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Direct and indirect effetcs of CYTOR lncRNA regulate HIV gene expression

ABSTRACT: The implementation of antiretroviral therapy (ART) has effectively restricted the transmission of Human Immunodeficiency Virus (HIV) and improved overall clinical outcomes. However, a complete cure for HIV remains out of reach, as the virus persists in a stable pool of infected cell reservoir that is resistant to therapy and thus a main barrier towards complete elimination of viral infection. While the mechanisms by which host proteins govern viral gene expression and latency are well-studied, the emerging regulatory functions of non-coding RNAs (ncRNA) in the context of T cell activation, HIV gene expression and viral latency have not yet been thoroughly explored. Here, we report the identification of the Cytoskeleton Regulator (CYTOR) long non-coding RNA (lncRNA) as an activator of HIV gene expression that is upregulated following T cell stimulation. Functional studies show that CYTOR suppresses viral latency by directly binding to the HIV promoter and associating with the cellular positive transcription elongation factor (P-TEFb) to activate viral gene expression. CYTOR also plays a global role in regulating cellular gene expression, including those involved in controlling actin dynamics. Depletion of CYTOR expression reduces cytoplasmic actin polymerization in response to T cell activation. In addition, treating HIV-infected cells with pharmacological inhibitors of actin polymerization reduces HIV gene expression. We conclude that both direct and indirect effects of CYTOR regulate HIV gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254771 | GEO | 2024/04/15

REPOSITORIES: GEO

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Project description:Aguilera 2014 - HIV latency. Interaction between HIV proteins and immune response This model is described in the article: Studying HIV latency by modeling the interaction between HIV proteins and the innate immune response. Aguilera LU, Rodríguez-González J. J. Theor. Biol. 2014 Nov; 360: 67-77 Abstract: HIV infection leads to two cell fates, the viral productive state or viral latency (a reversible non-productive state). HIV latency is relevant because infected active CD4+ T-lymphocytes can reach a resting memory state in which the provirus remains silent for long periods of time. Despite experimental and theoretical efforts, the causal molecular mechanisms responsible for HIV latency are only partially understood. Studies have determined that HIV latency is influenced by the innate immune response carried out by cell restriction factors that inhibit the postintegration steps in the virus replication cycle. In this study, we present a mathematical study that combines deterministic and stochastic approaches to analyze the interactions between HIV proteins and the innate immune response. Using wide ranges of parameter values, we observed the following: (1) a phenomenological description of the viral productive and latent cell phenotypes is obtained by bistable and bimodal dynamics, (2) biochemical noise reduces the probability that an infected cell adopts the latent state, (3) the effects of the innate immune response enhance the HIV latency state, (4) the conditions of the cell before infection affect the latent phenotype, i.e., the existing expression of cell restriction factors propitiates HIV latency, and existing expression of HIV proteins reduces HIV latency. This model is hosted on BioModels Database and identified by: BIOMD0000000573. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Direct and indirect effetcs of CYTOR lncRNA regulate HIV gene expression

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