Research in the Retrovirus Laboratory focuses on the molecular virology and pathogenesis of lentivirus infections. In particular, the simian immunodeficiency virus (SIV) is used to examine the molecular basis for the pathogenesis of HIV CNS disease. Research projects include studies of viral molecular genetics and host cell genes and proteins involved in the pathogenesis of disease. Further studies of lentivirus infections of macrophages and specific viral pathogenesis in the central nervous system and the lung are of interest. These studies have led us to identify the viral genes that are important in neurovirulence of SIV and the development of CNS disease. The SIV Envelope gene and the NEF gene both play important roles in infection of the CNS. The mechanisms of the action of these proteins in the CNS are complex and are under investigation.

Her group was the first to identify the role of CD4-independent virus entry in the pathogenesis of neurological disease. They have shown that neurovirulent SIV can infect cells in a CD4-independent, CCR5-dependent manner in primary CNS endothelial cells and cell lines that express only CCR5. Furthermore, studies have shown that the Nef protein from the neurovirulent virus interacts with different cellular kinases than the Nef protein from other strains of SIV. Their studies have demonstrated that replication of neurovirulent virus in vivo by quantitation of viral RNA copies in the brain and viral load in cerebral spinal fluid is directly correlated with the development of CNS lesions during SIV infection. Finally, they have shown that virus replication in the CNS is independently regulated from the peripheral blood. Because virus replication in the brain is mainly in macrophages while in the peripheral blood it occurs in lymphocytes, control of viral replication by innate immune responses in the brain is significant.

Current research is examining the role of these innate immune responses on restricting viral RNA transcription and gene expression.

Publications:

Edinger AL, Mankowski JL, Doranz BJ, Margulies BJ, Lee B, Rucker J, Sharron M, Hoffman TL, Berson JF, Hirsch VM, Clements JE, Doms RW. CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain. Proc Natl Acad Sci USA, 94(26):14742-14747, 1997.
PubMed Abstract

Zink MC, Coleman GD, Mankowski JL, Adams RJ, Tarwater PM, Fox K, Clements JE. Increased Macrophage chemoattractant protein-1 in cerebrospinal fluid precedes and predicts simian immunodeficiency virus encephalitis. J Infect Dis, 84:1015-1021, 2001.
PubMed Abstract

Clements JE, Babas T, Mankowski JL, Suryanarayana K, Piatak M Jr, Tarwater PM, Lifson JD, Zink MC. The central nervous system as a reservoir for simian immunodeficiency virus: steady-state levels of DNA in brain from acute through asymptomatic infection. J Infect Dis, 184:1015-1021, 2001.
PubMed Abstract

Shen A, Zink MZ, 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, 77(8):4938-4949, 2003.
PubMed Abstract

Bonavia A, Bullock BT, Gisselman KM, Margulies BJ, Clements, JE. A Single Amino Acid Change and Truncated TM are Sufficient for simian immunodeficiency virus to Enter Cells Using CCR5 in a CD4-Independent Pathway. Virology, 341(1):12-23, 2005.
PubMed Abstract

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.
PubMed Abstract

Barber SA, Gama L, Dudaronek JM, Voelker T, Tarwater PM, Clements JE. Mechanism for Establishment of Transcriptional HIV Latency in the Brain using an SIV Macaque Model. J. Infectious Disease, 193(7):963-70, 2006.
PubMed Abstract

Barber SA, Gama L, Li M, Voelker T, Anderson JE, Zink MC, Clements JE. Longitudinal Analysis of SIV Replication in the Lung: Compartmentalized Regulation of SIV. J. Infectious Disease, 194(7):931-8, 2006.
PubMed Abstract