Chad'sResearch

Viral Genetics and Control of Host Cell Gene Expression

By
Chad Clancy

Abstract:

Introduction:

The coevolution of hosts and pathogens has lead to advanced immune systems of the hosts and immune evasion systems by the pathogens. While hosts have evolved complex immune systems involving elaborate relationships between varying cell types and massive production of proteins in the form of antibodies, viruses have not been capable of evolving their own protein production system in order to evade the evolving immune response. Instead, viruses have relied on modifying their genomes to allow the host cell do the work in producing proteins allowing the evasion of the immune system, and also modified genomes that allowed control of host gene production.
A basic understanding of the workings of the immune system and viral life cycle is necessary to develop an appreciable understanding of viral-host interactions. An advanced host immune system relies on the recognition of pathogen specific molecules to recognize and attack the invading pathogen. Most often, the adaptive immune response relies on the presentation of viral specific proteins by antigen presenting cells (APCs). Activation of adaptive immune cells leads to a response for viral specific proteins within host cells. B-cells, an adaptive immune cell, produce antibodies specific to the viral proteins, the antigen. Once an antibody recognizes and attaches to an antigen, recognition by related immune cells leads to the death of the infected host cell and elimination of the infecting pathogen.
Viruses are encapsulated strands of nucleic acids incapable of self-replication, transcription and translation of their own genome, or self-packaging of viral products. Viruses rely on their host cell to accommodate all of their needs, and often destroy the cell after they have depleted it of all resources. Following successful infection of a host cell, viruses…Continue here on viral life cycle… .

Body:

As evolution provided more defense mechanisms for hosts against their invading pathogens*;* pathogens evolved ways to counter these defense mechanisms. One method of evading an immune response is preventing the host from recognizing the presence of the virus. One way this can be accomplished is by disrupting the pathway that leads from phagocytosis of a virion or viral product to presentation of these digested materials on APCs. The HIV virus accomplishes this feat by encoding in its genome the gene for Tat protein. This protein has been shown to repress the expression of several immune related genes (1). Repression of these genes leads to a down-regulation of the protein products, and relatively decreased recognition by the immune system.
Bovine and human papilloma viruses have evolved a slightly modified mechanism for evading recognition. Viral proteins E5 and E7, once produced, can be found in the host cell golgi apparatus and endoplasmic reticulum. These proteins control the presentation of antigens by maintaining the packaged antigens within the cell and also reduce major histocompatibility complex (MHC) protein mRNA levels within the cell (2,3). MHC proteins are the proteins responsible for presenting the antigens taken up by APCs. Therefore, reducing mRNA levels for MHC molecules would lead to decreased antigen presentation by these cells and a decreased likelihood for antigen recognition by the immune system.
Viral evolution has not been limited to ways of evading the immune system, but also harnessing the natural cell processes to their own benefit. One such pathway is the viral control of host cell miRNAs (Zhumer et al.). A more novel viral approach to harnessing the host can be observed in viruses such as HIV, vacinia virus and human cytomegalovirus. These viruses take the CD59 molecule, a molecule normally known to protect host cells from lysis during the complement cascade, and incorporate the molecule into their envelope, allowing for protection in the event of a complement cascade (8).
One function that all host-dependent pathogens must try to overcome is the death of the host. For viruses, host death means apoptosis, or programmed cell death. This death is either natural in an aged cell, or can be induced by immune cells to prevent further spread of infection. Apoptosis has major implications for host dependent pathogens. Once apoptosis is triggered, cellular protein production is ceased, leading to decreased virion production and decreased numbers of budding virions (4,5). One viral approach to avoid apoptosis is to force the host into a continual lifecycle, creating an immortal cell line, which is known as cancer. The human T-cell leukemia virus type 1 (HTLV-1) encodes a protein, Tax, a transcriptional activator that is responsible for the conversion of a normal T-cell to a cancer cell (6). Tax has also been shown to down-regulate apoptosis by deactivating p53, a pro-apoptotic protein (7).
The outcome of prolonging cellular death and continuing the life of the host is continually having the machinery needed to transcribe and translate the viral genome and hence replicate a single virion into hundreds of thousands of viruses. Unfortunately in this case, once the host cell has been infected, cellular death is inevitable either through immune system mediated apoptosis or through metabolic stress due to production of virion particles. If a cell is capable of escaping infection without programmed cell death, lasting affects may follow including uncontrolled replication resulting in cancer.

Conclusion:

Understanding the mechanism of viral evasion of the immune system and viral control of host gene expression may lead to an increased production of antiviral medications. Disrupting the protein production of viruses may lead to decreased evasion of the immune system, and therefore a higher recognition of viral particles by immune cells. Not only could these methods assist in eliminating pathogenic viruses from infected hosts, but these mechanisms could be added to beneficial viral vectors used to deliver vaccines or added to viruses used for gene therapy.
References:
1. Brown, J. A., Howcroft, T. K., Singer, D. S. (1998) HIV Tat protein requirements for transactivation and repression of transcription are separable. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 17, 9 –16.
2. Ashrafi, G. H., Tsirimonaki, E., Marchetti, B., O’Brien, P. M., Sibbet, G. J., Andrew, L., Campo, M. S. (2002) Down-regulation of MHC class I by bovine papillomavirus E5 oncoproteins. Oncogene 21, 248 –259.
3. Ashrafi, G. H., Haghshenas, M. R., Marchetti, B., O’Brien, P. M., Campo, M. S. (2005) E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I. Int. J. Cancer 113, 276 –283.
4. Clem, R. J., M. Fechheimer, and L. K. Miller. 1991. Prevention of apoptosis by a baculovirus gene during infection of insect cells. Science 254:1388-1390.
5. Clem, R. J., and L. K. Miller. 1993. Apoptosis reduces both the in vitro replication and the in vivo of a baculovirus. J. Virol. 67:3730-3738.
6. Ballard, D. W., E. Bohnlein, J. W. Lowenthal, Y. Wano, B. R. Franza, and W. C. Greene. 1988. HTLV-I tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science 241:1652–1655.
7. Pise-Masison, C.A., Choi, K.S., Radonovich, M., Dittmer, J., Kim, S.J. and Brady, J.N. 1997. Inhibition of p53 Transactivation Function of the Human T-Cell Lymphotropic Virus Type 1 Tax Protein. J. Virol. 72:1165-1170.
8. Alcami, A. and Koszinowski, U. H. 2000. Viral mechanisms of immune evasion. Immunology Today. 21:9:447-455.

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