Zoe Gleason, Class of 2023
Heat shock proteins (Hsp) are found in all cells, although their levels increase in response to stresses. Hence the name of these proteins, the stress can have environmental causes, such as extreme heat or cold. The levels also rise in response to a variety of other factors, including microbial infections, heavy metals, and hormones (Kiang and Tsokos 1998). The amount of hsp continues to remain above its normal level days to weeks after the stress. Hsp levels directly relate to the cell’s need for these proteins, as they rise due to disruptions of cellular metabolism and the tertiary folding of proteins (Maio 1999). Hsp protect the cell from stresses, ensuring proper folding of proteins, which is necessary for correct functioning, and assisting with protein transport within the cell. Heat shock cognate proteins (Hsc) have a similar function to heat shock proteins, as they facilitate protein folding and break down mutant proteins. Hsc and Hsp are very similar, but Hsc operates under normal cell activity, while Hsp operates after the cell has undergone stress.
Hsp70, a category of heat shock proteins, has been extensively studied due to its role in promoting the expression of viral genes (Kim and Oglesbee 2012). In protecting the cell, hsp70 allows for high levels of the virus to be expressed within the cell, and inhibits pathways leading to apoptosis, or programmed cell death. The preservation of the cell allows for more viral replication to occur. Without hsp70, the cell undergoes apoptosis, and viral replication cannot continue to occur. However, if hsp70 is repressed during the viral replication cycle, cell death allows viral particles to be released (Kim and Oglesbee 2012).
A group from the Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), researched how inhibiting hsp70/hsc70 could block the viral assembly of the hepatitis C virus. Both hsc70 and hsp70 bind to a non-structural hepatitis C protein to regulate activity. However, Hsp70 is involved with the ribosomal entry and translation of the virus, while hsc70 is involved with virion assembly.
To find this, the research group established the cell line Huh7.5, and determined cell viability. The Huh.75 cells were infected and treated with allosteric hsp70/hsc70 inhibitor at various points in the infection, to decrease activity of the virus. The inhibitor was added at different times to test what part of the viral life cycle could be affected. The stages tested were intracellular virus production, viral entry, and intercellular viral protein production. Allosteric hsp70/hsc70 inhibitor was added before the cells were infected, three hours after infection, and 33 hours after infection. The medium was replaced three hours post-infection. After this replacement, the infections were allowed to proceed for 48, 18, and 30 hours, respectively (Khachatoorian et al. 2016).
The research group found that the presence of the inhibitors did not affect the cell’s activity, despite playing an essential role in ensuring the proper development of proteins. Additionally, they found that the allosteric hsp70/hsc70 inhibitors significantly reduced the infectious virus proliferation, especially when JG-98, a type of inhibitor, was used (Khachatoorian et al. 2016).
The group determined that viral entry and viral translation were not affected by the presence of the inhibitors. However, they did find that the allosteric hsp70/hsc70 inhibitors did block the assembly of infectious virions within the cell. Finally, they determined that when the allosteric inhibitor was combined with HCV4, another inhibitor, the antiviral levels were even higher, because the inhibitors operated on different parts of the viral life cycle (Khachatoorian et al. 2016).
Because the inhibitors bind to the heat shock proteins, this means of inhibiting viral production is more sustainable than antivirals, which favor resistant strains (Khachatoorian et al. 2016). Since heat shock proteins are present in every cell, there is a fair likelihood that treatment of allosteric hsp70/hsc700 inhibitors will be effective for other types of viruses, not just the hepatitis C virus.
References
Khachatoorian R, Riahi R, Ganapathy E, Shao H, Wheatley NM, Sundberg C, Jung C-L, Ruchala P, Dasgupta A, Arumugaswami V, et al. Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly. 2016 [accessed 2020 Mar 7];47(4):289–296. https://www.sciencedirect.com/science/article/pii/S0924857916000509?via=ihub#bib020 5
Kiang J, Tsokos G. Heat Shock Protein 70 kDa Molecular Biology, Biochemistry, and Physiology. 1998 [accessed 2020 Mar 7];80(2):183–201. https://www.sciencedirect.com/science/article/pii/S016372589800028X#!
