Combination antiretroviral therapy (cART), no matter how effective, cannot eliminate viral infection from its lymphoid and brain reservoirs. The blood-brain-barrier presents a substantive challenge as drug penetrance is often impeded. Moreover, the locale and extent of the viral brain reservoir has yet to be defined. This proposal seeks funds to establish a humanized mouse model to monitor formation of HIV reservoirs in hemato-lymphoid and CNS compartments, and in immune and non-immune cells (such as astrocytes). The focused use of mice carrying human blood and glia in the brain makes applicability to humans problematic. In turn, we are developing a resource that will generate improved animal models to study human glial cells interaction with peripheral immunity during HIV infection. Double humanized mice will be validated as a tool to study effects of substances of abuse on HIV CNS reservoir formation and eradication. Our goals to improve existing humanized mice models are as follows: R21 phase - 1) engraft human astrocytes and confirm their role in CNS HIV reservoir in vivo; and 2) enhance the development and function of human innate immune cells by transgenic expression of human IL-34 and assess cytokine effects on HIV-1 reservoir formation. R33 phase - 1) explore the effects of substances of abuse on formation of CNS reservoir and clearance by new antiretroviral approaches.
NOD/scid-?c-/- mice can maintain human immune and glial cells, can be chronically infected with HIV-1 and develop viral reservoir in immune and glial cells in the central nervous system. The transgenic expression of human interleukin 34 in such animals will support tissue resident macrophages and formation of HIV reservoir. These mice will be involved in assessment of the role of substances of abuse, antiretroviral therapeutics or eradication strategies.
