MOLECULAR MECHANISM OF HIV-1 TAT INDUCED NEURONAL DYSFUNCTION

Abstract

In the early years of the AIDS epidemic, being infected with the virus that causes the disease was considered a virtual death sentence. But with the development of highly active antiretroviral therapy (HAART), many infected with HIV-1 are living much longer. In fact, it is estimated that by 2015, about half of all HIV-positive individuals will be older than 50. Yet those over 50 also progress to AIDS faster than adults in their 20s or 30s. And those in the younger age bracket, even those responding well to antiretroviral therapy, still exhibit illnesses and clinical conditions commonly associated with older people, such as HIV-associated neurocognitive disorders (HAND), certain cancers, liver and bones diseases. For the most part, the reasons for this have remained a mystery. However, one may ask, how in the absence of circulating detected virus, viral proteins could cause this kind of damage. The answer is that eradication of latent viruses still unsuccessful and studies showed the persistence of HIV-1 in brain cells as well as the presence of viral proteins in CSF. This notion was supported by the compelling neuropathological data suggesting that the loss of Synaptic Plasticity occurs with the ongoing presence of virus and despite HAART. Clinically, these neuropathological data manifest by a gradual loss of working memory and learning disability, which promote alteration of synaptic plasticity that may manifest by symptoms similar to the ones observed in aged brain or what is called PREMATURE BRAIN AGING. Anatomically, working memory and learning ability functions are assured by neurons of the hippocampus, a brain area known-to-be affected by HIV-1 proteins. Mechanistically, several laboratories, including ours, demonstrated that viral proteins perform their functions through deregulation of several molecular pathways that can cause mitochondrial damage (such as depletion of mitochondrial calcium and release of ROS), inhibition of axonal transport leading to prevent neuronal communications or loss of long-term potentiation (LTP). Interestingly, CREB and BDNF proteins have been shown to play an important role in this phenomenon directly or through its downstream target genes. In here, we examined the impact of HIV-1 Tat on CREB-BDNF pathway and whether Tat is using this pathway to cause neuronal deregulation.