CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Abstract

Abstract HIV enters the brain within days of infection causing neurocognitive impairment (NCI) in up to half of infected people despite suppressive antiretroviral therapy. The virus is believed to enter the brain in infected monocytes through chemotaxis to the major monocyte chemokine, CCL2, but direct demonstration of the role of CCL2 in NCI pathogenesis in vivo is lacking. We addressed this question during infection of conventional or CCL2 knockout mice with EcoHIV in which NCI can be verified in behavioral tests. NCI develops gradually during EcoHIV infection of mice, with chronic cognitive disease starting 25 days after infection. CCL2 knockout mice infected by intraperitoneal injection of virus failed to develop brain infection and NCI. However, when EcoHIV was directly injected into the brain, CCL2 knockout mice developed NCI. Knockout of CCL2 or its principal receptor, CCR2, slightly reduced macrophage infection in culture. Treatment of mice prior to and during EcoHIV infection with the CCL2 transcriptional inhibitor, bindarit, prevented brain infection and NCI, and reduced macrophage infection. In contrast, bindarit treatment of mice four weeks after infection affected neither brain virus burden nor NCI, suggesting that once established, brain disease was independent of CCL2. Our results indicate that HIV enters the brain mainly through infected monocytes but that resident brain cells are sufficient to maintain NCI. A conclusion from these findings is that NCI therapy must act within the brain. .