Recent groundbreaking research unveils how HIV-1, the virus accountable for AIDS, challenges conventional comprehension by circumventing cellular defenses to access the nucleus. The virus accomplishes this feat by infiltrating nuclear pore complexes (NPCs), typically recognized as the gatekeepers of the nucleus, employing an ingenious strategy distinct from traditional nuclear transport receptors (NTRs). Through a series of experiments, researchers have unveiled that HIV-1 capsids, the protein shells encapsulating the virus’s genetic material, engage in direct interactions with FG repeats within the NPC barrier. These interactions engender a barrier-like structure, enabling the capsids to emulate NTRs and seamlessly traverse the NPC’s narrow channel, surmounting size restrictions previously presumed to impede viral entry.
Contrary to prior assumptions, the penetration of NPCs by capsids operates autonomously, devoid of reliance on importing, pivotal participants in nuclear transport. Capsids selectively target specific FG motifs within cellular proteins such as CPSF6 and Nup153, effectively binding to NPCs and facilitating their passage into the nucleus. This finding challenges longstanding notions regarding the involvement of importing in capsid NPC targeting.
Subsequent investigations utilizing sophisticated methodologies such as biolayer interferometry have corroborated direct interactions between the HIV-1 capsid protein (CA) and FG domains, resembling interactions observed with NTRs. Capsid assemblies have exhibited remarkable efficacy in traversing simulated nuclear barriers consisting of FG domains, underscoring their potential for enhanced translocation. In cell-based assays, capsid spheres swiftly traversed NPCs, gaining access to the nucleus within minutes, thus affirming their adeptness at circumventing cellular defenses. Notably, mutations that impede capsid-FG interactions led to a hindered traversal of NPCs, emphasizing the pivotal role of these interactions in viral infection.
Furthermore, experiments involving encapsulated cargo within capsid-like particles provided insights into the stability of capsids upon entering the FG phase, exhibiting behavior akin to NTRs. Collectively, these findings illuminate the intricate mechanisms employed by HIV-1 to elude cellular defenses and establish infection. By functioning as its nuclear transport receptor, the virus ensures the efficient importation of its genetic material into the nucleus, thereby paving the way for novel avenues in antiviral research. In parallel developments, researchers employed advanced techniques for protein expression, purification, and various assays to unravel the complexities surrounding HIV-1 capsid interactions and nuclear entry mechanisms. These discoveries signify a significant stride forward in comprehending viral pathogenesis and promise to inform future therapeutic interventions.
The advancements made through these discoveries underscore a significant leap forward in understanding how HIV-1 navigates cellular defenses and establishes infection. By functioning as its nuclear transport receptor, the virus opens new avenues in antiviral research by ensuring the efficient transfer of its genetic material into the nucleus. These findings may pave the way for the development of more effective strategies for treating HIV-1 infection in the future. Moreover, they may encourage the wider adoption of advanced techniques in protein expression, purification, and various experimental assays. Together, these insights represent a pivotal advancement in comprehending viral pathogenesis and hold promise for informing future therapeutic interventions.
Author: Farahnaz Mammadbayli
Editor: Elif Duymaz
Reference: Fu, L., Weiskopf, E. N., Akkermans, O., Swanson, N. A., Cheng, S., Schwartz, T. U., & Görlich, D. (2024). HIV-1 capsids enter the FG phase of nuclear pores like a transport receptor. Nature. https://doi.org/10.1038/s41586-023-06966-w
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