Human immunodeficiency virus type 1 (HIV-1) enters the brain soon after serconversion. Consequently, the central nervous system (CNS) becomes a sanctuary for virus, and it can be damaged by virus or virally encoded proteins. A prominent model for viral entry into the CNS is the """"""""Trojan Horse"""""""" hypothesis, in which HTV- 1-infected CD4+ T-lymphocytes and monocytes transmigrate across the blood-brain barrier (BBB). Consistent with prior work, we observed that HIV-1 infection enhances T-cell and monocyte transmigration in vitro across a simple acellular barrier of Matrigel, which mimics basement membrane. More importantly, we made the novel discovery that clinically available inhibitors of cholesterol biosynthesis (statins) potently inhibit HTV-1 -induced transmigration. This finding arose from an essential synergy between two laboratories in different fields, lipid metabolism (Dr. Williams) and neurovirology (Drs. Mukhtar and Pomerantz). In addition, as noted in the Introduction and revised Preliminary Studies, we recently found a neuroprotective effect of statins as well. Our central hypothesis is that HIV-1 infection alters the expression of specific genes that play a central role in transmigration and cytotoxicity, and that statins restore the expression of these genes towards normal levels. Experimental systems available to us include primary human T-cells and monocytes, our acellular model barrier of Matrigel, and a sophisticated cellular BBB model that we created using well-characterized human BMVECs and astrocytes grown in transwell inserts over human neurons. There are two Specific Aims:
Aim I; Molecular mechanisms by which statins reduce transmigration of HIV-1-infected CD4+ T-cells and monocytes through an acellular model basement membrane. Three sub-Aims will study whether this effect results from (i) cholesterol-dependent or -independent (pleiotropic) effects of statins, (ii) involvement of specific genes identified on our focused gene array as altered by infection but restored by statins, e.g., MMPs, TIMPs, paxillin, and rho-related proteins, and (iii) alterations in specific inflammatory or cytotoxic cytokines.
Aim II : Effects of statins on transmigration of HIV-1-infected T-cells and monocytes through a cellular blood brain barrier model in vitro. Sub-aims will somewhat parallel Aim I, focusing on the effects of infection and statin treatment on specific gene expression, cytokine release, endothelial integrity, and transmigration. Overall, our proposed studies will provide new insights into HIV-1 neuropathogenesis. In addition, our work may provide a new use for statins to prevent or treat AIDS-related dementia and to deplete or eradicate the CNS as an HIV-1 sanctuary. ? ?
| Smith, Johanna A; Wang, Feng-Xiang; Zhang, Hui et al. (2008) Evidence that the Nijmegen breakage syndrome protein, an early sensor of double-strand DNA breaks (DSB), is involved in HIV-1 post-integration repair by recruiting the ataxia telangiectasia-mutated kinase in a process similar to, but distinct from, cellul Virol J 5:11 |
