Neuroregulatory Events Follow Adaptive Immune-Mediated Elimination of HIV-1-Infected Macrophages: Studies in a Murine Model of Viral Encephalitis

Abstract

HIV-1-specific cellular immunity serves to eliminate infected cells and disease. However, how this process specifically affects the CNS is poorly understood. To mirror the regulatory events that occur in human brain after HIV-1 infection, a murine model of viral encephalitis was used to study relationships, over time, among lymphocyte-mediated infected cell elimination, innate immune responses, and neuropathology. Nonobese diabetic SCID mice were reconstituted with human PBL and a focal encephalitis induced by intracranial injection of autologous HIV-1-infected, monocyte-derived macrophages (MDM). On days 7, 14, and 21 after MDM injection into the basal ganglia, the numbers of human lymphocytes and mouse monocytes, virus-infected MDM, glial (astrocyte and microglial) responses, cytokines, inducible NO (iNOS), neurotrophic factors, and neuronal Ags were determined in brain by immunohistochemistry, real-time PCR, and Western blot assays. Microglia activation, astrocytosis, proinflammatory cytokines, and iNOS expression accompanied the loss of neuronal Ags. This followed entry of human lymphocytes and mouse monocytes into the brain on days 7 and 14. Elimination of virus-infected human MDM, expression of IL-10, neurotropins, and a down-regulation of iNOS coincided with brain tissue restoration. Our results demonstrate that the degree of tissue damage and repair parallels the presence of infected macrophages and effectors of innate and adaptive immunity. This murine model of HIV-1 encephalitis can be useful in elucidating the role played by innate and adaptive immunity in disease progression and resolution.

Links between Progressive HIV-1 Infection of Humanized Mice and Viral Neuropathogenesis

“…A comparative description of previous mouse models of NeuroAIDS is presented in the Supplemental table, S1 (available at http://ajp.amjpathol.org). [1][2][3][4]6,7,[62][63][64][65][66][67][68][69][81][82][83][84][85][86][87][88][89][90] What is reported now can permit future studies of viral neuropathogenesis studies in rodents and for investigations of novel antiretroviral and adjunctive therapies.…”

“…Application of mice injected intracranially with HIV-1 infected human monocytederived macrophages (MDM) alone or in combination with peripheral blood lymphocytes (PBL) reconstitution for the study of neuroAIDS is well established. [1][2][3][4][5][6] However, traumatic injury to the brain from injection, PBL activation by the mouse environment and developed graft-versus host reactivity are significant disadvantages of these models.…”

Copolymer-1 Induces Adaptive Immune Anti-inflammatory Glial and Neuroprotective Responses in a Murine Model of HIV-1 Encephalitis

“…This is supported by the fact that nervous system dysfunction can occur throughout the course of viral infection associated with ongoing vigorous immune responses. On balance, the presence of T cells in brain at early stages of SIV infection (58) and in humanized HIVE mice (10) suggests that modulation of T cell function could also provide a neuronal protective response for disease.…”

“…Immune-deficient mice injected with HIV-infected human macrophages into the subcortex serve as a model for the studies of HIVE and were developed in our laboratories (10,31). However, the lack of long-lived adaptive immune component in these mice renders this model deficient to investigate immune-based therapies.…”

Human Dendritic Cells Transduced with Herpes Simplex Virus Amplicons Encoding Human Immunodeficiency Virus Type 1 (HIV-1) gp120 Elicit Adaptive Immune Responses from Human Cells Engrafted into NOD/SCID Mice and Confer Partial Protection against HIV-1 Challenge

“…Severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID mice) develop immune responses to viral antigens (11,38,47,55). Moreover, the model was utilized extensively in our laboratories and by others to study HIV-1 pathogenic mechanisms and for drug testing (33,37,39,43,44,55,56). Nonetheless, a limitation of the hu-PBL-SCID mouse model is the relatively modest level of T-cell engraftment and the dearth of human dendritic cells (DC) in the model system (6,53).…”