Active Infection & Immunity Cells, Biochemistry & Physiology

Investigating the structural basis for HIV-1 hijacking cytoskeletal motor adaptors and in situ studies of microtubule trafficking

Funder Wellcome Charity-funded
Recipient organisation University of Oxford
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

HIV-1 hijacks the cell’s internal transport network by latching onto motor proteins that walk along microtubules, and this project will capture the first atomic-scale images of that hijacking in action. More than 40 million people live with HIV worldwide, and the virus caused over 600,000 deaths in 2024. To replicate, HIV must move its genetic material from the cell’s edge to its nucleus. It does this by commandeering two molecular motors—dynein-1 and kinesin-1—but exactly how the viral capsid grabs and controls these motors is unknown. Without that structural detail, researchers cannot design drugs that block the transport step. This project will use cryo-electron microscopy to determine the first structures of the HIV capsid bound to five specific adaptor proteins (BICD2, BICDR1, CLIP-170, FEZ1, MARK2). It will also image infected human cells directly using correlative cryo-FIB and cryo-ET, revealing how the virus moves inside its host. If successful, the work will reveal new molecular targets for antiretroviral therapy. It may also provide a blueprint for engineering proteins that deliberately hijack the cytoskeleton—a tool with potential applications in drug delivery and synthetic biology.

View original technical description
The human immunodeficiency virus (HIV) caused over 600,000 deaths in 2024 and over 40 million people are currently infected worldwide. During the HIV replication cycle, its RNA genome is reverse transcribed into DNA and integrated into the host’s genome. The viral genome must be transported from an infected cell’s plasma membrane to the nucleus. The HIV-1 capsid (CA) hijacks the host’s microtubule motors to achieve this. Dynein-1 and Kinesin-1 are recruited and it is unknown how the capsid modulates their activity for productive trafficking. This project will build on the Zhang lab’s research on capsid binding host factors and in situ structural studies. I will focus on five specific adaptors that bind HIV-CA: BICD2, BICDR1, CLIP-170, FEZ1, MARK2. I specifically aim to: 1\. Determine the first structures of HIV-CA bound to a motor protein adaptor using recombinant expression and cryo-electron microscopy. 2\. Perform in situ structural studies of human cell lines infected with HIV-1, using correlative cryo-FIB and cryo-ET These aims will provide i): unprecedented structural detail of a virus’ interactions with host motor adaptors and HIV-1 association with microtubules, and ii) potential new targets for antiretroviral therapy and applications in biotechnology for designing proteins that hijack the cytoskeleton.

View the original record at the funder ↗

Researchers

Matthew Clark (EPMC Awardee)

Related Research

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Original classification

PhD Studentship (Basic)

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