Kelenis, Demetra

HIV/AIDS remains a significant cause of illness and mortality worldwide. There are ~41 million people living with HIV,1 including 1.2 million people in the U.S.2 The development of antiviral drugs has transformed HIV from a fatal disease to a chronic condition. However, existing medications are an imperfect solution. These medications cannot target the latent reservoir established following integration of the HIV viral genome into the host cell genome. These drugs must be taken for life to prevent viral rebound and destruction of the immune system. Even when treated with antivirals, HIV-infected individuals have an elevated risk of multiple cancers, cardiovascular conditions, and neurodegenerative diseases. A significant need for novel therapies remains. A greater understanding of the molecular events of HIV-1 replication will enable discovery of these therapies.

The alternative splicing of HIV-1 viral RNAs is a critical step in HIV replication. This process allows production of multiple essential viral proteins from a single, small genome. To splice its RNAs, HIV-1 depends upon the host cell’s alternative splicing machinery. My research centers on how HIV-1 manipulates this machinery using a post-translational modification called SUMOylation. SUMOylation, the covalent modification or proteins by Small Ubiquitin-like Modifiers (SUMOs), modulates the activity of thousands of proteins and multiple fundamental cellular pathways. I have previously shown that infection with HIV-1 leads to a reprogramming of host cellular SUMOylation, resulting in a pattern of increased SUMO-modification of RNA splicing factors. These findings are exciting because these same splicing factors are known to mediate correct HIV-1 RNA splicing. We also showed that splicing factor SUMOylation is driven specifically by Vif, a protein encoded by the HIV-1 viral genome, uncovering a new function for a protein that has been studied for decades. Together, these findings suggest a novel mechanism of Vif-driven SUMOylation as a means to “rewire” alternative splicing in virally infected cells.

In my lab, we will explore this mechanism from several angles. We will determine how the Vif protein drives splicing factor SUMOylation and the effects of this modification on the splicing of both HIV-1 and host cellular RNAs. Students will use safe, non-viral vectors, and will learn fundamental cell and molecular biology techniques such as mammalian cell culture, transfection, gene knockdown, western blotting, and immunoprecipitation. No prior experience with these techniques is required. Our work will characterize an unexplored frontier of virus-host interactions.

1. UNAIDS (2024). Global HIV and AIDS statistics - Fact Sheet.

2. HIV.gov (2025). U.S. Statistics (Fast Facts).