Overview

The background and objectives of our laboratory are to define the interactions between infectious diseases and aberrant apoptosis regulation with an emphasis on pathogenesis and therapy. Recent examples include:

1. Defining the mechanism by which HIV protease expression induces cell death, the activation off procaspase 8 (Nie Z, Phenix BN, Lum J, Alam A, Lynch, DH, Beckett B, Krammer PH, Sekaly, RF, Badley AD. HIV-1 protease processes procaspase 8 to cause mitochondrial release of cytochrome c, caspase cleavage and nuclear fragmentation. Cell Death and Differentiation, 2002, 9:1172-1184 and Nie Z, Bren GD, Vlahakis SR, Algeciras Schimnich A, Brenchley JM, Trushin SA, Warren S, Schnepple DJ, Kovacs CM, Loutfy MR, Douek DC, Badley AD. HIV-1 protease cleaves procaspase 8 in vivo. Journal of Virology, 2007, in press.)
2. Defining that a naturally occurring polymorphisms within Vpr (R77Q) have an impaired ability to induce cell death and that this polymorphism is associated with long-term non-progressive HIV (Lum JJ, Cohen OJ, Nie Z, Weaver JG, Gomez TS, Yao XJ, Lynch D, Pilon AA, Hawley N, Kim JE, Chen Z, Montpetit M, Sanchez-Dardon J, Cohen EA, Badley AD. Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis. Journal of Clinical Investigation, 2003, 111(10):1547-1554).
3. Defining that HIV gp120 can cause the death of hepatocytes through CXCR4 receptor binding (Vlahakis SR, Villasis-Keever A. Gomez T, Bren GD, Paya CV. Human immunodeficiency virus-induced apoptosis of human hepatocytes via CXCR4. Journal of Infectious Diseases, 2003, 188:1455-1460).
4. Demonstrating that HIV infected resting memory T cells (latently infected) die in response to TRAIL receptor ligation, raising the possibility that such treatment might be used as a therapy for HIV (Lum JJ, Pilon AA, Sanchez-Dardon J, Phenix BN, Kim JE, Mihowich J, Jamison K, Hawley-Foss N, Lynch DH, Badley AD. Induction of cell death in human immunodeficiency virus-infected macrophages and resting memory CD4 T cells by TRAIL/Apo2L. Journal of Virology, 2001, 75:11128-11136 and Lum JJ, Schnepple DJ, Nie Z, Sanchez-Dardon J, Mbisa GL, Mihowich J, Hawley N, Narayan S, Kim JE, Lynch DH, Badley AD. Differential effects of Interleukin-7 and Interleukin-15 on NK cell anti-Human Immunodeficiency Virus activity. Journal of Virology, 2004, 78:6033-6042).
5. Demonstration that HIV reactivation induced by TCR ligation requires both PKC and PKCq isoforms (Trushin SA, Bren GD, Asin S, Paya CV, Badley AD. HIV reactivation by phorbol esters or TCR ligation requires both PKCΑ and PKCθ. Journal of Virology, 2005, 79(15):9821-9830).
6. Demonstrating the observation and mechanism by which the HIV protease inhibitor class of drugs are intrinsically antiapoptotic both in vitro, and in vivo, and consequently improve survival in mouse models of hepatitis, sepsis, and stroke (Weaver JGR, Rouse MS, Steckelberg JM, Badley AD. Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis. The FASEB Journal, 2004, 18:1185-1191 and Weaver JG, Tarze A, Moffat TC, LeBras M, Deniaud A, Brenner C, Bren GD, Morin MY, Phenix BN, Dong L, Jiang SX, Sim VL, Zurakowski B, Lallier, J, Hardin H, Wettstein P, van Heeswijk RPG, Douen A, Kroemer RT, Miller B, Hou ST, Bennett SAL, Lynch DH, Kroemer G, Badley AD. Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor. Journal of Clinical Investigation, 2005, 115(7):1828-1837).
7. Defining the signal transduction pathway that occurs downstream of CXCR4 signaling by gp120 in order to result in cell death (Trushin SA, Algeciras-Schimnich A, Vlahakis SR, Bren GD, Warren S, Schnepple DJ, Badley AD. gp120 binding to CXCR4 causes p38-dependent primary T cell death that is facilitated by, but does not require cell-associated CD4. Journal of Immunology, 2007, 178(8)4846-4853).
8. Demonstrating that HIV protease inhibitors not only block viral replication in cells from HIV-infected patients, but also even in the face of antiviral resistance, HIV protease inhibitors exert anti-apoptotic effects which reduce cell death caused by HIV-associated proteins (Vlahakis SR, Bren GD, Algeciras-Schimnich A, Trushin SA, Schnepple DJ, Badley AD. Flying in the face of resistance: antiviral independent benefit of HIV protease inhibitors on T cell survival. Clinical Pharmacology and Therapeutics, 2007, in press).