didehydro-cortistatin-a and HIV-Infections

Antiretroviral therapy effectively controls human immunodeficiency virus (HIV) infection. However, a reservoir of latently infected cells persists under suppressive therapy, constituting a major barrier to an HIV cure. The block-and-lock approach to a functional cure aims at the transcriptional and epigenetic silencing of proviruses, blocking viral reactivation in the absence of therapy, preventing disease progression and transmission, despite the presence of detectable integrated proviruses. This approach has been put forward for exploration based on the activity of didehydro-cortistatin A, an inhibitor of the HIV transcriptional activator Tat. Here we review the mechanisms by which didehydro-cortistatin A inhibition of Tat's feedback loop transcriptional amplification results in epigenetic silencing of the HIV promoter, and we discuss the benefits and limitations of the block-and-lock approach for an HIV cure.

Topics: Animals; Anti-HIV Agents; Gene Expression Regulation, Viral; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Isoquinolines; Promoter Regions, Genetic; tat Gene Products, Human Immunodeficiency Virus

HIV-1 Tat activates viral transcription and limited Tat transactivation correlates with latency establishment. We postulated a "block-and-lock" functional cure approach based on properties of the Tat inhibitor didehydro-Cortistatin A (dCA). HIV-1 transcriptional inhibitors could block ongoing viremia during antiretroviral therapy (ART), locking the HIV promoter in persistent latency. We investigated this hypothesis in human CD4

Topics: Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; Chromatin; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Isoquinolines; Lymphocyte Activation; Mice; Mitogens; RNA Polymerase II; RNA, Viral; Viral Load; Virus Activation

Antiretroviral therapy can effectively suppress HIV-1 infection but is ineffective against integrated proviruses. A latent viral reservoir composed of latently infected CD4(+)T cells persists under suppressive therapy, and infected individuals must remain indefinitely on antiretroviral therapy to prevent viral reactivation and propagation. Despite therapy, some degree of low-level ongoing replication is detected and transient viral reactivation may replenish the latent reservoir. An analog of the natural compound, Cortistatin A, blocks HIV-1 transcription by specifically targeting the viral transactivator, Tat. Treatment of latently infected cells with this Tat inhibitor promotes a state of deep-latency from which HIV reactivation capacity is greatly diminished. Here we discuss the use of Tat inhibitors to limit the latent reservoir to achieve a functional cure.

Topics: Anti-HIV Agents; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Isoquinolines; tat Gene Products, Human Immunodeficiency Virus; Virus Latency

HIV-1 Tat protein has been shown to have a crucial role in HIV-1-associated neurocognitive disorders (HAND), which includes a group of syndromes ranging from undetectable neurocognitive impairment to dementia. The abuse of psychostimulants, such as cocaine, by HIV infected individuals, may accelerate and intensify neurological damage. On the other hand, exposure to Tat potentiates cocaine-mediated reward mechanisms, which further promotes HAND. Here, we show that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid, crosses the blood-brain barrier, cross-neutralizes Tat activity from several HIV-1 clades and decreases Tat uptake by glial cell lines. In addition, dCA potently inhibits Tat mediated dysregulation of IL-1β, TNF-α and MCP-1, key neuroinflammatory signaling proteins. Importantly, using a mouse model where doxycycline induces Tat expression, we demonstrate that dCA reverses the potentiation of cocaine-mediated reward. Our results suggest that adding a Tat inhibitor, such as dCA, to current antiretroviral therapy may reduce HIV-1-related neuropathogenesis.

Topics: Animals; Anti-HIV Agents; Chemokines; Cocaine; Cytokines; Disease Models, Animal; Dopamine Uptake Inhibitors; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Inflammation; Isoquinolines; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurocognitive Disorders; Reward; tat Gene Products, Human Immunodeficiency Virus

The human immunodeficiency virus type 1 (HIV) Tat protein, a potent activator of HIV gene expression, is essential for integrated viral genome expression and represents a potential antiviral target. Tat binds the 5'-terminal region of HIV mRNA's stem-bulge-loop structure, the transactivation-responsive (TAR) element, to activate transcription. We find that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid from a marine sponge, inhibits Tat-mediated transactivation of the integrated provirus by binding specifically to the TAR-binding domain of Tat. Working at subnanomolar concentrations, dCA reduces Tat-mediated transcriptional initiation/elongation from the viral promoter to inhibit HIV-1 and HIV-2 replication in acutely and chronically infected cells. Importantly, dCA abrogates spontaneous viral particle release from CD4(+)T cells from virally suppressed subjects on highly active antiretroviral therapy (HAART). Thus, dCA defines a unique class of anti-HIV drugs that may inhibit viral production from stable reservoirs and reduce residual viremia during HAART.

Topics: Alkaloids; Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Binding Sites; CD4-Positive T-Lymphocytes; Cells, Cultured; Female; Gene Expression Regulation, Viral; Heterocyclic Compounds, 4 or More Rings; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Microsomes, Liver; Polycyclic Compounds; Promoter Regions, Genetic; Proviruses; tat Gene Products, Human Immunodeficiency Virus; Transcription, Genetic; Virus Replication