear Cell><Persons><Pharmaceutical Preparations><Pharmacokinetics><Phase><Plasma><Plasma Serum><Production><Provirus Integration><RNA><RNA Expression><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Recrudescences><Regimen><Remission><Residual><Residual state><Resistance><Rest><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><Ribonucleic Acid><SHIV><SIV><Safety><Serum><Shock><Simian Immunodeficiency Viruses><T cell reconstitution><T-Cell Depletion><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><Therapeutic Hormone><Time><Tissue Distribution><Tissues><Toxic effect><Toxicities><Transcription><Variant><Variation><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Viral reservoir><Viremia><Virus><Virus Replication><Virus reservoir><Virus-HIV><accelerated aging><accelerated biological age><accelerated biological aging><acute infection><age acceleration><anti-retroviral><antiretroviral therapy><antiretroviral treatment><circulatory shock><co-morbid><co-morbidity><communicable disease transmission><comorbidity><cortistatin><developmental><disease transmission><drug/agent><epigenetic gene silencing><epigenetic silencing><experience><experiment><experimental research><experimental study><experiments><fighting><humanized mice><humanized mouse><immune activation><infectious disease transmission><inflammation marker><inflammatory marker><inhibitor><insight><lymph node biopsy><malignancy><memory CD4 T cell><memory CD4 T lymphocyte><mouse model><murine model><neoplasm/cancer><new approaches><novel approaches><novel strategies><novel strategy><particle><prevent><preventing><promoter><promotor><resistant><shocks><simian HIV><simian human immunodeficiency virus><small molecule><subcutaneous><subdermal><transcriptome sequencing><transcriptomic sequencing><viraemia><viral RNA><viral multiplication><viral rebound><viral replication><viral sepsis><virus RNA><virus multiplication><virus protein><virus rebound><virusemia>