Grant: CIHR Fellowship

Human immunodeficiency virus type 1 (HIV-1), the cause of acquired immune deficiency syndrome (AIDS), remains a global health concern, currently affecting 39 million individuals worldwide with 1.3 million new infections in 2022. Although antiretroviral therapy (ART) is effective at suppressing viral replication, it does not eliminate the virus. One of the main reasons for HIV-1 infection persistence is its ability to integrate into the human genome. Upon entering the host cell, the HIV-1 core, comprising the HIV-1 capsid that encapsulates the viral genome and associated enzymes, travels from the cytoplasm to the nucleus where it integrates its genetic material into the host cell genome. The capsid is a central player in many aspects of HIV-1 infection. It shields the viral genome from the immune surveillance of the host, hosts the reverse transcription of viral RNA into DNA, and, more recently, has been implicated in facilitating the delivery of viral DNA into the nucleus. However, the interplay between the capsid and the nuclear pore complex during viral nuclear entry remains poorly understood. This proposed research aims to understand how the capsid is docked and translocated into the nucleus using integrated structural biology approaches. Using cutting-edge techniques in cryo-electron microscopy/tomography (cryo-EM/ET) and crosslinking mass spectrometry, this research aims to provide structural insights into the capsid-nucleoporin interactions and molecular mechanisms mediating HIV-1 nuclear import. I will establish a cryo-correlative light and electron microscopy (cryo-CLEM) imaging pipeline to directly visualize HIV-1 nuclear entry in a native cellular context, offering insights into the highly dynamic process. Together, this research will inform future efforts to develop novel antiviral therapeutics for HIV-1 prevention, provide a framework to study the nuclear import of other viruses and advance the fundamental understanding of nuclear pore function.