Experiments have been carried out by scientists in order to identify and also characterize species determinants that exists within the human CRM1 and that overcomes the defects that were build up in the murine cells of the human immunodeficiency virus type 1 in the post-transcriptional stages. The human immunodeficiency virus type-1 can be defined as a protein that affects the movement of introns with ribonucleic acid (RNAs) in it. The impact is achieved if the CRM1nuclear export receptor is introduced. Cytoplasmic is supported by the human CRM1 which are in the murine cells and increases introns-containing viral ribonucleic acid, the end results of overall production is stimulation of human immunodeficiency virus type-1 particles.
According to one of the experiments that were conducted by a number of scientist, listed as: Nathan M. Sherer, Chad M. Swanson, Stephane Hue, Roland G. Roberts, Julien R. C. Bergeron, and Michael H. Malim, in order to attain a stimulatory effect, an exposed surface element is needed that is in the heat repeat helices 9A and 10A so as to allow hCRM1 to stimulate HIV-1 production. In the experiment, it indicated the uniqueness of CRM1 proteins for higher primate; that its evolution has moved from a non-functional ancestral sequence.
Primates and mice were used in the experiment. The results that were found in the rodents such as the mice among others within its class exhibit multiple cellular deficiencies that are needed in order to successfully replicate HIV-1. The reason that made the selection of small animals may have been due to fact that their deficiencies as a model with which to study HIV-1. In non-human species, HIV-1 is not easily replicated, the reason being that they have numerous cellular factors that are different thereby making it impossible for viral replication. TRIM5, APOBEC3G and tetherin are some of the factors that hinder HIV-1 replication in non-human species. The factors restrict replication since they are encoded. In some cases, replication of HIV-1 may not work owing to the fact that they lack functional versions of cellular proteins that are needed in order to complete key components of virus lifecycle.
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The role of murine cells being a useful tool is to identify key molecular functions of species-specific HIV-1 co-factors, some of the co-factors include the cyclin T1 (CycT1/CCNT1) transcription co-factor CD4 entry receptor and CCR5 co-receptor.
Basing on the experiment that was conducted by the scientists on the HIV-1, it reveled that genomic RNA acted as a messenger as they encoded both the Gag and Gag-polymerase structural proteins where the gRNA took the part of the pre-RNA. Messenger RNA that has the introns are shown from leaving the nucleus, this was actually a barrier to retrovirus. There is a possibility for HIV-1 to overcome the challenge through the use regulatory protein Rev that it has. Nucleus is targeted by the protein as it connects cis-acting HIV-1 RNA referred to as Rev Response element that can be found in the HIV-1 introns-containing mRNAs. Rev response element connects the cellular chromosomal area maintenance CRM1 via the leucine-rich nuclear export signal, and thus creating the viral ribonucleoprotein carriage complex. CRM1 takes the role of a switch that starts the final stages of virus life cycle. This is because of cytosolic grouping of gRNA that is required in order to express the Gag and Gag-pol proteins that virus is assembled in.
As the process was conducted, murine NIH 3T3 cells were introduced by the scientists so as to be used as a platform to screen the cellular and viral determinants. This influenced HIV-1 post-transcriptional regulatory routes. Basing on post-transcriptional events, the scientists engineered introns-containing HIV-1 gRNA surrogates that encoded Gag and Gag-pol and circumvent rodent specific deficiencies impacting transcriptional elongation, and viral pre-RNA splicing. In this part they placed the native HIV-1 promoter together with the hCMV-IE promoter as HIV-1 Tat was not needed. This then minimizes the likelihood of over splicing. The pol and gag genes are got within the major introns thus gag and gag-pol can be expressed through full-length transcripts; the nuclear export can be controlled through the introduction HIV-1 RRE where Rev and CRM1 are recruited and four copies of CTE emerging from the M-PMW are introduced, also, heterodimer of NXT1/2 and NXF1 are recruited. Expression of gag and elements of the virus were continuously reducing in production in 3T3 cells in relation to human cells as per identical transfection situations. During the improvement of VLP, the end result was a CTE-dependent nuclear export in 3T3 cells. The cells of a mouse cells that exhibited hCycT1, the cytoplasmic abundance of HIV-1 gRNA and the synthesis of Gag protein were reduced greatly in comparison to human cells. On the other hand, restoration of the HIV-1 production in a mouse cells could be done through the regulation of Gags amino-terminal matrix (MA) membrane in a manner that would increase membrane binding. Moreover, reprogramming could also be nuclear export pathway with the use of Gag encoding mRNAs without necessarily modifying the gag coding area.
