Joseph P. Casazza, M.D., Ph.D.
Specialty(s): Infectious Disease, Internal Medicine Provides direct clinical care to patients at NIH Clinical Center
Major Areas of Research
- HIV Vaccines
- HIV pathogenesis
My work at the NIH concentrates on two aspects of HIV infection: the control of HIV-infection by the immunologic mechanism and the description of the changes in the CD4 T cell transcriptome caused by HIV-infection. In collaboration with individuals at the VRC, the California Institute of Technology and the Ragon Institute I am responsible for a clinical trial in which an AAV vector carries the coding sequence for VRC07, a potent broadly neutralizing Ab, into muscle cells of HIV-infected individuals on effective anti-retroviral therapy. In some individuals production of VRC07 occurred at ug/ml serum quantities for over 3 years. Although this level of VRC07 is not protective, this study shows that it is possible to side-step some of the difficulties in producing an immunogen capable of inducing a broadly neutralizing antibody by using a viral vector to transduction muscle cells. I have also established methods to identify and sort live HIV-infected CD4 T cells. Unlike matrix proteins, envelope proteins are fully mature when transported to the surface of CD4 T cells. By using fluorescently labeled broadly neutralizing antibodies that bind HIV envelope protein expressed on the surface of CD4 T cells, it is possible to use index sorting to identify live HIV-infected CD4 T cells. The transcriptomes of these cells are then characterized using RNA seq. We have used these methods to characterize the transcriptomes from HIV-infected peripheral CD4 T cells and in ACH2 cells transitioning from “latent-infection” to “active-infection”. These studies have allowed us to correlate markers of disease progression such as CD4 down regulation, viral RNA concentrations and viral RNA splice patterns, with activation of NF-B pathway and increased HIV-RNA transcription. We are currently using these methods to identify and characterize the longitudinal effect of SHIV infection on the CD4 T cell transcriptome of individual SHIV infected CD4 T cells from rhesus macaque lymph nodes.
Ph.D., Biochemistry, Iowa State University
M.D., Internal Medicine, University of Texas Southwestern Medical Center
Dr. Casazza received his Ph.D. in Biochemistry from Iowa State University in 1978 and then did a Post-doc at the National Institutes on Alcohol and Alcoholism studying near equilibrium thermodynamics and intermediary metabolism. At the age of 40, he started medical school in 1991 at the University of Texas Southwestern Medical Center where he did his internship and residency in Internal Medicine and a fellowship in Infectious Disease. Dr. Casazza came to the Vaccine Research Center in 2002 as a staff clinician where he has both scientific and clinical responsibility. His scientific and clinical interests are in HIV pathophysiology and vaccine development.
VRC 200 (03-I-0263): Apheresis and Specimen Collection Procedures to Obtain Plasma, Peripheral Blood Mononuclear Cells (PBMCs) and Other Specimens for Research Studies- Associate Investigator.
VRC 323 (NIH 20-I-0145): A Phase I Open-Label Clinical Trial to Evaluate the Dose, Safety, Toerablity and Immunogenicity of an Influenza H10 Stabilized Stem Ferritin Vaccine, VRC-FLUNPF0103-VP, in Healthy Adults- Principal Investigator
VRC 325 (NIH000410): A Phase I Open-Label Clinical Trial to Evaluate the Dose, Safety, Tolerability and Immunogenicity of Mosaic Quadrivalent Influenza Vaccine Compared with a Licensed Inactiviated Seasona QIV, in Healthy Adults – Associate Investigator
VRC-603 (NIH-18-I-0030): A Phase 1 Dose-Escalation Study of the Safety of AAV8-VRC07 (VRC-HIVAAV070-00-GT) Recombinant AAV Vector Expressing VRC07 HIV-1 Neutralizing Antibody in Antiretroviral-Treated, HIV-1 Infected Adults with Controlled Viremia -Principal Investigator.
VRC609 (NIH 20-I-0096) A Phase I Open-Label Dose Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB091-00-AB (N6LS), Administered Intravenously or Subcutaneously to Healthy Adults- Medical Officer
VRC611 (NIH 000536) A Phase I Safety and Pharmacokinetics Study to Evaluate a Human Monoclonal Antibody (mAb) VRC-HIVMAB0102-00-AB (CAP256V2LS) Administered Via Subcutaneous and Intravenous Injection in Healthy Adults- Medical Officer
VRC 614 (NIH 000536) A Phase 1, Dose Escalation, Open-Label Clinical Trial with Experimental Controlled Human Malaria Infections (CHMI) to Evaluate Safety and Protective Efficacy of an Anti-Malaria Human Monoclonal Antibody, VRC-MALMAB0114-00-AB (L9LS), in Healthy, Malaria-Naive Adult- Medical Officer
VRC 900 (10-I-0109): Evaluation of Tissue-Specific Immune Responses in Adults 18 Years of Age and Older -Associate Investigator.
Casazza JP, Cale EM, Narpala S, Yamshchikov GV, Coates EE, Hendel CS, Novik L, Widge AT, Apte P, Gordon I, Gaudinski MR, Conan-Cibotti M, Lin BC, Trofymenko O, Telscher S, Plummer SA, Wycuff D, Adams WC, Pandey JP, McDermott A, Roederer M, Sukienik AN, Doria-Rose NA, O’Dell S, Gall JG, Flach B, Nason MC, Saunders KO, Stein JA, Schwartz RM, Balazs AB, Baltimore D, Nabel GJ, Koup RA, Graham BS, Ledgerwood JE, Mascola JR and the VRC 603 Study Team (2022) Nat Med. 2022 May;28(5):1022-1030. doi: 10.1038/s41591-022-01762-x. Epub 2022 Apr 11.PMID: 35411076.
Pegu A, Xu L, DeMouth ME, Fabozzi G, March K, Almasri CG, Cully MD, Wang K, Yang ES, Dias J, Fennessey CM, Hataye J, Wei RR, Rao E, Casazza JP, Promsote W, Asokan M, McKee K, Schmidt SD, Chen X, Liu C, Shi W, Geng H, Foulds KE, Kao SF, Noe A, Li H, Shaw GM, Zhou T, Petrovas C, Todd JP, Keele BF, Lifson JD, Doria-Rose NA, Koup RA, Yang ZY, Nabel GJ, Mascola JR. Potent anti-viral activity of a trispecific HIV neutralizing antibody in SHIV-infected monkeys. Cell Rep. 2022 Jan 4;38(1):110199.
Hataye JM, Casazza JP, Best K, Liang CJ, Immonen TT, Ambrozak DR, Darko S, Henry AR, Laboune F, Maldarelli F, Douek DC, Hengartner NW, Yamamoto T, Keele BF, Perelson AS, Koup RA. Principles Governing Establishment versus Collapse of HIV-1 Cellular Spread. Cell Host Microbe. 2019 Dec 11;26(6):748-763.e20.
Casazza JP, Bowman KA, Adzaku S, Smith EC, Enama ME, Bailer RT, Price DA, Gostick E, Gordon IJ, Ambrozak DR, Nason MC, Roederer M, Andrews CA, Maldarelli FM, Wiegand A, Kearney MF, Persaud D, Ziemniak C, Gottardo R, Ledgerwood JE, Graham BS, Koup RA; VRC 101 Study Team. Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire. J Infect Dis. 2013 Jun 15;207(12):1829-40.
Casazza JP, Betts MR, Price DA, Precopio ML, Ruff LE, Brenchley JM, Hill BJ, Roederer M, Douek DC, Koup RA. Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation. J Exp Med. 2006 Dec 25;203(13):2865-77.