The AIDS virus is replicated through mitosis

Consequences of a cell cycle independent viral gene expression for the lytic infection cycle of the human cytomegalovirus


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https://refubium.fu-berlin.de/handle/fub188/23992
http://dx.doi.org/10.17169/refubium-1767
dc. description. abstract
The human cytomegalovirus (HCMV) is a ubiquitous pathogen that belongs to the herpes virus group. In immunosuppressed patients such as AIDS patients or organ transplant recipients, but also in newborns, HCMV infection can cause severe disease that can even lead to death. In addition, HCMV is the most common cause of congenital infection and can lead to both mental and physical disability. The existing antiviral drugs are characterized by significant side effects and the development of resistance. At the cellular level, a distinction is made between lytic and latent infections. The lytic infection cycle is initiated by the expression of the immediate early (IE) genes, which set a cascade of further gene expression programs in motion and are therefore essential for viral DNA replication and the production of new virus particles. While HCMV can enter the cell at any phase of the cell cycle, IE gene expression is blocked in S / G2-phase cells and can only be initiated in G0 / G1-phase cells. This blockage is mediated by the interaction of the cellular cyclin A-dependent kinase with the viral protein pp150. In this work the physiological relevance of the cell cycle dependent IE gene expression of HCMV was investigated. For this purpose, a virus mutant was used in which pp150 is no longer able to bind with cyclin A. It could be shown that IE gene expression in S-phase cells leads to a stable G2 arrest, which supports viral gene expression and DNA replication well. Only a small subpopulation of mitosis-arrested cells was noticeable, in which no viral DNA replication took place. The virus-permissive G2 arrest was found to be dependent on pUL21a. It was recently shown that this HCMV gene product destabilizes cyclin A and thus leads to an arrest of the cell cycle at the transition from the G1 to the S phase. A colon mutant of HCMV in which both pp150 and pUL21a can no longer interact with cyclin A led to considerable negative consequences for virus and host. A large part of the cells entered mitosis, associated with a severe loss of cell viability. The production of new virus particles was restricted approximately 500 times. The effects of the two mutations in pUL21a and pp150 were not additive but rather synergistic. In summary, it was shown that the viral proteins pp150 and pUL21a functionally work together to prevent an unproductive mitotic state of HCMV-infected cells. The results suggest a model in which pp150 alone as a cyclin A sensor is not absolutely necessary for a productive infection, but rather was developed by HCMV to strengthen and secure the cell cycle synchronization through pUL21a.
dc. description. abstract
Human Cytomegalovirus (HCMV), also known as Human Herpesvirus-5, is a widespread pathogen. In immunocompromised individuals, such as AIDS patients and transplant recipients, as well as in neonates, HCMV infection can lead to severe disease and death. It is the most common congenital infection leading to disabilities such as mental retardation and hearing impairment. The available virostatic drugs are characterized by severe side effects and emergence of resistant strains. At the cellular level, HCMV can either remain latent or start its lytic replication cycle. Lytic replication is initiated by the expression of immediate early (IE) genes which trigger a cascade of subsequent gene expression programs, eventually leading to viral DNA replication and the production of new virus progeny. While HCMV is able to enter the cell at any cell cycle stage, IE gene expression can only be initiated in G0 / G1 phase cells and is blocked in S / G2 phase cells. This block is mediated by the interaction of cellular cyclin A-dependent kinase and the viral tegument protein pp150. Here, the physiological relevance of cell cycle-dependent IE gene expression for HCMV was addressed by employing a mutant virus lacking the cyclin A-binding motif in the pp150 protein. It was observed that the initiation of IE gene expression in S phase cells results in a stable G2 arrest followed by efficient expression of further viral gene products and viral DNA replication. Only a small subpopulation of cells entered a mitotic arrest and showed no signs of viral DNA replication. The virus-permissive G2-arrest was dependent on pUL21a. This viral protein has recently been shown to destabilize cyclin A, thereby leading to a cell cycle arrest at the transition from G1 to S phase. An HCMV double-point mutant where both pp150 and pUL21a are disabled in cyclin A-binding showed severe negative consequences for virus and host. A majority of infected cells was forced into mitosis accompanied by a sharp decrease in cell viability. Analysis of the production of new virus progeny revealed an approximately 500-fold growth defect. These were not only additive but synergistic effects of pUL21a and pp150 mutations. Taken together, it could be shown that the viral proteins pp150 and pUL21a functionally cooperate to prevent HCMV from entering a non-productive mitotic state of infection. These results may point to a model where cyclin A sensing by pp150 alone is not absolutely required for productive HCMV infection but has been developed to strengthen and support cell cycle synchronization by pUL21a.
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
600 Technology, Medicine, Applied Sciences :: 610 Medicine and Health :: 610 Medicine and Health
Consequences of a cell cycle independent viral gene expression for the lytic infection cycle of the human cytomegalovirus
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dc. contributor. furtherReferee
urn: nbn: de: kobv: 188-refubium-23992-4
Charité - University Medicine Berlin
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