Dr. Richard Syd Kornbluth

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Multimeric Biotherapeutics, Inc.
Research & Development
Chief Scientific OfficerAppointed: 2008
Multimeric Biotherapeutics, Inc.
Research & Development
PresidentAppointed: 2008
University of California, San Diego
School of Medicine
Medicine
Infectious Diseases
Associate Professor
Professional Headshot of Richard Syd Kornbluth

Mailing Address

Stein Clinical Sciences Bldg.
University of California, San Diego
9500 Gilman Drive - 0679
Room 304
La Jolla, California 92093-0679
United States

Contact Information

Phone: (619) 846-8603
rkornbluth@ucsd.edu

Qualifications

Ph.D., Columbia University, Pathology, 1983.
M.D., New York Medical College, Medicine, 1975.
A.B., Harvard College, Philosophy, 1970.

Expertise and Research Interests

My lab studies two areas: (1) Using CD40L, GITRL, and other TNFSF ligands as vaccine and anti-tumor immunostimulants; and (2) HIV integration.

1. Soluble, multimeric TNF superfamily (TNFSF) molecules have been produced by fusing the extracellular domains of CD40L and other TNFSF ligands with the body of collectin molecules such as surfactant protein D (e.g., SP-D-CD40L). SP-D-CD40L activates human dendritic cells, macrophages, and B cells in culture. As plasmid DNA, pSP-D-CD40L dramatically augments the activities of DNA vaccines against HIV and malaria. A soluble, multimeric form of GITRL (which turns off regulatory CD4+CD25+ T cells or Tregs) is also immunostimulatory as part of a DNA vaccine. Plasmids for either soluble, multimeric CD40L, or GITRL have antitumor activity when injected directly into established tumors in mice. These studies indicate that fusion with the body of collectin molecules is a general way produce bioactive, soluble, multimeric forms of TNFSF ligands for vaccines and tumor immunotherapy.

2. To study HIV integration, we have developed the first highly sensitive and quantitative assay for HIV integration based on PCR detection of integration junctions. This permits the detection of preintegration complexes (PICs) in very small samples. Studies are underway using this assay to measure and identify the host cell factors which affect integration in primary cells. With suitable modifications, the assay is ideal for the discovery of new inhibitors of HIV integration.

Other Expertise

Protein Purification
Macrophage Immunology
Tumor Immunology
AIDS
HIV Infection
Molecular Biology
Integrase
Tumor Necrosis Factor Superfamily (TNFSF)

Future Research

Novel Vaccines for HIV and Malaria
Vaccines for Biodefense

Industrial Relevance

1. Our platform for producing soluble, multimeric CD40L and other TNFSF ligands makes it possible to administer these molecules as therapeutics. The multimerization step is key, as most TNFSF ligands work as membrane proteins that cluster their receptors on responding cells in order to induce a signaling event. Given the potential of TNFSFs such as CD40L and GITRL for stimulating immunity, this platform should be useful in the design of new vaccines for HIV and other infectious diseases. In addition, as some TNFSF ligands stimulate vascular growth and wound healing, this soluble, multimerization platform may provide a means of using these difficult molecules to induce angiogenesis or to promote wound healing.

2. We have developed the first PCR-based assay for quantifying HIV preintegration complexes (PICs) with high sensitivity. A single 50 ml culture of HIV-infected cells yields enough PICs for 10,000 assays. With suitable modifications, this will make it possible, for the first time, to use authentic PICs in a high-throughput, drug discovery screen for inhibitors of HIV integration.

Keywords

COS Keywords:

AIDS, Arteriosclerosis Or Atherosclerosis, Arthritis, Autoimmunity, Brain Tumors, Breast Cancer, Cancer Or Carcinogenesis, Health and Medicine, HIV, Hypersensitivity, Immune System Disorders, Immunology, Immunotherapy, Infectious Diseases Or Agents, Inflammation, Injury Immunophysiology, Leprosy, Lupus, Lymphoma, Malaria, Microbiology, Multiple Sclerosis, Prostate Cancer, Pulmonary Diseases, Respiratory Diseases, Scleroderma, Thrombosis, Trauma, Cell Biology, Tuberculosis, Tumor Immunology, Tumors, Vaccine.

Additional Terms:

Breast Cancer, Cancer, Immunology, Integrase, Lymphoma, Melanoma, Prostate Cancer, Tumor Immunotherapy, Vaccines.

