Cocaine exacerbates neurological impairments and neuropathologies in the iTat model of HIV-associated neurocognitive disorder through genome-wide alterations of DNA methylation and gene expression

HIV infection of the central nervous system causes HIV-associated neurocognitive disease (HAND) in up to 50% HIV-infected individuals. Cocaine use is prevalent in the HIV-infected population and has been shown to facilitate the HAND progression. However, the cellular and molecular mechanism of the cocaine-facilitated HAND progression remains largely unknown. In this study, we took advantage of the doxycycline inducible and brain-specific HIV Tat transgenic mouse model (iTat) of HAND and characterized effects of chronic cocaine exposure and long- term Tat expression on HAND-associated neurology and neuropathology. We found that cocaine exposure worsened the learning and memory of iTat mice, coupled with dendritic spine swelling, increased synaptophysin expression, and diminished microglia and astrocyte activation. We then employed the single-base resolution whole genome bisulfate sequencing and RNA sequencing and identified 14,838 hypermethylated CpG-related differentially methylated regions (DMR) and 15,800 hypomethylated CpG-related DMR that were linked to 52 down- and 127 up-regulated genes by cocaine and Tat. We further uncovered these genes to be mostly enriched at neuronal function- and cell morphology- and synapse formation-related ECM-receptor interaction pathway, and to be linked to behavioral and pathological changes altered by cocaine and Tat. Eight mostly affected genes included four in microglia Ift172, Eif2ak4, Pik3c2a, and Phf8, two in astrocytes Garem1 and Adgrb3, and two in neurons Dcun1d4 and Adgrb3. These findings demonstrated for the first time that cocaine and Tat interactively contributed to HAND neurology and neuropathology through genome-wide changes of DNA methylation and gene expression and suggest that targeting epigenetic changes serves as a potentially new therapeutic strategy to treat cocaine use disorder in people living with HAND.