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The missions of the Laboratory of Antiviral Drug Mechanisms are to facilitate discovery of novel chemical and biological therapeutics for viral pathogens responsible for AIDS and AIDS-associated malignancies through advanced high throughput screening (HTS) assays; to elucidate the mechanisms of observed antiviral effects; and to explore novel viral molecular targets, using a variety of cellular and molecular biology techniques. Our current projects are focused against HIV and human herpes virus 8 (HHV8), causative agent for Kaposi's sarcoma and a subset of AIDS-associated non-Hodgkin's lymphoma so called Body Cavity Based Lymphoma. The LADM screens compounds submitted by intramural and extramural investigators for anti-HIV activity and characterizes antiviral mechanisms of potentially active compounds, using various cell and molecular based screening assays. In order to find anti-HIV agents that act through novel mechanisms other than inhibition of viral reverse transcriptase (RT) or protease (PR), we are currently developing cell based HTS, using specific HIV-1 strains resistant to many conventional inhibitors of RT or PR. Recently, we have established microplate-based HHV8 polymerase (POL) and POL-processivitiy factor (PPF) inhibition assay for HTS operation, and have begun screening of chemical libraries to discover novel inhibitors of HHV8 POL/PPF. Additional molecular targets of HHV8 currently pursued in our lab include HHV8 helicase/primase and latency-associated nuclear antigen.
Dr. Shizuko Sei (formerly Aoki) obtained her M.D. from Shinshu University
School of Medicine, Nagano, Japan in 1980. After completing internship
and pediatric residency in Japan, she joined the Pediatric Branch,
National Cancer Institute in 1986. During her fellowship in pediatric
hematology-oncology at NCI, she began her laboratory research in
human retrovirology in the Laboratory of Clinical Oncology Program
headed by Dr. Samuel Broder. She was one of the first to establish
quantitative PCR methodologies that permitted the determination
of HIV viral load in patients' blood or tissue specimens, and demonstrated
the usefulness of viral load as a surrogate marker for HIV disease
as well as HIV tissue distribution dynamics in vivo. She further
pursued her research interest in pathogenesis of AIDS and AIDS-associated
illnesses in the Laboratory of Pediatric Retrovirology at Pediatric
Branch, NCI, from 1992 to 1997, where she focused on characterization
of phenotypic and genotypic determinants of HIV disease progression,
development of immunotherapeutic HIV vaccine, and neuropathogenesis
of HIV-1 infection. Dr. Sei joined the research community at NCI-Frederick
in September 1997 to set up the HIV Clinical Interface Laboratory.
During her tenure at HCIL, she discovered a key viral target sequence,
which may be exploited as a novel antiviral genetic target. She
also investigated roles of genetic traits in altered risk of AIDS-associated
lymphoma and its potential mechanisms. She became the head of the
Laboratory of Antiviral Drug Mechanisms in October 2001, and has
concentrated on the development of novel therapeutics for AIDS and
AIDS-related malignancies.
Recent Publications NCBI PubMed listing of publications by Shizuko Sei. Dorjsuren D, Badralmaa Y, Mikovits J, Li A, Fisher R, Ricciardi R, Shoemaker R, Sei S. Expression and purification of recombinant Kaposi's sarcoma-associated herpesvirus DNA polymerase using a Baculovirus vector system. Protein Expr Purif 2003; 29:42-50 Stephen AG, Worthy KM, Towler E, Mikovits JA, Sei S, Roberts P, Yang QE, Akee RK, Klausmeyer P, McCloud TG, Henderson L, Rein A, Covell DG, Currens M, Shoemaker RH, Fisher RJ. Identification of HIV-1 nucleocapsid protein: nucleic acid antagonists with cellular anti-HIV activity. Biochem Biophys Res Commun 2002; 296:1228-37 Sei S, Boler AM, Nguyen GT, Stewart SK, Yang Q, Edgerly M, Wood LV, Brouwers P, Venzon DJ. Protective effect of CCR5 ?32 heterozygosity is restricted by SDF-1 genotype in children with HIV-1 infection. AIDS 2001; 15:1343-52. Sei S, O'Neill DP, Stewart SK, Yang Q, Kumagai M, Boler AM, Adde MA, Zwerski SL, Wood LV, Venzon DJ, Magrath IT. Increased level of stromal-cell derived factor-1 mRNA in peripheral blood mononuclear cells from children with AIDS-related lymphoma. Cancer Res 2001; 61:5028-37. Brouwers P, Civitello L, DeCarli C, Wolters P, Sei S. Cerebrospinal fluid viral load is related to cortical atrophy and not to intracerebral calcifications in children with symptomatic HIV disease. J Neurovirol 2000; 6:390-7. Sei S, Yang QE, O'Neill D, Yoshimura K, Nagashima K, Mitsuya H. Identification of a key target sequence to block human immunodeficiency virus type 1 replication within the gag-pol transframe domain. J Virol 2000; 74:4621-33. |
