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Professor and Vice Dean for Faculty
Division of Comparitive Medicine; Molecular Biology and Genetics
Dept. of Molecular and Comparative Pathobiology
733 North Broadway
Baltimore MD 21205
Molecular Pathogenesis and Latency of SIV & HIV
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.
Reactivation of SIV Reservoirs in the Brain of Virally Suppressed Macaques Gama L, Abreu CM, Shirk EN, Price SL, Li M, Laird GM, Pate KA, Wietgrefe SW, O'Connor SL, Pianowski L, Haase AT, Van Lint C, Siliciano RF, Clements JE; LRA-SIV Study Group. AIDS. 2017 Jan 2;31(1):5-14.
Avalos CR, Price SL, Forsyth ER, Pin JN, Shirk EN, Bullock BT, Queen SE, Li M, Gellerup D, O'Connor SL, Zink MC, Mankowski JL, Gama L, Clements JE. Quantitation of Productively Infected Monocytes and Macrophages of Simian Immunodeficiency Virus-Infected Macaques. J Virol. 2016 May 27;90:5643-56.
Williams DW, Engle EL, Shirk EN, Queen SE, Gama L, Mankowski JL, Zink MC, Clements JE. Splenic Damage during SIV Infection: Role of T-Cell Depletion and Macrophage Polarization and Infection. Am J Pathol. 2016 Jun 17. pii: S0002-9440(16)30127-4.
Dual Role of Novel Ingenol Derivatives in HIV Replication: Inhibition of De Novo Infection and Activation of the Viral LTR. Abreu CM, Price SL, Shirk EN, Cunha RD, Pianowski LF, Clements JE, Tanuri A, Gama L. Dual Role of Novel Ingenol Derivatives from Euphorbia tirucalli in HIV PLoS One. 2014 May 14;9(5):e97257.
A Murine Viral Outgrowth Assay to Detect Residual HIVType 1 in Patients with Undetectable Viral Load. Metcalf Pate KA, Pohlmeyer CW, Walker-Sperling VE, Foote JB, Najarro KM, Cryer CG, Salgado M, Gama L, Engle EL, Shirk EN, Queen SE, Chioma S, Vermillion MS, Bullock B, Li M, Lyons CE, Adams RJ, Zink MC, Clements JE, Mankowski JL, Blankson JN. J Infect Dis. 2015 Nov 1;212(9):1387-96.