Languages

(Reading, Writing, Speaking)

English: (Fluent, Fluent, Fluent)

Memberships

Alpha Omega Alpha
American Association of Immunologists
American Society for Microbiology
American Thoracic Society
Society for Leukocyte Biology

Honors and Awards

1999, GSK Drug Discovery & Development Award, GlaxoSmithKline

Patents

Immunostimulatory combinations of TNFRSF, TLR, NLR, and cytokine receptor agonists with polymer-enhanced delivery, Patent Number: , 2006, Institution, United States of America.
Multimeric fusion proteins of TNF superfamily ligands, Patent Number: US20050158831A1, 2005, Institution, United States of America.
Immunostimulatory polynucleotides in treatment of mycobacterial infection, Patent Number: 6552006, 2003, Institution-owned, United States.
Nucleic acid integration assay, Patent Number: Patent Pending, 2000, Institution-owned, United States of America.
Multimeric forms of CD40L and other TNF family members, Patent Number: Patent Pending, 1999, Institution-owned, United States of America.
Substantially pure cytotoxicity triggering factor, Patent Number: 4785077, 1986, Institution-owned, United States.

Funding Received

  • National Institutes of Health (NIH): HIV Effects on T Cell Activation of Macrophage Functions, $633,263, Sep 30, 1987 to Jul 31, 1995.
  • National Institutes of Health (NIH): Immune and therapeutic suppression of HIV in the Lung, $875,000, Sep 29, 1996 to Jul 31, 2001.
  • National Institutes of Health (NIH): Macrophage-Tuberculosis Interactions: Functional Effects, $705,946, Sep 1, 1993 to Jun 30, 1999.
  • American Foundation for AIDS Research (amfAR): Macrophage/Interferon Interactions in HIV Infection, $49,911, Oct 1, 1990 to Sep 30, 1991.
  • National Institutes of Health (NIH): HIV effects on macrophages as antitumor effector cells, $24,725, Jul 10, 1996 to Jun 30, 1998.
  • State of California, Universitywide AIDS Research Program: Regulation of macrophage-produced HIV suppressive factors, $100,000, Jul 1, 1997 to Jun 30, 1999.
  • Universitywide AIDS Research Program (UARP): Macrophage HIV infection by apoptotic T cell debris, $32,175, Jul 1, 1995 to Jun 30, 1997.
  • National Institutes of Health (NIH): Alveolar Macrophages and Defense of the Lung in AIDS, $782,330, Jul 1, 1989 to Jun 30, 1994.
  • Sequella Global Tuberculosis Foundation: Effects of ISS and CD40L on M. tuberculosis infection in mice, $50,000, Jan 1, 2001 to Dec 31, 2001.
  • Elizabeth Glazer Pediatric AIDS Foundation: The Role of CD40L in HIV-1 Infection, $160,000, Jan 1, 1999 to Dec 31, 2000.
  • American Foundation for AIDS Research (amfAR): Non-Integrase-Directed PIC Inhibitors of HIV-1, $90,000, Apr 1, 2002 to Mar 31, 2003.
  • American Foundation for AIDS Research (amfAR): Host cell factors which activate preintegration complexes, $90,000, Apr 1, 2001 to Mar 31, 2002.
  • American Foundation for AIDS Research (amfAR): TNFSF ligand enhancement of HIV vaccines, $72,000, Apr 1, 2000 to Mar 31, 2001.
  • National Institutes of Health (NIH): Vaccines to generate neutralizing, 275,000, 2007 to 2009.
  • State of California, Universitywide AIDS Research Program: CD40L and GITRL adjuvants for anti-HIV Ad5 vector vaccines, 81,850, 2006 to 2007.
  • National Institutes of Health (NIH): Combined TNFSF and TLR Stimulation of HIV Vaccines, $433,200, 2005 to 2007.
  • Mesothelioma Applied Research Foundation: Immunotherapy with Soluble Multimeric CD40L and other TNFSF Ligands, $100,000, 2005 to 2007.
  • National Institutes of Health (NIH): Combined TNFSF and TLR stimulation of HIV vaccines, $433,200, 2005 to 2007.
  • UCSD Center for AIDS Research: Detection of HIV production at the single cell level, $30,000, 2004 to 2004.
  • Universitywide AIDS Research Program: TNFSF adjuvants for HIV vaccines, $125,000, 2004 to 2006.
  • National Institutes of Health (NIH): Regulation of HIV-1 Preintegration Complexes (PICs), $246,225, 2002 to 2004.
  • National Institutes of Health (NIH): TNFSF APC Activators for HIV Vaccines, $422,100, 2002 to 2004.

