Viral diseases have taken an enormous toll on human health: HIV-1 is fueling a worldwide pandemic that has killed over 25 million people; herpesvirus, such as cytomegalovirus (CMV), infect a majority of the world’s population and cause tens of thousands of birth defects each year in the US and EU alone; Hepatitis C (HCV) infects over 200 million people worldwide and kills 10-20,000 people each year in the US; and each year influenza kills 250-500,000 people worldwide. Vaccines are exceptionally difficult to create (only 27 vaccines have been successful against human diseases) and despite extensive efforts, no effective vaccines exist against the aforementioned viruses. We propose a radical shift in treatment strategy toward developing conditionally replicating viruses that must use the wild-type pathogen machinery to replicate. We are capitalizing upon our expertise in HIV-1 transcriptional regulation to develop conditionally replicating viruses that can interfere with HIV and commit the virus to a less pathogenic life-style. We have recently succeeded in biasing HIV-1 toward dormancy by over-expressing a cellular anti-aging gene SirT1. In order to develop these strategies that can manipulate pathogen lifecycles, it is imperative that we obtain a detailed understanding of their regulatory mechanisms. Thus, we are interested in defining the fundamental molecular mechanisms that underlay fate-determination in pathogens and cell-fate in general.