by Researchers at UNSW have made a significant discovery regarding how the human immunodeficiency virus (HIV) breaches the cell nucleus to establish infection. This finding has implications beyond HIV biology and could have applications in gene therapy.
For HIV to infect cells, it must enter the target cell and make its way to the nucleus where it can produce enough copies of its genetic code to infect other cells. To achieve this, the virus builds a protective protein coat called a capsid to shield itself from the host’s immune defenses. Up until now, it has remained a mystery as to how the entire capsid moves through the pores embedded in the nuclear envelope to enter the nucleus.
The latest research, published in Nature, reveals the mechanism by which the HIV capsid enters the nuclear pore barrier channel. The nuclear pore complex, composed of a combination of proteins, regulates the movement of molecules in and out of the nucleus. While small molecules can pass through the nuclear pore complex, larger proteins require chaperone proteins, known as karyopherins, to transport them through the layered molecular gate.
The UNSW team led by Dr. David Jacques showed that the HIV capsid, despite being significantly larger than the molecules that filter through the barrier layers, can enter the nuclear transport channels without chaperones. The capsid is able to interact with barrier proteins in the same way as the host’s chaperone proteins, allowing it to pass through the restricted pathway.
Contrary to previous theories, which suggested that HIV relied on a host chaperone to gain access to the nucleus, the study findings indicate that HIV does not require a chaperone because it functions as its own. It mimics the interaction of the host’s chaperones with the gatekeeper proteins in the nuclear pore complex to gain entry.
Dr. Claire Dickson, co-first author of the study, expressed excitement about directly addressing assumptions made about how the capsid could pass through the selective barrier. The research was made possible by a single-molecule method developed by the UNSW team, allowing them to systematically screen proteins of the nuclear pore complex to identify those that interact with the intact HIV capsid.
The multidisciplinary team at UNSW, along with the infrastructure available, including the Mark Wainwright Analytical Center, played a crucial role in enabling this research. The team utilized various technologies and methods, such as protein production, structural biology, super-resolution imaging, and electron microscopy.
The researchers believe that the molecular understanding gained from this study goes beyond HIV and can be applied to other host-pathogen interactions. This knowledge could be exploited for applications such as gene therapy.
Dr. Jacques highlighted the significance of the findings, stating that HIV’s ability to penetrate the nucleus without damaging it or needing the cell to divide, like other viruses, is unique. This observation provides insights into how cargo can be delivered into the nucleus.
As HIV remains one of the most extensively studied pathogens, this study sheds new light on its lifecycle, allowing for a better understanding of the infection process. The breakthrough discovery made by the UNSW team marks a significant contribution to HIV research and offers potential avenues for further exploration in the field.
