Publications

Cells harboring infectious, but transcriptionally latent, human immunodeficiency virus type 1 (HIV-1) proviruses currently pose an insurmountable barrier to viral eradication in infected patients. To better understand the molecular basis for HIV-1 latency, we used the J-Lat model of postintegration HIV-1 latency to assess the kinetic relationship between the induction of NF-kappaB and the activation of latent HIV-1 gene expression. Chromatin immunoprecipitation analyses revealed an oscillating pattern of RelA recruitment to the HIV-1 long terminal repeat (LTR) during continuous tumor necrosis factor alpha (TNF-alpha) stimulation. RNA polymerase II (Pol II) recruitment to the HIV-1 LTR closely mirrored RelA binding. Transient stimulation of cells with TNF-alpha for 15 min induced only a single round of RelA and RNA Pol II binding and failed to induce robust expression of latent HIV-1. Efficient formation of elongated HIV-1 transcripts required sustained induction by NF-kappaB, which promoted de novo synthesis of Tat. Cyclin-dependent kinase 9 (CDK9) and serine-2-phosphorylated RNA Pol II were rapidly recruited to the HIV-1 LTR after NF-kappaB induction; however, these elongating polymerase complexes were progressively dephosphorylated in the absence of Tat. Okadaic acid promoted sustained serine-2 phosphorylation of the C-terminal domain of RNA Pol II and stimulated efficient transcriptional elongation and HIV-1 expression in the absence of Tat. These findings underscore important differences between NF-kappaB and Tat stimulation of RNA Pol II elongation. While NF-kappaB binding to the HIV-1 LTR induces serial waves of efficient RNA Pol II initiation, elongation is impaired by the action of an okadaic acid-sensitive phosphatase that dephosphorylates the C-terminal domain of RNA Pol II. Conversely, the action of this phosphatase is overcome in the presence of Tat, promoting very efficient RNA Pol II elongation.

Patent foramen ovale (PFO) has been implicated in the pathogenesis of cryptogenic stroke, arterial desaturation, decompression illness, and migraine headache (MH). This study evaluated the safety of percutaneous transcatheter PFO closure in patients with cryptogenic stroke, transient ischemic attack, or arterial desaturation. Additionally, symptomatic reduction in MH was determined after interatrial shunt closure. Of the 252 patients referred to the University of California, Los Angeles, with PFO, 131 underwent closure of the interatrial communication with a CardioSEAL (n = 30) or Amplatzer (n = 101) device. PFO morphology was evaluated with transesophageal echocardiography. Follow-up was conducted at 1 to 2 months with echocardiography, with clinical assessment annually thereafter. At an average follow-up of 30 months, there was no recurrence of any thromboembolic event (transient ischemic attack, stroke, or peripheral). There was a reduction in MH, defined as the complete resolution of headache or a >50% reduction in the number of headache days, in 85% of patients after PFO closure. Temporary problems after device implantation, including chest discomfort and palpitations, were reported in 23% of patients and occurred more frequently in patients with nickel hypersensitivity (p <0.05). In conclusion, transcatheter PFO closure is an effective and safe therapeutic modality in the prevention of thromboembolic events and MH associated with interatrial shunting in patients who present with cryptogenic stroke. Pending randomized, controlled trials are necessary to determine if this invasive approach is preferable to medical therapy for the prevention of recurrent stroke or as primary treatment for patients with MH.