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The liver is the major site of replication of HCV. Its interaction with the innate immune system as an antiviral defense mechanism is a complex process. HCV activates the cellular signaling pathways for interferon production early in the infection and later on suppress the activity. The synthesis of the Type 1 Interferons and the associated Interferon-stimulated genes (ISPs) are activated and are suppressed by the virus when the viral proteins begin to get accumulated in the cell.
NS3 is a multifunctional protein with a serine protease activity and the NS4A is an essential cofactor for the full expression of the NS3 protease activity. This NS3/4A accumulates in the infected cell and blocks the various interferon signaling pathways: IRF-3 pathway, RIG-1 signaling pathway, disruption of the NFÑœB activation etc.
Interferon regulatory factor 3 (IRF-3), a transcription factor, constitutively expressed in the cytoplasm plays a key role in the signaling pathway for interferon production. Typically, upon viral infection the specific C-terminal phophorylation of the C-terminal end of IRF-3 results in its dimerization and its transport to the nucleus. This is mediated by the kinases of IKK complex that are activated by infection with RNA viruses. In the nucleus, activated IRF-3 coordinates with other transcription factors such as NF-ÑœB and ATf-2/c-Jun, form an enhanceosome complex on the interferon-Î²-promoter. Secreted interferon- Î² binds to the interferon Î±/Î² receptors, by the activation of the JAK-STAT pathway. This results in the increased production of INF-Î± and other ISGs.
Pathogen associated molecular pattern (PAMP) receptors sense double-stranded RNA through Toll-like Receptors-3 and Retinoic acid-inducible gene -1 (RIG-1). These are the two pathways by which the kinases mediate the C-terminal phosphorylation of IRF-3 induced Interferon production. RIG-1 is found to be more dominant PAMP receptor recognizing intracellular dsRNA and inducing interferon production, while the role of Toll-like receptors in antiviral defenses is less certain. Although both pathways are found in normal liver cells, activation of RIG-pathway has been shown to suppress HCV replication.
The NS3/4A serine protease effectively blocks the phosphorylation of IRF-3 via either of these pathways by specific proteolysis of cellular proteins required for signal transduction. The TLR-3 receptors are expressed on the surface of the cells which induces IRF-3 activation upon binding with the extracellular ds RNA. However NS3-4A proteolytically cleaves the TLR-3 adaptor protein: Toll-IL-1 receptor domain containing adaptor-inducing interferon-Î² (TRIF or TICAM-1).
RIG-1 signaling results in the activation of NF-ÑœB and is inhibited by NS3/4A protease. The cellular substrate cleaved by the viral protease in blocking interferon induction has been found to be a novel outer-mitochondrial membrane protein, IPS-1. The proteolytic cleavage by NS3/4A of the IPS-1 releases IPS-1 from the mitochondrial outer membrane, eliminating its ability to function in signaling.
Disruption of both these pathways by the viral protease disrupts the activation of NF-ÑœB but has not been well studied. However the activation of the NF-ÑœB by the inhibition of the two pathways could be reversed in-vitro when NS3/4A was inhibited. It has been suggested that the core of the HCV virus modulate the signaling pathways through the JAK/STAT pathway. It was found that this pathway was strongly inhibited when the binding of the STAT transcription factors with the ISG promoters were inhibited.
The Dendritic cells (DC) belonging to the myeloid and plasmacytoid lineages play a critical role at the interface of the innate and adaptive immunity. Natural killer cells (NK cells) that are able to control HCV replication might fail because of inadequate activation signals from DC. It has been found that even a transient virus-mediated subversion of the innate signaling can significantly affect the DC maturation and initiation of the adaptive immune system.
The evasion of the NS3/4A of the interferon signaling pathways suggest that these pathways play a major role in controlling the virus in vivo and prevent persistent infection. The net effect of these interactions show the invasion of the virus into the antiviral defense cellular responses rendering the virus relatively resistant to interferons and subsequently affect the development of adaptive immunity.
Part B. Cellular genomes contain genetic elements that have similarities to virus genetic material. Do these findings suggest that there are evolutionary relationships between cellular and viral genetic material? What might this mean for the evolution of viruses?
With the human genome sequenced, it became evident that most part of the genome contained derived-sequences. Half of the mammalian genome is derived from ancient transposable elements comprising mainly of DNA transposons and retroelements. About 90% of the transposable elements constitute retroelements which depend on RNA transcripts which gets retro-transcribed by reverse transcriptase into DNA prior to getting integrated into the genome. Genome sequencing of RNA viruses have also revealed the relatedness between the cellular transposable elements and retroviruses which could explain their obligate parasitic activity of cells. The viral genomes initially attained different forms, acquired genes from host cells and developed different strategies to infect cells and replicate its genome in them.
