Altered gene expression in HIV gp120 transgenic mouse brains: Effects of methamphetamine treatment.

Purpose: Antiretroviral therapy (ART) has extended lifespans by decades for HIV-infected individuals. However, the prevalence of HIV-associated neurocognitive disorders (HAND) continues to be high despite successful ART therapy. Brain astrocytes can harbor provirus and express neurotoxic HIV proteins such as gp120 and TAT, potentially contributing to HAND. In addition, neurocognitive decline is exacerbated in individuals who use methamphetamine (METH). We hypothesize that METH treatment in gp120+ mice will cause changes in gene expression and damage/death to specific cell populations. Methods: To examine the role of METH in HAND, we used a transgenic mouse line expressing GFAP-controlled HIV gp120 protein (gp120+). Mice were injected intraperitoneally with either 0.9% saline vehicle or successive weekly escalating doses of 1, 5, 10, or 30 mg/kg METH, and their brains were harvested 7 days post-injection for qPCR, immunohistochemistry and protein analyses. Results: In qPCR experiments, gp120+ mice showed dramatically increased levels of GFAP mRNA, suggesting chronic gp120 expression causes astrocyte activation. However, a qPCR probe designed to distinguish the transgene versus the endogenous GFAP transcripts showed lower levels of GFAP activation, suggesting that some of the GFAP mRNA expression is read-through from the transgene construct. GFAP expression in the rostral portion of the brain (anterior to ~0 bregma) was lower than the caudal portion in the gp120- mice, whereas GFAP was higher in the rostral portion in the gp120+ mice, suggesting enhanced astrocyte activation in the rostral portion of the brain encompassing the striatum and frontal cortex. Tissue inhibitor of metalloproteinase-1 (TIMP1) and interleukin 1-beta (IL1b) mRNA levels were increased in gp120+ mice compared to gp120- mice. Gene expression levels of excitatory amino acid transporter-2, tyrosine hydroxylase, and dopamine transporter were not changed in gp120+ mice. None of the METH treatments changed in gene expression in either mouse group at 7 days post-injection. Conclusions: Long-term expression of gp120 in brain leads to altered gene expression of neuroinflammatory mediators. Single-dose METH treatment did not alter gene expression for the targets studied in either the gp120- or gp120+ mouse lines. Future experiments will focus on changes in protein expression and functional properties of specific cell populations in the brain at different times post-METH treatment.