HIV Tat and cocaine interactively alter genome-wide DNA methylation and gene expression and exacerbate learning and memory impairments

Cocaine use is a major comorbidity of HIV-associated neurocognitive disorder (HAND). In this study, we show that cocaine exposure worsens the learning and memory of doxycycline-inducible and brain-specific HIV Tat transgenic mice (iTat) and results in 14,838 hypermethylated CpG-related differentially methylated regions (DMRs) and 15,800 hypomethylated CpG-related DMRs, which are linked to 52 down- and 127 upregulated genes, respectively, in the hippocampus of iTat mice. These genes are mostly enriched at the neuronal function-, cell morphology-, and synapse formation-related extracellular matrix (ECM) receptor-ligand interaction pathway and mostly impacted in microglia. The accompanying neuropathological changes include swollen dendritic spines, increased synaptophysin expression, and diminished glial activation. We also find that sex (female) and age additively worsen the behavioral and pathological changes. These findings together indicate that chronic cocaine and long-term Tat expression interactively contribute to HAND, likely involving changes of DNA methylation and ECM receptor-ligand interactions. [Display omitted] •Cocaine use worsens impaired learning and memory in brain-specific Tat transgenic mice•Cocaine/Tat alters gene expression in ECM receptor pathways and microglia•Cocaine/Tat changes dendritic spines, synaptophysin expression, and glial activation•Sex and age are both important contributing factors to cocaine and Tat interaction Zhao et al. investigate combined effects of HIV Tat and cocaine on HIV-associated neurocognitive disorder and the underlying molecular mechanisms, using doxycycline-inducible and brain-specific HIV Tat transgenic mice. They uncover specific changes in behavior, neuropathologies, genome-wide DNA methylation, gene expression, and processes affected by combined cocaine and Tat.