Publications

  • Liu J, Yu Q, Stone GW, Yue FY, Ngai N, Jones RB, Kornbluth RS, Ostrowski MA (Jul 2008) CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals., Vaccine, 26 (32), 4062-72 Abstract
  • Kornbluth RS, Smee DF, Sidwell RW, Snarsky V, Evans DH, Hostetler KY (2006) Mutations in the E9L Polymerase Gene of Cidofovir-Resistant Vaccinia Virus Strain WR Are Associated with the Drug Resistance Phenotype., Antimicrob Agents Chemother., 50 (2), 4038-43
  • Stone GW, Barzee S, Snarsky V, Spina CA, Lifson JD, Pillai VK, Amara RR, Villinger F, Kornbluth RS (2006) Macaque Multimeric Soluble CD40 Ligand and GITR Ligand Constructs Are Immunostimulatory Molecules In Vitro., Clin Vaccine Immunol. 2006 Nov;13(11):1223-30. Epub 2006 Sep 20., 13 (11), 1223-30
  • Kornbluth RS, Stone GW (2006) Immunostimulatory combinations: designing the next generation of vaccine adjuvants., J Leukoc Biol., 80 (5), 1084-102
  • Kornbluth RS (2006) HIV creates an immunologic black hole, Blood, 107 (5), 1743-1744
  • Stone GW, Barzee S, Snarsky V, Kee K, Spina CA, Yu XF, Kornbluth RS (2006) Multimeric soluble CD40 ligand and GITR ligand as adjuvants for human immunodeficiency virus DNA vaccines, J Virol, 80 (4), 1772
  • Wang JP, Hayashi T, Datta SK, Kornbluth RS, Raz E, Guiney DG (Aug 2005) CpG oligonucleotides partially inhibit growth of Mycobacterium tuberculosis, but not Salmonella or Listeria, in human monocyte-derived macrophages., Fems Immunology and Medical Microbiology, 45 (2), 303-10 Abstract
  • Woelk CH, Ottones F, Plotkin CR, Du P, Royer CD, Rought SE, Lozach J, Sasik R, Kornbluth RS, Richman DD, Corbeil J (Nov 2004) Interferon gene expression following HIV type 1 infection of monocyte-derived macrophages., Aids Research and Human Retroviruses, 20 (11), 1210-22 Abstract
  • Kornbluth RS (1 Mar 2004) Invited Commentary: HIV envelope becomes unhinged by PID for entry, Blood, 103 (1567), 1567
  • Kornbluth RS (Oct 2002) An expanding role for CD40L and other tumor necrosis factor superfamily ligands in HIV infection., Journal of Hematotherapy & Stem Cell Research, 11 (5), 787-801 Abstract
  • Brooun A, Richman DD, Kornbluth RS (Dec 2001) HIV-1 preintegration complexes preferentially integrate into longer target DNA molecules in solution as detected by a sensitive, polymerase chain reaction-based integration assay., The Journal of Biological Chemistry, 276 (50), 46946-52 Abstract
  • Hayashi T, Rao SP, Takabayashi K, Van Uden JH, Kornbluth RS, Baird SM, Taylor MW, Carson DA, Catanzaro A, Raz E (Oct 2001) Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase., Infection and Immunity, 69 (10), 6156-64 Abstract
  • Kornbluth RS (Sep 2000) The emerging role of CD40 ligand in HIV infection., Journal of Leukocyte Biology, 68 (3), 373-82 Abstract
  • Martin-Orozco E, Kobayashi H, Van Uden J, Nguyen MD, Kornbluth RS, Raz E (Jul 1999) Enhancement of antigen-presenting cell surface molecules involved in cognate interactions by immunostimulatory DNA sequences., International Immunology, 11 (7), 1111-8 Abstract
  • Hayashi T, Rao SP, Meylan PR, Kornbluth RS, Catanzaro A (Jul 1999) Role of CD40 ligand in Mycobacterium avium infection., Infection and Immunity, 67 (7), 3558-65 Abstract
  • Kornbluth RS, Kee K, Richman DD (Apr 1998) CD40 ligand (CD154) stimulation of macrophages to produce HIV-1-suppressive beta-chemokines., Proceedings of the National Academy of Sciences of the United States of America., 95 (9), 5205-10 Abstract
  • Roman M, Martin-Orozco E, Goodman JS, Nguyen MD, Sato Y, Ronaghy A, Kornbluth RS, Richman DD, Carson DA, Raz E (Aug 1997) Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants., Nature Medicine, 3 (8), 849-54 Abstract
  • Perno CF, Crowe SM, Kornbluth RS (Jul 1997) A continuing enigma: the role of cells of macrophage lineage in the development of HIV disease., Journal of Leukocyte Biology, 62 (1), 1-3 Abstract
