Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

Human immunodeficiency virus type 1 (HIV-1) infects the brain and sets up a reservoir of virus there, early in the course of the disease. HIV-1 infection of the brain causes breakdown of neurons, resulting in a syndrome called HIV-associated neurocognitive disorder (HAND). This syndrome currently affects ~20% of persons with HIV/AIDS who receive highly active antiretroviral therapy (HAART). HAND is defined by memory loss, difficulty in making decisions, and slowed mental and physical abilities. HAND is a major clinical problem, leaving patients with impaired ability to work and/or to care for themselves as well as a reduced chance of surviving HIV/AIDS. The effects of HAART on HIV-1 in blood are well understood, but we know much less about its impact on the brain as a viral reservoir and on HAND. To eliminate virus throughout the body, we must understand HAARTs effects on production of virus in the brain. We will investigate the effects of HAART on HIV-1 infection of brain cells, as well as how HIV-1 causes HAND. In our experiments, we will grow human brain cells in the lab, infect them with HIV-1, and measure HIV-1 production. We will also measure associated inflammation of cells and death of neurons. In similar experiments, we will measure the individual effects of current antiretroviral drugs on HIV-1 production, inflammation and death of neurons. Additionally, we will measure viral production in brain compartments during infection by the closely related feline immunodeficiency virus (FIV). In the FIV model, we will also test the effects of current antiretroviral drugs on brain cell injury and death. From these data, we will determine the effects of antiretroviral drugs on the HIV-1 reservoir within the brain and their effects on degeneration of neurons. These data will offer a rational route to optimize HAART, to potentially clear HIV-1 from the brain, and to prevent or treat HAND.