Kim MY, Oglesbee M. Virus-Heat Shock Protein Interaction and a Novel Axis for Innate Antiviral Immunity. 2012 [accessed 2020 Mar 7];1(3):646–666. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901102/
Maio AD. Heat Shock Proteins: Facts, Thoughts, And Dreams. 1999 [accessed 2020 Mar 7];11(1):1–12.
https://journals.lww.com/shockjournal/Abstract/1999/01000/HEAT_SHOCK_PROTEIN
S__FACTS,_THOUGHTS,_AND_DREAMS.1.aspx
Wikimedia Commons contributors. File:PDB 3hsc EBI.jpg [Internet]. Wikimedia Commons, the
free media repository; 2009 Mar 11, 01:39 UTC [cited 2020 Mar 9]. Available from: https://commons.wikimedia.org/w/index.php?title=File:PDB_3hsc_EBI.jpg&oldid=1917 4853 .
Hsp70, a category of heat shock proteins, has been extensively studied due to its role in promoting the expression of viral genes (Kim and Oglesbee 2012). In protecting the cell, hsp70 allows for high levels of the virus to be expressed within the cell, and inhibits pathways leading to apoptosis, or programmed cell death. The preservation of the cell allows for more viral replication to occur. Without hsp70, the cell undergoes apoptosis, and viral replication cannot continue to occur. However, if hsp70 is repressed during the viral replication cycle, cell death allows viral particles to be released (Kim and Oglesbee 2012).
A group from the Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), researched how inhibiting hsp70/hsc70 could block the viral assembly of the hepatitis C virus. Both hsc70 and hsp70 bind to a non-structural hepatitis C protein to regulate activity. However, Hsp70 is involved with the ribosomal entry and translation of the virus, while hsc70 is involved with virion assembly.
To find this, the research group established the cell line Huh7.5, and determined cell viability. The Huh.75 cells were infected and treated with allosteric hsp70/hsc70 inhibitor at various points in the infection, to decrease activity of the virus. The inhibitor was added at different times to test what part of the viral life cycle could be affected. The stages tested were intracellular virus production, viral entry, and intercellular viral protein production. Allosteric hsp70/hsc70 inhibitor was added before the cells were infected, three hours after infection, and 33 hours after infection. The medium was replaced three hours post-infection. After this replacement, the infections were allowed to proceed for 48, 18, and 30 hours, respectively (Khachatoorian et al. 2016).
The research group found that the presence of the inhibitors did not affect the cell’s activity, despite playing an essential role in ensuring the proper development of proteins. Additionally, they found that the allosteric hsp70/hsc70 inhibitors significantly reduced the infectious virus proliferation, especially when JG-98, a type of inhibitor, was used (Khachatoorian et al. 2016).
The group determined that viral entry and viral translation were not affected by the presence of the inhibitors. However, they did find that the allosteric hsp70/hsc70 inhibitors did block the assembly of infectious virions within the cell. Finally, they determined that when the allosteric inhibitor was combined with HCV4, another inhibitor, the antiviral levels were even higher, because the inhibitors operated on different parts of the viral life cycle (Khachatoorian et al. 2016).
Because the inhibitors bind to the heat shock proteins, this means of inhibiting viral production is more sustainable than antivirals, which favor resistant strains (Khachatoorian et al. 2016). Since heat shock proteins are present in every cell, there is a fair likelihood that treatment of allosteric hsp70/hsc700 inhibitors will be effective for other types of viruses, not just the hepatitis C virus.
References
Khachatoorian R, Riahi R, Ganapathy E, Shao H, Wheatley NM, Sundberg C, Jung C-L, Ruchala P, Dasgupta A, Arumugaswami V, et al. Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly. 2016 [accessed 2020 Mar 7];47(4):289–296. https://www.sciencedirect.com/science/article/pii/S0924857916000509?via=ihub#bib020 5
Kiang J, Tsokos G. Heat Shock Protein 70 kDa Molecular Biology, Biochemistry, and Physiology. 1998 [accessed 2020 Mar 7];80(2):183–201. https://www.sciencedirect.com/science/article/pii/S016372589800028X#!
Kim MY, Oglesbee M. Virus-Heat Shock Protein Interaction and a Novel Axis for Innate Antiviral Immunity. 2012 [accessed 2020 Mar 7];1(3):646–666. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901102/
Maio AD. Heat Shock Proteins: Facts, Thoughts, And Dreams. 1999 [accessed 2020 Mar 7];11(1):1–12.
https://journals.lww.com/shockjournal/Abstract/1999/01000/HEAT_SHOCK_PROTEIN
S__FACTS,_THOUGHTS,_AND_DREAMS.1.aspx
Wikimedia Commons contributors. File:PDB 3hsc EBI.jpg [Internet]. Wikimedia Commons, the
free media repository; 2009 Mar 11, 01:39 UTC [cited 2020 Mar 9]. Available from: https://commons.wikimedia.org/w/index.php?title=File:PDB_3hsc_EBI.jpg&oldid=1917 4853 .
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