Final Report Summary - LIPOHCV (HEPATITIS C VIRUS AND HOST LIPOPROTEIN METABOLISM)
With around 150 million cases worldwide and despite the success in the development of highly efficient antiviral treatments, HCV infection is still regarded as a major biomedical problem. The approval of treatments based on direct-acting antivirals (DAAs), opens a new era in the treatment of HCV infection, as these treatments have been shown to eradicate viral infection in most cases. However, limited availability of these treatments as well as cost considerations are still important limitations to implement these treatments globally. Although the drug armamentarium against HCV is increasing significantly, there is still a need to deepen in our understanding of HCV biology, to develop cost-effective antivirals, and HCV pathogenesis, to optimize the management of chronically infected patients. Gastaminza´s group is focused on the identification of cellular genes involved in HCV replication to be considered as targets for host-targeting antivirals (HTAs), which may be less prone to select for resistant virus variants that may cause treatment failure.
In particular, the resources obtained from this CIG program, were used to study the role of lipid and lipoprotein metabolism in HCV infection. This field of HCV biology has moved really fast during the funding period and the published work of several groups overlapped significantly with the objectives initially proposed in the research plan. However, many questions remained unanswered in the field and the objectives were modified to further advance in our knowledge of virus-host interactions focusing in lipid metabolism.
In order to gain insight into the interplay between HCV and host lipid metabolism, Dr. Gastaminza focuses his attention in a family of cellular genes, lipins, involved in the regulation of lipid and lipoprotein metabolism in normal cells. The results obtained by his group suggest that several members of the lipin family mediate different aspects of the HCV lifecycle, as infection by HCV is reduced when experimentally interfering with the expression of two members of the family. Thus, lipins may be considered as potential molecular targets for anti-HCV therapy. Since some of the studied genes present partial functional overlapping, pharmacological inactivation of one of the members of this family of proteins may interfere with viral infection without significantly interfering with lipid homeostasis, and this may result in an effective treatment with reduced adverse effects. These studies also pave the road to understanding with greater detail how HCV alters cellular lipid metabolism to produce liver disease and future avenues to treat HCV-induced liver damage.
Using sophisticated imaging techniques and in collaboration with an international consortium of structural biologists, Dr. Gastaminza´s team produced three-dimensional nanoscale maps of the physical alterations produced by HCV in the host cell. Their data indicate that HCV takes over the mitochondrial metabolism to produce the viral structures necessary for viral replication. Moreover, his group discovered a cellular gene (SIGMAR1) involved in the functional crosstalk between different cellular organelles, including mitochondria, that is essential to produce virus replication factories. This cellular gene is also involved in the regulation of lipid metabolism as its protein product interacts with key enzymes of cholesterol biosynthesis and depletion of SIGMAR1 protein from cells alters the expression of genes involved in the metabolism of cholesterol and other lipid species. Currently, his group is performing an unbiased proteomic analysis of the proteins that physically interact with SIGMAR1 to determine the molecular mechanisms underlying this functional association. The functional implications of this physical association for viral replication and pathogenesis will be certainly one of the focuses of future studies by Dr. Gastaminza´s group.
Thus, Dr. Gastaminza identified novel cellular factors regulating early aspects of HCV infection that lead to target cell colonization. These factors are candidate molecular targets for host-targeting agents (HTAs) that may complement the antiviral activity of the novel anti-HCV therapies based on DAAs, potentially raising the genetic barrier to resistance and covering a wider range of viral genotypes. Moreover they provide new avenues to decipher the molecular details underlying the host-virus interactions during HCV infection that may inform on potential new ways of intervening therapeutically to revert HCV-induced pathologies.
Thanks to the CIG funding, Dr. Gastaminza was able to recruit valuable personel to initiate his own research group. This was instrumental to establish an independent research group that has permited him conducting his research as an independent investigator. Additional funding, personel and resources from other funding agencies and industry, put Dr. Gastaminza in an excellent position to access a tenure position at the National Research Council (CSIC), a prospect that was not yet possible mostly due to the reduced hiring capacity of CSIC in recent periods, a capacity that may be partially restored in the next few years.
In particular, the resources obtained from this CIG program, were used to study the role of lipid and lipoprotein metabolism in HCV infection. This field of HCV biology has moved really fast during the funding period and the published work of several groups overlapped significantly with the objectives initially proposed in the research plan. However, many questions remained unanswered in the field and the objectives were modified to further advance in our knowledge of virus-host interactions focusing in lipid metabolism.
In order to gain insight into the interplay between HCV and host lipid metabolism, Dr. Gastaminza focuses his attention in a family of cellular genes, lipins, involved in the regulation of lipid and lipoprotein metabolism in normal cells. The results obtained by his group suggest that several members of the lipin family mediate different aspects of the HCV lifecycle, as infection by HCV is reduced when experimentally interfering with the expression of two members of the family. Thus, lipins may be considered as potential molecular targets for anti-HCV therapy. Since some of the studied genes present partial functional overlapping, pharmacological inactivation of one of the members of this family of proteins may interfere with viral infection without significantly interfering with lipid homeostasis, and this may result in an effective treatment with reduced adverse effects. These studies also pave the road to understanding with greater detail how HCV alters cellular lipid metabolism to produce liver disease and future avenues to treat HCV-induced liver damage.
Using sophisticated imaging techniques and in collaboration with an international consortium of structural biologists, Dr. Gastaminza´s team produced three-dimensional nanoscale maps of the physical alterations produced by HCV in the host cell. Their data indicate that HCV takes over the mitochondrial metabolism to produce the viral structures necessary for viral replication. Moreover, his group discovered a cellular gene (SIGMAR1) involved in the functional crosstalk between different cellular organelles, including mitochondria, that is essential to produce virus replication factories. This cellular gene is also involved in the regulation of lipid metabolism as its protein product interacts with key enzymes of cholesterol biosynthesis and depletion of SIGMAR1 protein from cells alters the expression of genes involved in the metabolism of cholesterol and other lipid species. Currently, his group is performing an unbiased proteomic analysis of the proteins that physically interact with SIGMAR1 to determine the molecular mechanisms underlying this functional association. The functional implications of this physical association for viral replication and pathogenesis will be certainly one of the focuses of future studies by Dr. Gastaminza´s group.
Thus, Dr. Gastaminza identified novel cellular factors regulating early aspects of HCV infection that lead to target cell colonization. These factors are candidate molecular targets for host-targeting agents (HTAs) that may complement the antiviral activity of the novel anti-HCV therapies based on DAAs, potentially raising the genetic barrier to resistance and covering a wider range of viral genotypes. Moreover they provide new avenues to decipher the molecular details underlying the host-virus interactions during HCV infection that may inform on potential new ways of intervening therapeutically to revert HCV-induced pathologies.
Thanks to the CIG funding, Dr. Gastaminza was able to recruit valuable personel to initiate his own research group. This was instrumental to establish an independent research group that has permited him conducting his research as an independent investigator. Additional funding, personel and resources from other funding agencies and industry, put Dr. Gastaminza in an excellent position to access a tenure position at the National Research Council (CSIC), a prospect that was not yet possible mostly due to the reduced hiring capacity of CSIC in recent periods, a capacity that may be partially restored in the next few years.