Effects of Morphine on Gp120-induced Neuroinflammation Under Immunocompetent Vs. Immunodeficient Conditions.

HIV-associated neurocognitive disorder (HAND) is a common complication of HIV infection, whose development is known to be facilitated by inflammation and exacerbated by morphine. Previously, using the gp120 transgenic (tg) mouse model in combination with LP-BM5 (a murine retrovirus that can cause systemic immunodeficiency in susceptible mouse strains) we demonstrated differential gp120-associated central nervous system (CNS) neuroinflammatory responses under immunocompetent (-LP-BM5) vs. immunocompromised (+LP-BM5) conditions. Here, we further investigated the effects of morphine on gp120-associated neuroinflammatory response within the hippocampus under differential immune status. First, we confirmed that morphine treatment (2 × 25 mg pellets) did not significantly affect the development of immunodeficiency induced by LP-BM5 and all brain regions examined (hippocampus, striatum, and frontal lobe) had detectable LP-BM5 viral gag genes. Morphine notably reduced the performance of gp120tg+ mice in the alteration T-maze assay when 2-minute retention was used, regardless of LP-BM5 treatment. Morphine further enhanced GFAP expression in gp120tg+ mice regardless of host immune status, while promoted CD11b expression only in immunocompetent mice, regardless of gp120tg expression. In immunocompetent gp120tg+ mice, morphine increased the RNA expression of CCL2, CCL5, CXCL10, IL-12p40, and IFNß; while under the immunodeficient condition, morphine downregulated the expression of CCL2, CCL5, CXCL10, IL-12p40, and IL-1ß. Further, expression of TNFα and IFNγ were enhanced by morphine regardless of host immune status. Altogether, our results suggest that the effects of morphine are complex and dependent on the immune status of the host, and host immune status-specific, targeted anti-neuroinflammatory strategies are required for effective treatment of HAND.

Effects of HIV gp120 on Neuroinflammation in Immunodeficient vs. Immunocompetent States.

HIV affects 37 million people worldwide, 25-69% of which develop HIV-associated neurocognitive disorders (HAND) regardless of antiviral treatment. HIV infection of the brain decreases cognitive function, disrupts/impairs learning and memory, and reduces quality of life for those affected. HIV-induced neuroinflammation has been associated with viral proteins such as gp120 and Tat, which remain elevated in the CNS even in patients with low peripheral viremia counts. In this study, we examined the effects of gp120 on neuroinflammation in immunodeficient vs. immunocompetent states by examining neuroinflammatory markers in gp120tg mice with or without systemic immunodeficiency caused by murine retroviral administration (LP-BM5 murine AIDS). Changes in inflammatory cytokine/chemokine mRNA expression was complex and dependent upon expression of gp120 protein, immunodeficiency status, brain region (hippocampus, frontal lobe, or striatum), and age. Gp120 expression reduced hippocampal synaptophysin expression but did not affect animals' learning/memory on the spontaneous T-maze test in our experimental conditions. Our results emphasize the critical role of the neuroinflammatory micro-environment and the peripheral immune system context in which gp120 acts. Multiple factors, particularly system-level differences in the immune response of different brain regions, need to be considered when developing treatment for HAND. Graphical Abstract.