TMARC Pilot Studies - Completed

METH Effects on Epigenetic Regulation of HIV-1 in the Brain (Desplats)

Agency: TMARC
PI: Desplats, Paula, Ph.D.

Abstract

Successful antiretroviral therapy has increased the life expectancy of HIV seropositive (HIV+) patients, while making apparent the decline in brain function that still impairs their quality of life. Poor penetration of antiviral drugs and the combined effects of co-morbidity factors such as drug abuse (e.g. methamphetamine) generate latent forms of the virus that persist in the brain as reservoirs from where productive infections and chronic CNS injury might emerge. HIV latency is regulated by epigenetic remodeling of the chromatin facilitating or restricting HIV productive infections.

Methamphetamine (METH) is a psycho stimulant abused worldwide and its use is particularly high in the HIV+ population. METH affects gene transcription by modulating the expression and activity of transcription factors and by affecting the expression of epigenetic regulatory proteins, as DNA methyltransferase 1 in the brain. HIV+ METH users (HIV+/METH+) present higher viral loads in plasma and have a higher incidence of HIV encephalitis than non-users. In the U.S. drug abuse is directly linked to one-third of all HIV- infections, therefore understanding the effects of METH on the epigenetic regulation of HIV infection and its impact on neurological disease is crucial for virus eradication and therapy development.

This proposal will investigate the effects of METH on the epigenetic regulation of HIV-1 expression in the brain. We hypothesize that METH alters DNA methylation at the viral LTR regions and histone modifications around the viral insertion sites, triggering local changes in chromatin structure an overall increase of HIV-1 expression that results in neurodegeneration.

Sponsored by NIH/NIDA P50DA026306

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