gsk1210151a and HIV-Infections

gsk1210151a has been researched along with HIV-Infections* in 2 studies

Other Studies

2 other study(ies) available for gsk1210151a and HIV-Infections

ArticleYear
Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice.
    Cell, 2014, Aug-28, Volume: 158, Issue:5

    Latent reservoirs of HIV-1-infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, immunologically invisible, and may undergo homeostatic proliferation, a "shock and kill" approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.

    Topics: Animals; Anti-HIV Agents; Antibodies, Neutralizing; CD4-Positive T-Lymphocytes; CTLA-4 Antigen; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Hydroxamic Acids; Immunoglobulin Fc Fragments; Mice; Receptors, Fc; Transcription, Genetic; Virus Latency; Vorinostat

2014
BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism.
    Cell cycle (Georgetown, Tex.), 2013, Feb-01, Volume: 12, Issue:3

    The therapeutic potential of pharmacologic inhibition of bromodomain and extraterminal (BET) proteins has recently emerged in hematological malignancies and chronic inflammation. We find that BET inhibitor compounds (JQ1, I-Bet, I-Bet151 and MS417) reactivate HIV from latency. This is evident in polyclonal Jurkat cell populations containing latent infectious HIV, as well as in a primary T-cell model of HIV latency. Importantly, we show that this activation is dependent on the positive transcription elongation factor p-TEFb but independent from the viral Tat protein, arguing against the possibility that removal of the BET protein BRD4, which functions as a cellular competitor for Tat, serves as a primary mechanism for BET inhibitor action. Instead, we find that the related BET protein, BRD2, enforces HIV latency in the absence of Tat, pointing to a new target for BET inhibitor treatment in HIV infection. In shRNA-mediated knockdown experiments, knockdown of BRD2 activates HIV transcription to the same extent as JQ1 treatment, while a lesser effect is observed with BRD4. In single-cell time-lapse fluorescence microscopy, quantitative analyses across ~2,000 viral integration sites confirm the Tat-independent effect of JQ1 and point to positive effects of JQ1 on transcription elongation, while delaying re-initiation of the polymerase complex at the viral promoter. Collectively, our results identify BRD2 as a new Tat-independent suppressor of HIV transcription in latently infected cells and underscore the therapeutic potential of BET inhibitors in the reversal of HIV latency.

    Topics: Azepines; Benzodiazepines; CD4-Positive T-Lymphocytes; Cell Cycle Proteins; Cells, Cultured; HEK293 Cells; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Jurkat Cells; Nuclear Proteins; Positive Transcriptional Elongation Factor B; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; RNA Interference; RNA, Small Interfering; tat Gene Products, Human Immunodeficiency Virus; Transcription Factors; Transcription, Genetic; Triazoles; Virus Latency

2013