The Role of HIV-Tat protein in the Pathogenesis of HIV Dementia

Despite the use of antiretroviral drugs, the incidence and prevalence of HIV dementia has not been significantly impacted. While the more severe forms of HIV dementia have certainly become rare, a more chronic form of dementia has emerged. Since HIV infection occurs in patients in the prime of their youth and in an age group that is most productive in society, HIV dementia has vast socioeconomic consequences. The reasons for the failure of antiretroviral drugs are several, but importantly, these drugs have no effect on the production of early viral proteins once the provirus is integrated in the chromosome. One of these proteins is called the Tat protein. It is one of the first proteins to be formed by the viral genome and is necessary for viral replication. It is also actively released from the infected cell into the extracellular environment. Here it has the opportunity to interact with other uninfected cells. It can thus cause glial cell activation and neuronal injury.

Our laboratory is interested in determining the mechanisms by which this protein causes injury to brain cells. Using tissue culture models of human brain cells, neural progenitor cells, transgenic animals, Tat mutant proteins and Tat expressing cell lines generated in our laboratory we are defining the cell surface receptors with which Tat interacts on neurons and glial cells. We are also characterizing the subcellular mechanisms by which Tat protein causes neuronal and glial cell dysfunction with the hope of identifying unique targets with therapeutic potential.