Janice E. Clements, Ph.D.Image

Professor and Director, Molecular & Comparative Pathobiology (formerly Comparative Medicine)

Contact Information

Room 819, Broadway Research Building
410-955-9770
410-955-9823 (Fax)
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Research Interests

Molecular and Cellular Basis of Viral Diseases - SIV Model for HIV Pathogenesis

Lentiviruses, HIV being the best known, are non-oncogenic retroviruses that cause chronic progressive diseases of the immune system, central nervous system, lungs and joints. My laboratory seeks to understand the molecular basis for virus cell-interactions that lead to cell dysfunction, damage and ultimately disease in infected humans and animals. We use the simian immunodeficiency virus (SIV) as an animal model of AIDS.  We have shown the importance of infection of cells by a CD4-independent pathway that is particularly important for infection of cells in the central nervous system (CNS). Infection of the CNS is a frequent result of HIV-1 infection of humans and the SIV model provides the best model to study the contribution of viral and cellular genes in the disease process. Approaches to specifically control HIV infection in the CNS are vitally important since anti-retroviral therapy has varying abilities to cross the Blood Brain Barrier. We are examining the role of host genetics as well as novel drug therapies that target the cell rather than the virus. A recent study from our group on the antibiotic minocycline demonstrated that this drug inhibits the replication of both HIV and SIV by affecting a cellular pathway. Studies are ongoing to understand the mechanisms by which this drug inhibits cellular activation, virus replication and maintains HIV & SIV latency.

Recent studies in vivo and in vitro have identified the role of innate immune responses that regulate viral gene expression at the transcriptional and post-transcriptional level. IFN? is induced in SIV and HIV infected cells resulting in the induction of cellular transcription factors that repress viral transcription in macrophages. The molecular mechanisms involved in the regulation of HIV and SIV is being studied in specific cells and tissues in a well-defined animal model and primary cells. In addition, post-transcriptional mechanisms induced by the innate immune response also restrict virus replication both in vitro and in vivo. Understanding these regulatory mechanisms is essential for understanding the pathogenesis of HIV induced AIDS and nervous diseases such as CNS encephalitis and dementia and peripheral neuropathy.

Selected Publications

  • Babas, T., Dewitt, J.B., Mankowski, J.L., Tarwater, P.M., CLEMENTS, J.E., Zink, M.C.: Progressive Selection for Neurovirulent Genotypes in the Brain of Simian Immunodeficiency Virus (SIV) Infected Macaques. AIDS, 20(2):197-205, 2006.
  • Barber, S.A.,Gama, L. Li, M., Voelker, T., Anderson, J.E., Zink, M.C. and CLEMENTS, J.E. Longitudinal Analysis of SIV Replication in the Lung: Compartmentalized Regulation of SIV.  J. Infectious Disease, 193(7):963-70, 2006.
  • Barber, S.A., Gama, L., Dudaronek, J.M., Voelker, T., Tarwater, P.M. and. CLEMENTS, J.E. Mechanism for Establishment of Transcriptional HIV Latency in the Brain using an SIV Macaque Model. J. Infectious Disease, 193(7):963-70, 2006.
  • Zink, MC, Uhrlaub, J, DeWitt, J, Voelker, T, Bullock, B, Mankowski, J, Tarwater, P, CLEMENTS, J, Barber, S. Neuroprotective and Anti-Human Immunofeficiency Virus Activity of Minocycline. JAMA, 293(16):2003-2011, 2005
  • Barber SA, Herbst DS, Bullock BT, Gama L, Clements JE. Innate immune responses and control of acute simian immunodeficiency virus replication in the central nervous system. J Neurovirol. 2004;10 Suppl 1:15-20.
  • Shen A, Zink MC, Mankowski JL, Chadwick K, Margolick JB, Carruth LM, Li M, Clements JE, Siliciano RF. Resting CD4+ T lymphocytes but not thymocytes provide a latent viral reservoir in a simian immunodeficiency virus-Macaca nemestrina model of human immunodeficiency virus type 1-infected patients on highly active antiretroviral therapy. J Virol. 2003 Apr;77(8):4938-49
  • Rue SM, Roos JW, Amzel LM, Clements JE, Barber SA. Hydrogen bonding at a conserved threonine in lentivirus capsid is required for virus replication. J Virol. 2003 Jul;77(14):8009-18.
  • Clements, J.E., Babas, T., Mankowski, J., Suryanarayana, K., Piatak, M.J., Tarwater, P.M., Lifson, J., and Zink, M.C.  The CNS is a Reservoir for SIV:  Steady-state levels of SIV DNA in Brain from acute through asymptomatic infection. J. Infect. Dis. 186:905-13 2002.
  • Edinger, A.L., Mankowski, J.L., Doranz, B.J., Margulies, B., Lee, B., Rucker, J., Sharron, M., Hoffman, T. Berson, J., Hirsch, V., Clements, J.E., and Doms, R.W. (1997) CD4- independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent SIV strain. Proc. Natl. Acad. Sci. USA, 94, 14742-14747
  • Donahue, R.E., Bunnell, B.A., Zink, M.C., Metzger, M.E., Wersto, R., Kirby, M., Unangst, T., Clements, J.E. and Morgan, R.A. (1998) Reduction in SIV replication in rhesus macaques infused with autologous lymphocytes engineered with anti-viral genes. Nature Medicine, 4, 181-186.
 
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