Abnormal activation of monocytes, microglia and astrocytes in mice transgenic for monocyte-tropic HIV-1 provirus and human cyclin T1 contributes to the pathogenesis of HIV-1 infection
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This project focused on developing and utilizing a transgenic mouse model to study the effect of HIV-1 gene expression in the central nervous system (CNS) to recapitulate the pathogenesis of HIV-associated dementia (HAD). For this purpose, we examined the utility of a mouse line we constructed that is transgenic for a full-length proviral clone of a monocyte-tropic HIV-1 isolate, HIV-1JR-CSF (JR-CSF mice). We demonstrated that expression of HIV transgene was increased by stimulation with lipopolysaccharide in the microglia of these transgenic mice. Furthermore, chemokine expression by JR-CSF mouse microglia and brains was more responsive to stimulation with lipopolysaccharide than were microglia and brains from control mice. This study established that the JR-CSF mice might represent a new mouse model to study the effect of HIV-1 replication on microglia function and its contribution to HIV-1-associated neurological disease. However, HIV-1 virus production by JR-CSF mice was limited by the inability of Tat to function as a transcriptional activator in mouse cells due to a single amino acid reciprocal change that prevents binding of mouse cyclin T1 to Tat. Another limitation is that in contrast to humans where HIV-1 replication occurs predominantly in CD4-expressing cells, in the HIV transgenic mice the provirus is integrated in every cell and can be expressed by any cell that supports HIV LTR transcription. We hypothesized that expression of a human cyclin T1 transgene would markedly increase HIV-1 replication in the JR-CSF transgenic mouse cells. We demonstrated that expression of human cyclin T1 under the control of a CD4 expression construct in JR-CSF/hu-cycT1 mice markedly increased HIV-1 production by mouse CD4-expressing cells, was associated with selective depletion of CD4+ T lymphocytes in the peripheral blood and was associated with increased CCL2/MCP-1 production by stimulated mouse myeloid-committed cells. Furthmore, inflammatory signals increased in vivo brain HIV and chemokine production and associated with increased activation of microglia and astrocytes in the brains of JR-CSF/hu-cyclinT1 mice. Therefore, JR-CSF/hu-cycT1 mice may represent an improved new model for studying the pathogenesis of HIV-1-mediated disease in the CNS.
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