Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 μM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART

Simultaneous Priority and Detection Based Carrier Sense Multiple Access Protocol

Carrier Sense Multiple Access (CSMA) protocol, along with collision detection in wired communication, helps in further increasing the efficiency of channel usage. It helps in terminating its transmission over the channel immediately once collision is detected, releasing the channel for other useful transmissions. Whereas in wireless communication, the packet collision cannot be detected until the completion of the entire transmission. To detect the collision immediately, the robust mechanism is requested. In this paper, we introduce Simultaneous Priority and Detection based Carrier Sense Multiple Access (SPD-CSMA) protocol to establish an efficient connection and immediate collision detection. The SPD-CSMA handles the situation using an additional antenna and a unique code message. SPD-CSMA is also supported with Shortest First (SF) algorithm for prioritizing the transmission. The proposed SPD-CSMA approach is validated by using NS3 on Ubuntu 13.10 operating system. The experimental results demonstrate that a reduced collision rate helps with improving the Quality of Service

Simultaneous Priority and Detection Based Carrier Sense Multiple Access Protocol

Carrier Sense Multiple Access (CSMA) protocol, along with collision detection in wired communication, helps in further increasing the efficiency of channel usage. It helps in terminating its transmission over the channel immediately once collision is detected, releasing the channel for other useful transmissions. Whereas in wireless communication, the packet collision cannot be detected until the completion of the entire transmission. To detect the collision immediately, the robust mechanism is requested. In this paper, we introduce Simultaneous Priority and Detection based Carrier Sense Multiple Access (SPD-CSMA) protocol to establish an efficient connection and immediate collision detection. The SPD-CSMA handles the situation using an additional antenna and a unique code message. SPD-CSMA is also supported with Shortest First (SF) algorithm for prioritizing the transmission. The proposed SPD-CSMA approach is validated by using NS3 on Ubuntu 13.10 operating system. The experimental results demonstrate that a reduced collision rate helps with improving the Quality of Service