Grant: Operating Grant - PA: HIV/AIDS Bridge Funding - Biomedical/Clinical Stream

An early event in HIV-1 infection is the entry of the virus into the central nervous system (CNS), which may result ultimately in the development of several types of neurological defects. Neurological disorders associated with HIV-1 affect between 40% and 70% of infected individuals, involving the CNS and the peripheral nervous system. HIV-1 enters the CNS early in infection and productive replication within the brain occurs only in perivascular macrophages and microglia. Replenishment of the perivascular macrophage population by circulating monocytes that migrate into the brain has the consequence of enabling HIV-1 entry through trafficking of infected monocytes from the circulation. After the monocytes enter the CNS, they differentiate into macrophages, as they do in other tissues, which increase their ability to support virus replication. This process has been described as the «Trojan horses» mechanism of neuroinvasion. The first part of this research project will permit to shed the light on the mechanism leading to the entry of monocytes in the CNS. In our laboratory, we showed for the first time that CCR7, a chemokine receptor implicated in chemotaxis, is expressed on monocytes. This understanding will provide information crucial to the development of strategies to selectively target infected monocytes migration. On the other hand, current antiretroviral drugs often fail to effectively reduce the HIV viral load in the brain. This, in part, is due to the poor transport of many antiretroviral drugs, in particular protease inhibitors, across the blood brain barrier. Using CCR7+ monocytes as carrier for nanoformulated antiretroviral therapy, we think that this cell-based delivery system could be more specific and efficient for brain targeting. Drug development must move into a more rational phase aimed at optimizing conditions for efficient delivery to the CNS.