Inhibition of Tat-mediated HIV-1 replication and neurotoxicity by novel GSK3-beta inhibitors.

The HIV-1 protein Tat is a critical regulator of viral transcription and has also been implicated as a mediator of HIV-1 induced neurotoxicity. Here using a high throughput screening assay, we identified the GSK-3 inhibitor 6BIO, as a Tat-dependent HIV-1 transcriptional inhibitor. Its ability to inhibit HIV-1 transcription was confirmed in TZM-bl cells, with an IC(50) of 40nM.

Erratum to: microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection.

[This corrects the article on p. 386 in vol. 6, PMID: 20628499.

microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection.

RNA interference plays a significant role in manipulating cellular and viral mechanisms to maintain latency during HIV-1 infection. HIV-1 produces several microRNAs including one from the TAR element which alter the host's response to infection. Since cyclin/cdk complexes are important for viral transcription, these studies focus on the possible cdk inhibitors that inhibit viral transcription, without affecting normal cellular mechanisms.

Methylation of the tumor suppressor protein, BRCA1, influences its transcriptional cofactor function.

Background: Approximately half of hereditary breast cancers have mutations in either BRCA1 or BRCA2. BRCA1 is a multifaceted tumor suppressor protein that has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. This multifunctional nature of BRCA1 is achieved by exerting its many effects through modulation of transcription.

Transcription through the HIV-1 nucleosomes: effects of the PBAF complex in Tat activated transcription.

The SWI/SNF complex remodels nucleosomes, allowing RNA Polymerase II access to the HIV-1 proviral DNA. It has not been determined which SWI/SNF complex (BAF or PBAF) remodels nucleosomes at the transcription start site. These complexes differ in only three subunits and determining which subunit(s) is required could explain the regulation of Tat activated transcription.

Absence of DICER in monocytes and its regulation by HIV-1.

MicroRNAs (miRNAs) are a class of small RNA molecules that function to control gene expression and restrict viral replication in host cells. The production of miRNAs is believed to be dependent upon the DICER enzyme. Available evidence suggests that in T lymphocytes, HIV-1 can both suppress and co-opt the host's miRNA pathway for its own benefit.

Human T-lymphotropic virus type 1 transcription and chromatin-remodeling complexes.

Human T-lymphotropic virus type 1 (HTLV-1) encodes the viral protein Tax, which is believed to act as a viral transactivator through its interactions with a variety of transcription factors, including CREB and NF-kappaB. As is the case for all retroviruses, the provirus is inserted into the host DNA, where nucleosomes are deposited to ensure efficient packaging. Nucleosomes act as roadblocks in transcription, making it difficult for RNA polymerase II (Pol II) to proceed toward the 3' end of the genome.

Cell-type-specific proteome and interactome: using HIV-1 Tat as a test case.

HIV-1 is a small retrovirus that wreaks havoc on the human immune system. It is a puzzle to the scientific community how a virus that encodes only nine proteins can take complete control of its host and redirect the cell to complete replication or maintain latency when necessary. One way to explain the control elicited by HIV-1 is through numerous protein partners that exist between viral and host proteins, allowing HIV-1 to be intimately involved in virtually every aspect of cellular biology.

The utilization of humanized mouse models for the study of human retroviral infections.

The development of novel techniques and systems to study human infectious diseases in both an in vitro and in vivo settings is always in high demand. Ideally, small animal models are the most efficient method of studying human afflictions. This is especially evident in the study of the human retroviruses, HIV-1 and HTLV-1, in that current simian animal models, though robust, are often expensive and difficult to maintain.

9-Aminoacridine inhibition of HIV-1 Tat dependent transcription.

As part of a continued search for more efficient anti-HIV-1 drugs, we are focusing on the possibility that small molecules could efficiently inhibit HIV-1 replication through the restoration of p53 and p21WAF1 functions, which are inactivated by HIV-1 infection. Here we describe the molecular mechanism of 9-aminoacridine (9AA) mediated HIV-1 inhibition. 9AA treatment resulted in inhibition of HIV LTR transcription in a specific manner that was highly dependent on the presence and location of the amino moiety.