There is still much to be discovered about how HIV-1 virus infects our cells. Scientists know that it bypasses our immune system’s defenses, infiltrates white blood cells to deliver its genetic transport, and attacks the cell’s transcription machinery, which produces it. copies of the RNA virus and the new HIV-1 virus. But many details are still vague.
The HIV-1 capsid encapsulates its genetic material, traveling to the nucleus of infected white blood cells before bursting to release its deadly genetic cargo. Empirical evidence-based simulations have been developed on TACC’s Frontera supercomputer. They revealed capsid stress patterns just before a critical degradation stage, revealing potential vulnerabilities to exploit for drug design. The image shows the HIV-1 capsid strain, with red and blue colors representing the compressed strain and the expanded strain, respectively. Image credit: Yu, et al. DOI: 10.1073 / pnas.2117781119
A big test discover performed in 2021 unraveled the mystery and discovered that the viral capsid, a protein coat that protects its RNA genome, remained intact in the nucleus of the target cell. Finally, the capsid must hold steady long enough to deliver its deadly genetic cargo into the cell nucleus. But eventually, it had to split to release its genetic material. What scientists still don’t know is how and why the HIV-1 virus capsid can become unstable.
The Frontera supercomputer at the Texas Advanced Computing Center at the University of Texas at Austin has enhanced scientists’ understanding of how HIV-1 is transmitted and helped create the first realistic simulations of the capsid. its protein, water, genetic material, and an important cofactor called IP6 that was recently discovered to stabilize and help form capsid.
Adult HIV-1 capsids have different variations in size and shape. (A) The Fullerene geometry for the HIV-1 capsid is derived from cryo-ET images of intact virions. The atomic models for the capsid contain (B) liquid water inside the capsid, (C) a model of a ribonucleoprotein complex (RNP), (D) IP6 molecules bound to the capsid pores, or (E) both RNP and IP6. CA NTD and CTD are colored green and brown, while genomic RNA, nucleocapsid protein and IP6 molecules are colored purple, teal, and orange, respectively. Pentamer defects are colored red. Image credit: Yu, et al. DOI: 10.1073 / pnas.2117781119
“Vulnerabilities in the armor of the HIV-1 virus have been revealed by these very large simulations and analysis that we have done,” said Gregory Voth, Haig P. Papazian Distinguished Service Professor at the University of Chicago. perform. Voth is lead author on HIV-1 capsid research was published in March 2022 in the Proceedings of the National Academy of Sciences.
Voth and colleagues started with cold electron tomography data from actual viruses obtained by the coauthor’s lab John Briggs, Department of Cell Structure and Viruses, Max Planck Institute of Biochemistry. Using experimental data, they developed an all-atom molecular dynamics simulation of the HIV-1 capsid reaching a whopping 100 million atoms.
The images in the study showed ridges on the cap, indicating stress. They pinpointed where the protein lattice was compressed or expanded and was experiencing unpleasant stress, which tells the scientists that the stress is not perfectly distributed.
“That’s important because we can correlate those models of how the lattice stretches to how the lids actually break off,” Voth commented. The stress lines will be vulnerable to the pressure generated inside the capsid of the HIV-1 virus as it begins to undergo reverse transcription and begins to make DNA.
The authors conclude that stress patterns correlate well with how capsid breaks through additional cold electron tomography experiments by one of the study collaborators. Owen PornillosDepartment of Molecular Physiology and Biophysics, University of Virginia.
“This is the most realistic simulation of HIV capsid to date,” Voth said. “We were also able to see that the proteins encapsulated in the viral capsid have a slightly different structure from the simpler crystal structure or the in vitro reconstitution process.”
Voth pointed to previous work published in 2017 in the journal Nature by Juan R. Perilla, University of Delaware, and the late Klaus Schulten, University of Illinois at Urbana-Champaign and colleagues. Those authors developed the first model of HIV-1 capsid on the Blue Waters supercomputer. However, as a pioneer at the time, it lacked the genetic material inside, the IP6 cofactor, and was not constructed from cold electron tomography data of actual viral capsid.
The new model builds in all these missing elements. “Our work is a big step forward in real-world modeling, which I think will help us better understand this type of hat,” Voth said.
An approach taken by the pharmaceutical company Gilead in the production of the drug for HIV-1 lenacapavir takes knowledge of the HIV-1 virus’ capsid to make it more brittle, which impedes its critical stage of decomposition before releasing its genetic material.
“That’s what we’re doing now,” Voth said, “is to study, given the heterogeneous nature of this capsid virus, we can understand how the drug interacts with it, and what can we do to understand it. design new drugs?”
Furthermore, drug designers are interested in the potential of a one-to-two punch drug, in which one drug molecule binds to a network of capsid proteins, thereby helping another drug molecule to bind.
“The supercomputers combined with the methods we developed have helped reveal essential elements of the HIV-1 virus that are currently extremely difficult to detect in experiments,” Voth said. I don’t think we can easily do those simulations anywhere other than Frontera. It is an incredibly valuable resource for us. ”
Source: TACC
