Professor and Director
HIV, the agent that causes acquired immunodeficiency (AIDS), is a lentivirus that causes persistent infection, immunosuppression with resultant opportunistic infections and chronic disease including encephalitis and pneumonia in humans. One of the important characteristics of lentiviruses is their ability to replicate in macrophages; replication in these cells is linked to the development of neurological disease and pneumonia in infected individuals. We study the SIV/macaque model of HIV infection to understand how HIV causes systemic and tissue-specific diseases.
We have demonstrated that SIV replication in the brain induces the expression of chemokines, particularly MCP-1, that recruit lymphocytes and macrophages to the tissue. This influx of cells results in inflammation within the tissue, which may have both beneficial and detrimental effects. On the one hand, the inflammatory cells may include specific immune cells that can kill virus-infected cells and lower viral load. On the other hand, some of the inflammatory cells may themselves be infected, resulting in an increase in viral load. How these two scenarios play out in the tissue probably determines the outcome of infection.
We have recently identified an antibiotic that is inexpensive (patent has expired) and completely safe that suppresses replication of HIV/SIV and significantly suppresses the encephalitis and neurodegeneration associated with HIV/SIV infection. We are currently examining the mechanism by which this exciting drug functions in the CNS.
We also are performing pre-clinical testing of a number of other drugs that have shown neuroprotective activity in high throughput assays, treating SIV-infected macaques with these drugs to ameliorate the effects of SIV replication and the resulting inflammation on the brain.
Susan C. Follstaedt, Sheila A. Barber, M. Christine Zink. Mechanisms of minocycline-induced suppression of SIV encephalitis: Inhibition of apoptosis signal-regulating kinase 1. J Neurovirol 2008;14:1-13.
Clements JE, Mankowski JL, Gama L, Zink MC. The accelerated simian immunodeficiency virus macaque model of human immunodeficiency virus-associated neurological disease: From mechanism to treatment. J Neurovirol 2008: 14:309-317.
Zink MC, Brice AK, Kelly KM, Queen SE, Gama L, Li M, Adams RJ, Bartizal C, Varrone J, Rabi SA, Graham DR, Tarwater PM, Mankowski JL, Clements JE. Simian Immunodeficiency Virus-Infected Macaques Treated with Highly Active Antiretroviral Therapy Have Reduced Central Nervous System Viral Replication and Inflammation but Persistence of Viral DNA. J Infect Dis. 2010 May 24.
Witwer KW, Gama L, Li M, Bartizal CM, Queen SE, Varrone JJ, Brice AK, Graham DR, Tarwater PM, Mankowski JL, Zink MC, Clements JE. Coordinated regulation of SIV replication and immune responses in the CNS. PLoS One. 2009 Dec 17;4(12):e8129.
Dinoso JB, Rabi SA, Blankson JN, Gama L, Mankowski JL, Siliciano RF, Zink MC, Clements JE. A simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy. J Virol. 2009 Sep;83