TMARC Pilot Studies - Completed

The Combined Effects of HIV & METH on Brain Vascular Aging (Soontornniyomkij)

Agency: TMARC
PI: Soontornniyomkij, Virawudh, M.D.

Abstract

METH dependence increases the risk of cognitive impairment in HIV+ patients. Chronic METH use is associated with white matter (WM) lesions (i.e., ischemic changes resulting from cerebral small-vessel disease [CSVD]). Both HIV infection and antiretroviral therapy (ART) with protease inhibitors (ARV-PI) increase the risk of CSVD. Even at its early stages when the reduction in cerebral blood flow (CBF) is not sufficiently severe to cause complete infarcts or WM lesions, CSVD can lead to disturbance of cerebrovascular autoregulation and deficiency in functional hyperemia, and subclinical cognitive deficits that may only be detectable with neuropsychological tests (e.g., in milder forms of HIV-associated neurocognitive disorders (HAND)). CSVD is generally associated with aging. Physiological vascular aging is characterized by prelamin-A accumulation in vascular smooth muscle cells (VSMC), associated with oxidative stress-mediated down-regulation of lamin-A processing enzyme Zmpste24. HIV, METH, and ARV-PI cause endothelial cell injury by inducing oxidative stress. We propose a novel concept that CSVD in the HIV-METH-ART co-morbidity is mediated by oxidative stress-induced premature VSMC aging and may be one of the underpinnings of HAND. We will study in human brain VSMC cultures the combined effects of HIV, METH, and ARV-PI by measuring the levels of oxidative stress, VSMC markers of synthetic and contractile phenotypes, Zmpste24, prelamin-A, lamin-A, and markers of cellular aging in the presence or absence of rescue drugs. If dysregulation of lamin-A processing is substantiated in the HIV-METH-ART co-morbidity, we plan to explore this mechanism in future studies in animal models of neuroAIDS and postmortem human brain specimens. This Pilot will interact closely with the Neuroscience and Animal Models (NAM) Core, which will provide infrastructure and methods support.

Sponsored by NIH/NIDA P50DA026306

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