  • Crowe SM, Kornbluth RS (Feb 1996) Managing HIV. Part 3: Mechanisms of disease. 3.3 How HIV leads to opportunistic infections., The Medical Journal of Australia, 164 (3), 171-3 Abstract
  • Meylan PR, Kornbluth RS, Zbinden I, Richman DD (Dec 1994) Influence of host cell type and V3 loop of the surface glycoprotein on susceptibility of human immunodeficiency virus type 1 to polyanion compounds., Antimicrobial Agents and Chemotherapy, 38 (12), 2910-6 Abstract
  • Kornbluth RS (Dec 1994) The immunological potential of apoptotic debris produced by tumor cells and during HIV infection., Immunology Letters, 43 (1-2), 125-32 Abstract
  • Crowe SM, Kornbluth RS (Sep 1994) Overview of HIV interactions with macrophages and dendritic cells: the other infection in AIDS., Journal of Leukocyte Biology, 56 (3), 215-7 Abstract
  • Kornbluth RS (Sep 1994) Significance of T cell apoptosis for macrophages in HIV infection., Journal of Leukocyte Biology, 56 (3), 247-56 Abstract
  • von Schwedler U, Kornbluth RS, Trono D (Jul 1994) The nuclear localization signal of the matrix protein of human immunodeficiency virus type 1 allows the establishment of infection in macrophages and quiescent T lymphocytes., Proceedings of the National Academy of Sciences of the United States of America., 91 (15), 6992-6 Abstract
  • Kornbluth RS, Matsuzaki H, Meylan PR, Richman DD (Oct-Dec 1994) Interferon interactions with HIV1 in macrophages., Research in Immunology, 145 (8-9), 664-6; discussion 66 Abstract
  • Kornbluth RS, McCutchan JA (Aug 1993) Skin test responses as predictors of tuberculous infection and of progression in HIV-infected persons., Annals of Internal Medicine, 119 (3), 241-3 Abstract
  • Meylan PR, Guatelli JC, Munis JR, Richman DD, Kornbluth RS (Mar 1993) Mechanisms for the inhibition of HIV replication by interferons-alpha, -beta, and -gamma in primary human macrophages., Virology, 193 (1), 138-48 Abstract
  • Meylan PR, Spina CA, Richman DD, Kornbluth RS (Mar 1993) In vitro differentiation of monocytoid THP-1 cells affects their permissiveness for HIV strains: a model system for studying the cellular basis of HIV differential tropism., Virology, 193 (1), 256-67 Abstract
  • Kornbluth RS, Rhodes J, Richman DD (Feb 1993) Recovery of infectious HIV following the passage of apoptotic cellular debris through phagocytic macrophages., Chest, 103 (2 Suppl), 102S-103S Abstract
  • Meltzer MS, Kornbluth RS, Hansen B, Dhawan S, Gendelman HE (Feb 1993) HIV infection of the lung. Role of virus-infected macrophages in the pathophysiology of pulmonary disease., Chest, 103 (2 Suppl), 103S-108S Abstract
  • Pauza CD, Kornbluth R, Emau P, Richman DD, Deftos LJ (Feb 1993) Vitamin D3 compounds regulate human immunodeficiency virus type 1 replication in U937 monoblastoid cells and in monocyte-derived macrophages., Journal of Leukocyte Biology, 53 (2), 157-64 Abstract
  • Kornbluth RS, Rhodes J, Richman DD (Feb 1993) Recovery of infectious HIV following the passage of apoptotic cellular debris through phagocytic macrophages., Chest, 103 (2 Suppl), 102S-103S Abstract
  • Meylan PR, Richman DD, Kornbluth RS (Aug 1992) Oxygen tensions and mycobacterial infections., Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America., 15 (2), 372-3 Abstract
  • Munis JR, Kornbluth RS, Guatelli JC, Richman DD (Aug 1992) Ordered appearance of human immunodeficiency virus type 1 nucleic acids following high multiplicity infection of macrophages., The Journal of General Virology, 73 ( Pt 8), 1899-906 Abstract
  • Meylan PR, Richman DD, Kornbluth RS (Apr 1992) Reduced intracellular growth of mycobacteria in human macrophages cultivated at physiologic oxygen pressure., The American Review of Respiratory Disease, 145 (4 Pt 1), 947-53 Abstract
