Curaxin CBL0137 has the potential to reverse HIV-1 latency.

A cure for human immunodeficiency virus type-1 (HIV-1) has been hampered by the limitation of current combination antiretroviral therapy (cART) to address the latent reservoirs in HIV-1 patients. One strategy proposed to eradicate these reservoirs is the "shock and kill" approach, where latency-reversing agents (LRAs) are used to reactivate and promote viral cell death and/or immune killing of reactivated cells. Here, we report that curaxin CBL0137, an antitumor compound, can potentiate tumor necrosis factor-α-mediated reactivation of latently infected HIV-1cell lines. Additionally, the single use of CBL0137 is sufficient to reactivate HIV-1 latent reservoirs in peripheral mononuclear cells (PBMCs) isolated from HIV-1 positive, cART-treated, aviremic patients. Thus, CBL0137 possesses capabilities as a LRA and could be considered for the "shock and kill" approach.

Current Strategies for Elimination of HIV-1 Latent Reservoirs Using Chemical Compounds Targeting Host and Viral Factors.

Since the implementation of combination antiretroviral therapy (cART), rates of HIV type 1 (HIV-1) mortality, morbidity, and newly acquired infections have decreased dramatically. In fact, HIV-1-infected individuals under effective suppressive cART approach normal life span and quality of life. However, long-term therapy is required because the virus establish a reversible state of latency in memory CD4+ T cells. Two principle strategies, namely "shock and kill" approach and "block and lock" approach, are currently being investigated for the eradication of these HIV-1 latent reservoirs. Actually, both of these contrasting approaches are based on the use of small-molecule compounds to achieve the cure for HIV-1. In this review, we discuss the recent progress that has been made in designing and developing small-molecule compounds for both strategies.

Inhibition of Tip60 Reduces Lytic and Latent Gene Expression of Kaposi's Sarcoma-Associated Herpes Virus (KSHV) and Proliferation of KSHV-Infected Tumor Cells.

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus responsible for the development of Kaposi's sarcoma, primary effusion lymphoma (PEL), and Multicentric Castleman's disease in immunocompromised individuals. Despite the burden of these diseases there are few treatment options for afflicted individuals, due in part to our limited understanding of virus-host interactions. Tip60, a histone aceytltransferase (HAT) has been previously shown to interact with both the KSHV latency associated nuclear antigen protein (LANA), which is the main factor in maintaining the viral latent state, and ORF36, a viral kinase expressed in the lytic phase. We further investigated Tip60-virus interaction to ascertain Tip60's role in the viral life cycle and its potential as a target for future therapeutics. Through modulation of Tip60 expression in HEK293T cells harboring a plasmid containing the KSHV viral episome, Bac36, we found that Tip60 is vital for both lytic replication as well as efficient expression of latent genes. Interestingly, Tip60 small molecule inhibitors, MG149 and NU9056, similarly inhibited latent and lytic genes, and reduced virion production in wild-type KSHV+/EBV- PEL, BCBL-1 cells. Long-term treatment with these Tip60 inhibitors selectively decreased the viability of KSHV-infected B lymphoma cells compared to uninfected cells. From this study, we conclude that Tip60 is important for KSHV infection and its associated cancer development, and Tip60 is therefore a potential target for future antiviral and anticancer therapeutics.

Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation.

Despite combination antiretroviral therapy (cART), acquired immunodeficiency syndrome (AIDS), predominantly caused by the human immunodeficiency virus type 1 (HIV-1), remains incurable. The barrier to a cure lies in the virus' ability to establish a latent infection in HIV/AIDS patients. Unsurprisingly, efforts for a sterilizing cure have focused on the "shock and kill" strategy using latency-reversing agents (LRAs) to complement cART in order to eliminate these latent reservoirs. However, this method faces numerous challenges. Recently, the "block and lock" strategy has been proposed. It aims to reinforce a deep state of latency and prevent sporadic reactivation ("blip") of HIV-1 using latency-promoting agents (LPAs) for a functional cure. Our studies of curaxin 100 (CBL0100), a small-molecule targeting the facilitates chromatin transcription (FACT) complex, show that it blocks both HIV-1 replication and reactivation in in vitro and ex vivo models of HIV-1. Mechanistic investigation elucidated that CBL0100 preferentially targets HIV-1 transcriptional elongation and decreases the occupancy of RNA Polymerase II (Pol II) and FACT at the HIV-1 promoter region. In conclusion, CBL0100 is a newly identified inhibitor of HIV-1 transcription that can be used as an LPA in the "block and lock" cure strategy.

Adult zebrafish hearts efficiently compensate for excessive forced overload cardiac stress with hyperplastic cardiomegaly.

Although human cardiomyocytes (CMs) are capable of some cell division, this response is neither sufficient to repair damaged cardiac tissue nor efficient to compensate for pathological stress. Danio rerio (zebrafish) CMs have been shown to have high proliferative capability to completely repair hearts after injury; however, no reports have focused on their physiological and cellular response to cardiac overload stress. We hypothesized that forced excessive long-term cardiac overload stress would elicit a proliferative response similar to regenerative cardiac repair in zebrafish. We completed a 10-week forced fast-speed swimming exercise regimen, comparing exercised hearts to nonexercised controls for physiological function and histological evidence of cell proliferation. Our results indicate that exercised heart ventricles are 33% larger, yet exhibit no significant changes in cardiac physiological function as evaluated by the heart rate and the percent shortening fraction. We found 8% more CM nuclei per cross-sectional area within exercised ventricular tissue, indicating that cardiomegaly was not due to individual cell hypertrophy, but due to hyperplasia. This novel zebrafish cardiac stress model may be used to identify genes or proteins with therapeutic potential for treating cardiac stress pathologies, as well as molecules that could be used as initiators of cardiac cell proliferation in humans.