HIV-1 Infection Increases Brain Amyloid Beta

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DESCRIPTION (provided by applicant): Prior to highly active anti-retroviral therapy (HAART), HIV-associated dementia (HAD) was an acute neurodegenerative disease. Fortunately where treatment with HAART is available, there is a decrease in incidence and severity of HAD. However, patients on HAART with high CD4 counts and low viral loads still become demented and postmortem studies on HIV-l-infected individuals show the brain continues to be affected. We hypothesize that as individuals with HIV-1 infection live longer, there may be a new set of age-related complications in the brain; specifically an increase in amyloid beta (A beta), which is thought to be the initiating step in the development of neuritic plaques of Alzheimer's disease (AD). We have data to show that a major A beta catabolizing enzyme in the brain is inhibited by the HIV-1 nonstructural protein, Tat, which may result in an accumulation of A beta. It is our objective to further study the Tat/NEP interaction and determine its role in neurodegeneration. Our specific aims are: 1) To determine if other HIV-1 associated proteins or products of HIV infection can inhibit NEP, 2) To identify Tat interactions in neural cells that determine whether A beta accumulation is a consequence of NEP inhibition alone or involves the low density lipoprotein receptor-related protein (LRP), which binds A beta and initiates its degradation and 3) To investigate the role of cholesterol, Tat and the genetic risk factor APOE for A beta accumulation and 4) To determine whether HIV-1 co-localizes with elevated A beta in postmortem brain tissue. These studies will use human brain cultures that produce A beta and can easily be genotyped. We suggest that aging patients with HIV-1 may be at risk for neurodegeneration through chronic accumulation of A beta, a similar mechanism to that seen in Alzheimer's disease. We believe that mechanisms derived from these experiments will have implications for long term survivors of HIV-1 infection and hopefully give us new clues for therapeutic strategies against HIV-associated dementia.