Wow, researchers from our #SFB1129 are implicated in the Science 2024 Breakthrough of the Year, because they showed that HIV-capsids are flexible and go through nuclear pores. The latest paper on Lenacapavir-induced capsid damage just came out in @embojournal.org

link.springer.com/article/10.1...

If you’re interested in HIV capsids, nuclear speckles, or capsid-targeting antivirals, we’d love for you to check it out and share! 🙌
link.springer.com/article/10.1...

Huge thanks to all co-authors incl. Hans-Georg Kräusslich, Severina Klaus, Vojtech Zila, Barbara Müller, @marinalusic.bsky.social, @ulrichschwarz.bsky.social, other collaborators @ciid-heidelberg.bsky.social, funders who made this possible #SFB1129, and to @embojournal.org

Conceptually, this links:
- capsid mechanics
- nuclear trafficking & speckles
- timing/location of uncoating
- integration into active chromatin

Understanding HIV uncoating has implications for HIV latency and cure strategies. These results also refine our understanding of how Lenacapavir works.

Our data indicate that reverse transcription can be functionally completed inside a closed capsid, and that dsDNA synthesis alone is not sufficient to trigger immediate uncoating. Instead, it seems likely that nuclear speckle–associated factors could regulate when and where the capsid opens.

Crucially, LEN and PF74 rapidly expose previously hidden HIV-1 genomes. These genomes are integration-competent: short LEN pulses actually increase the amount of integrated provirus in macrophages, showing that exposed genomes are functionally complete and can finish infection.

This finding in context of other data directly suggests a possible mechanism: flattening of the lattice predominantly in pentamer-dense regions leads to rupture of capsids.

Using CLEM-ET, we uncover a distinct structural damage signature: LEN induces "lobster-like" bifurcated protrusions at the narrow end of the conical capsid and leaves behind apparently fused lattice remnants.

We find that intact and broken capsids cluster in nuclear speckles of primary macrophages. When we add LEN or PF74, capsid-associated CPSF6 is displaced, and these subviral complexes rapidly exit nuclear speckles. So capsid inhibitors actively re-route nuclear HIV complexes.

We addressed these questions by comprehensive ultrastructural characterization of subviral complexes in primary human monocyte-derived macrophages and cell lines ± Lenacapavir or PF74.

we combine:
-Live-cell imaging of viral DNA
-Super-resolution microscopy
-CLEM + Electron Tomography

Background: HIV-1 capsids can travel largely intact through nuclear pores, and genomes integrate into speckle-associated, transcriptionally active chromatin. But the mechanisms that orchestrate nuclear trafficking, genome uncoating, and integration site selection remain elusive.

Lenacapavir is a long-acting HIV capsid inhibitor, now approved for multidrug-resistant HIV and highly promising in PrEP. We asked: what does it actually do to HIV capsids inside the nucleus, and how does that affect uncoating and integration?

New paper out!

How can we force HIV genomes out of their capsid shells and what can we learn about HIV biology doing so?

Hint: capsid inhibitors actively re-route nuclear HIV complexes, and expose genomes via intriguing structural effects!
open access:
link.springer.com/article/10.1...
read below