Publications (7)27.57 Total impact

  • K D Mack · X Jin · S Yu · R Wei · L Kapp · C Green · B Herndier · N W Abbey · A Elbaggari · Y Liu · M S McGrath
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    ABSTRACT: HIV integration within host cell genomic DNA is a requisite step of the viral infection cycle. Yet, characteristics of the sites of provirus integration within the host genome remain obscure. The authors present evidence that in diseased tissues showing a high level of HIV DNA and macrophage-associated HIV p24 antigen expression from end stage forms of HIV disease, HIV-1 integration sites were favored within genes and transcriptionally active host cell genomic loci. Using an inverse PCR (IPCR) technique that identified dominant integrated forms of HIV, clonal IPCR products were isolated from AIDS dementia, AIDS lymphoma, and angioimmunoblastic lymphadenopathy tissues. Thirty of 34 disease-associated HIV-1 insertions were identified within annotated and hypothetical genes, an unexpected but highly nonrandom genetic coding region association (p <.026). The 1% sensitivity thresholds used for HIV IPCR suggested some form of selective expansion of cells containing these HIV proviruses. Consistent with this interpretation were the HIV-1 insertion sites identified within introns of genes that encoded for factors associated with signal transduction, apoptosis, and transcription regulation. In addition, HIV-1 proviruses were frequently found proximal to genes that encoded for receptor-associated, signal transduction-associated, transcription-associated, and translation-associated proteins. HIV-1 integration within host cell genomic DNA potentially represents a significant insertional mutagenic event. In certain cases, provirus insertions may mediate the dysregulation of specific gene expression events, providing mechanisms contributing to the pathogenesis associated with certain AIDS-related diseases.
    No preview · Article · Aug 2003 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: The pathogenesis of immunodeficiency-associated lymphoma is poorly understood. During the past several years, numerous lines of evidence implicating a multistep process of malignant transformation, also known as sequential pathogenesis, have emerged. Tumor-associated macrophage production of specific lymphostimulatory products has been demonstrated and hypothesized to be central to this process. While attempting to establish primary effusion lymphoma in severe combined immunodeficient (SCID) mice, we discovered a potential model of murine lymphomagenesis consistent with the sequential pathogenesis model. This pathogenesis-based model of lymphoma could significantly impact the current thinking about posttransplantation and other immunodeficiency-related lymphoproliferative disorders. Human primary effusion lymphoma-derived CD14+ cell-injected SCID mice developed aggressive murine large cell lymphomas. Tumor cell preparations containing CD14 cells or isolated CD14 cells induced lymphoma/lymphoproliferative diseases in 74% (20 of 27) of injected SCID mice. No tumors were induced by tumor-associated CD3 cells (0 of 4), normal human macrophages (0 of 13), or a murine macrophage cell line (0 of 10). Human macrophages were detected in tumor-bearing animals up to 6 months postinjection in association with the murine T-cell tumors but were not detected in controls or unaffected animals. These observations are consistent with the macrophage-initiated sequential pathogenesis model of disease (M. S. McGrath et al., Acquir. Immune Defic. Syndr., 8: 379-385, 1995; M. S. McGrath et al., Infectious Causes of Cancer: Targets for Intervention, pp. 231-242, Totowa, NJ: Humana Press, 2000).
    Preview · Article · Nov 2002 · Cancer Research

  • No preview · Article · May 1999 · JAIDS Journal of Acquired Immune Deficiency Syndromes
  • B. Shiramizu · A. Elbaggari · T. Foran · L. Franks · N. Perin

    No preview · Article · Jul 1997 · The American journal of pediatric hematology/oncology

  • No preview · Article · Mar 1997 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    R F Rando · J Ojwang · A Elbaggari · G R Reyes · R Tinder · M S McGrath · M E Hogan
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    ABSTRACT: An oligonucleotide (I100-15) composed of only deoxyguanosine and thymidine was able to inhibit human immunodeficiency virus type-1 (HIV-1) in culture assay systems. I100-15 did not block virus entry into cells but did reduce viral-specific transcripts. As assessed by NMR and polyacrylamide gel methods, I100-15 appears to form a structure in which two stacked guanosine tetrads are connected by three two-base long loops. Structure/activity experiments indicated that formation of intramolecular guanosine tetrads was necessary to achieve maximum antiviral activity. The single deoxyguanosine nucleotide present in each loop was found to be extremely important for the overall antiviral activity. The toxicity of I100-15 was determined to be well above the 50% effective dose (ED) in culture which yielded a high therapeutic index (>100). The addition of a cholesterol moiety to the 3′ terminus of I100-15 (I100-23) reduced the ED value to less than 50 nM (from 0.12 μM for I100-15) and increased the duration of viral suppression to greater than 21 days (versus 7-10 days for I100-15) after removal of the drug from infected cell cultures. The favorable therapeutic index of such molecules coupled with the prolonged suppression of HIV-1, suggest that such compounds further warrant investigation as potential therapeutic agents.
    Preview · Article · Jan 1995 · Journal of Biological Chemistry
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    ABSTRACT: Oligonucleotide compounds composed of only deoxyguanosine and deoxythymidine were able to significantly inhibit human immunodeficiency virus type -1 (HIV-1)-induced syncytium formation and virus production (as measured by p24 core antigen expression) in an acute infection assay system. The oligonucleotides did not share any homology with or possess any complementary (antisense) sequence motifs to the HIV-1 genome. The guanosine/thymidine-containing oligonucleotides (GTOs) that showed this anti-HIV activity contained natural phosphodiester (PD) linkages (backbones) between the nucleosides. One of the PD oligonucleotide sequence motifs tested was capable of inhibiting HIV-1-induced syncytium formation and p24 production with a median effective dose in culture (ED50) in the submicromolar range. In addition, oligonucleotides tested were able to significantly suppress HIV-1 p24 levels > or = 7 days after removal of the drug from the infected cell culture medium. The growth inhibition properties (toxicity) of this genre of oligonucleotides was determined to be well above the ED50 values yielding high selective indexes. In vitro results showed that GTOs with PD backbones were potent competitive inhibitors of HIV-1 reverse transcriptase. These same molecules were capable of blocking the interaction between gp120 and CD4. All measured activities of these molecules were increased by factors of 10-500 when the PD backbone was replaced with a PT backbone in a sequence-dependent manner. The enhanced antiviral activity displayed by the sulfur group on the oligonucleotide backbone and the lack of any sequence-specific interactions suggest that a percentage of antiviral activity of oligonucleotide-based therapeutics is due to mechanisms other than those originally postulated for oligonucleotides. The good selective index of GTOs coupled with the prolonged suppression of HIV-1 in culture after removal of oligonucleotides from the infected cell culture make this a class of compounds that warrant investigation as therapeutic agents to be used against HIV-1.
    No preview · Article · Jun 1994 · Journal of acquired immune deficiency syndromes