However, the origin of the viruses or the evolutionary pathway that leads to the evolution of DNA and RNA viruses remains elusive. The presence of retroelements in the cellular genome gives the idea that retroviruses evolved from cellular genomes. Endogeneous retroviruses (ERVs) are one such example, where they are transmitted vertically through host generations. They are the proviral form of the exogenous retroviruses that have infected the germline cells. The Human endogenous retroviruses (HERVs) have brought a significant impact in understanding genome evolution, diversity and genetic variation.
The retroelements which constitute 90% of the transposable elements present in the human genome are classified into two groups LTR and non-LTR groups. Two members of the non-LTR group are present in high copy numbers in the mammalian germ line: Long-terminal Interspersed elements (LINE) and the Short Interspersed Elements (SINE). SINEs have no protein coding capacity and therefore depend on LINEs for their amplification. The LTR class includes retrotransposons, endogenous retroviruses (ERVs) and repeat elements with HERV origin. Most of the retroelements appear to be deeply fixed in the primate genomes and virus free alleles are not known. These fixed retroviral elements integration in the genome were exerted by recombination events. Recombination events that could replace these integrated proviruses are largely unknown. The provirus contains ORFs for all retroviral genes and all known functional domains are preserved. The HERV-K113 (K-lysine) is the best studied candidate and its age was identified to be <200,000 yrs ago. However, HERV-K113 was not found to be fixed in the human population as it was rare in Caucasians and abundant in Africans, Asians and polynesion population. This shows that it is present either in low frequency in the human population or in high frequency in genetically separated ethnic groups. (Norbert Bannert and Reinhard Kurth, 2004)
Genomic rearrangements caused by scattered homologous proviral sequences gave rise to countless genetic variations. Retroelements are found to be present in rapidly evolving genes with a high rate of mutation which indicates an increased diversifying selection. Such genes are mostly involved in immunity, stress responses, and responses to external stimuli. This shows that these transposable elements play a role in the diversification which increases with the increasing speed of evolution in humans
(Norbert Bannert and Reinhard Kurth, 2004).
The origin of viruses has always been a conundrum and their nature has always been controversial. Three hypothesis have been suggested to explain their evolution: First hypothesis suggest they are relics of pre-cellular life forms - THE VIRUS-FIRST HYPOTHESIS. It suggests that the formation of cells occurred relatively late in the evolution of life. Since viruses contain proteins, they should have originated after the emergence of a ribosome. It appears unlikely that a world of free molecules could have evolved to produce a ribozyme capable to synthesize proteins. Hence, on the basis of the present-day viruses the virus-first theory is widely rejected.
Secondly, the ESCAPE HYPOTHESIS which views viruses as elements of cellular genomes that escaped from their cellular environment, becoming autonomous and infectious selfish elements. In this view, plasmids and mobile elements are often considered to be viral precursors. But this theory does not address the idea behind how a free nucleic acid could have recruited a capsid and complex mechanisms required by viruses to deliver to their host cells. Based on this theory, there should be evidence of evolutionary affinities between viral proteins encoded by viruses and their cellular homologues in that domain. With more than 250 cellular genomes from the three domains of life being sequenced, no cellular homologues have been detected. The third hypothesis: REDUCTION HYPOTHESIS views viruses as being derived by reduction from unicellular organisms. This has also been rejected due to no knowledge of an intermediate between calls and viruses and also all three domains of life have retained their cellular characters. (Patrick Forterre, 2006).
However, when endogenous retroelements was discovered in a number of animal species, it was initially believed to be a part of the developmental process of the host. After closer examination it was found that it indeed did not participate in the developmental process but represent a "selfish genetic element". The selection of retroelements has been successful in their endogenous state since they do not belong to the "too harmful" category as their exogenous counterparts.
Endogenous proviruses increase in copy number with time. They cause mutations in their hosts upon reintegration which could sometimes lead to the removal of the host from the population. The hosts seems to have developed mechanisms for combating this by homologous recombination, where the high level of the proviral load in the host is prevented from spreading further or eliminated. This could have been a selective advantage of those animals which have survived the germ line integration of such retroelements.
The presence of retroelements in host has indeed been a useful tool to study the phylogeny apart from their role in diversification and expansion, where the specific integration site of a retroelement could be indicative of a common ancestor. Other biological implications include that some of the analyzed human promoter sequences harbored sequences derived from these retroelements.
Because retroelements are more widespread than DNA transposons, because they have a likely connection with the RNA world, and because retrotransposon/retrovirus integrases are similar to transposases encoded by DNA transposons we can say that DNA transposons also evolved from retroelement ancestors. It is speculated that a more infectious virus particle originally evolved from a simpler retrotransposon, although it is believed that an infectious retrovirus lost its infectivity to remain in the host to be called endogenous retroviruses.