  • Meylan PR, Munis JR, Richman DD, Kornbluth RS (Jan 1992) Concurrent human immunodeficiency virus and mycobacterial infection of macrophages in vitro does not reveal any reciprocal effect., The Journal of Infectious Diseases, 165 (1), 80-6 Abstract
  • Meylan PR, Tam EK, Kornbluth RS, Richman DD (Jan 1992) HIV infectivity is not augmented by treatment with trypsin, Factor Xa or human mast-cell tryptase., Aids (lLondon, England), 6 (1), 128-30 Abstract
  • Terai C, Kornbluth RS, Pauza CD, Richman DD, Carson DA (May 1991) Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1., The Journal of Clinical Investigation, 87 (5), 1710-5 Abstract
  • Kornbluth RS, Munis JR, Oh PS, Meylan PR, Richman DD (Aug 1990) Characterization of a macrophage-tropic HIV strain that does not alter macrophage cytokine production yet protects macrophages from superinfection by vesicular stomatitis virus., Aids Research and Human Retroviruses, 6 (8), 1023-6 Abstract
  • Meylan PR, Richman DD, Kornbluth RS (Aug 1990) Characterization and growth in human macrophages of Mycobacterium avium complex strains isolated from the blood of patients with acquired immunodeficiency syndrome., Infection and Immunity, 58 (8), 2564-8 Abstract
  • Terkeltaub R, Firestein GS, Kornbluth RS, Martin J, Curran D, Manolagas S (Feb 1990) The effects of gamma-interferon on human peripheral blood monocyte/macrophage-mediated bone particle degradation., Bone and Mineral, 8 (2), 131-43 Abstract
  • Kornbluth RS, Oh PS, Munis JR, Cleveland PH, Richman DD (Feb 1990) The role of interferons in the control of HIV replication in macrophages., Clinical Immunology and Immunopathology, 54 (2), 200-19 Abstract
  • Munis JR, Richman DD, Kornbluth RS (Feb 1990) Human immunodeficiency virus-1 infection of macrophages in vitro neither induces tumor necrosis factor (TNF)/cachectin gene expression nor alters TNF/cachectin induction by lipopolysaccharide., The Journal of Clinical Investigation, 85 (2), 591-6 Abstract
  • Kornbluth RS, Oh PS, Munis JR, Cleveland PH, Richman DD (Mar 1989) Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro., The Journal of Experimental Medicine, 169 (3), 1137-51 Abstract
  • Kornbluth RS, Gregory SA, Edgington TS (Sep 1988) Initial characterization of a lymphokine pathway for the immunologic induction of tumor necrosis factor-alpha release from human peripheral blood mononuclear cells., Journal of Immunology (baltimore, Md. : 1950), 141 (6), 2006-15 Abstract
  • Richman DD, Kornbluth RS, Carson DA (Oct 1987) Failure of dideoxynucleosides to inhibit human immunodeficiency virus replication in cultured human macrophages., The Journal of Experimental Medicine, 166 (4), 1144-9 Abstract
  • Gregory SA, Kornbluth RS, Helin H, Remold HG, Edgington TS (Nov 1986) Monocyte procoagulant inducing factor: a lymphokine involved in the T cell-instructed monocyte procoagulant response to antigen., Journal of Immunology (baltimore, Md. : 1950), 137 (10), 3231-9 Abstract
  • Kornbluth RS, Edgington TS (Oct 1986) Tumor necrosis factor production by human monocytes is a regulated event: induction of TNF-alpha-mediated cellular cytotoxicity by endotoxin., Journal of Immunology (baltimore, Md. : 1950), 137 (8), 2585-91 Abstract
  • Osman MM, Kornbluth RS, Hosannah YT, Manahan J, Keller S, Mandl I, Turino GM (Jul 1982) A simple procedure for the isolation of pulmonary parenchyma free of major blood vessels and airways for biochemical studies., The American Review of Respiratory Disease, 126 (1), 156-9 Abstract
  • Kornbluth RS, Turino GM (Jan 1980) Respiratory control in diffuse interstitial lung disease and diseases of the pulmonary vasculature., Clinics in Chest Medicine, 1 (1), 91-102 Abstract

Profile Details

Last Updated: 6/12/2009

COS Expertise ID #424380
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