In order to restore the particles in the virus that exist in the mouse cells, the scientists illustrated by replacing the RRE in introns-composed of the Gag mRNAs which had four copies that were independent of the constitutive transport element (CTE) in mason-Pfizer monkey virus (M-PMV). Through the joining of HIV-1 infected mouse cells and that of human cells caused as increased in the level production in the number of virus. This indicated a fact that at least one human cellular factor worked as a complementing murine-specific defects. Later, human and mouse cells were joint together so as to figure out an appropriate human chromosome.
During the rat study, the scientists identified activities of specific species within the CRM1 gene which is a product of Chr2. This proved that CRM1 (hCRM1) protects the nucleocytoplasmic from any defect in the transport of viral introns-containing RNAs such as the gRNA. gRNA is assigned with two roles, it mainly works as a messenger to the RNAs, that encode the viral gag structural protein, secondly, its role is to work as a genetic substrate, which is joined and packaged by into virions. This thus, gRNAs brings in a firm background the study grouping of virus pathway with cellular machineries and RNA transportation is transported and expressed.
It is through this experiment that CRM1 protein is proved to contain specific species element that are necessary for nucleocytoplasmic transportation of Rev dependent HIV-1 introns containing RNAs and HIV-1 production in murine cells. CRM1 is the main nuclear export receptor for cellular proteins, this is because of its role of maintenance to the nucleocytoplasmic, and various cellular factors are also partitioned so as to control the cell signaling and gene. CRM1 stresses on these roles with great level of sequence conservation. For instance, 98% of amino acids are believed to be shared between a human and mouse while 96%are shared between a fish and human. The outcome of this experiment indicates how changes ha evolved within a host protein, without any proves of general cellular function hindrance can suffer from substantial consequences from replication of a useful human pathogen.
Focusing on hCRM1, there is full evidence that there is an insertion of primate configuration of phenylalanine-414, proline -411, and methionine-412 to the mouse protein and removal of methionine-412 and phenylalanine-414 from the central domain of a human being in the M-Ancestral-M chimera had effect on CRM1 activity, this introduced the biological usefulness of this surface-exposed element. Amino acids within heat repeats 9A and 10A are fully completed in all sequence placental animals, with two vital important changes in the primate and rodents lineages. Mouse, human and ancestral sequence has some varied differences in the CRM1 and can affect the way they can interact with the Rev on the RRE and with other nuclear export factors.
Assessment was later done by the scientists on the effects of hCRM1 so as to ascertain the functional impact of post-transcriptional stages at the individual on the HIV-1. As part of their assessment, they tested to measure whether the virus was infectious, the results revealed that the virus was able to affect. Expression of hCRM1 enhanced Gag’s ability to move to the plasma membrane especially to the mouse cells and effectively
Nuclear Modulation membrane transport is quite important in retroviral replication. This was supported by the fact that all lentiviruses like HIV-1 encode Rev-like proteins which use CRM1 in controlling movement of introns-containing RNA from the nucleus. The lentiviruses are linked with natural infection of rodents.
The hypothesis of the experiment was that CRM1 was subject to a lengthy selection activity that took place in the primate lineage 80 million years ago. As a result, the selection was altered by sequence of heat repeat 9A. To date, the pathogen that takes part in the task have not yet identified although in the experiment, the scientists illustrated that the final product of CRM1 sequence was in a position to support HIV-1 Rev’s function where it worked as a mediator of nuclear export. This was used as an example to show the complexities that were witnesses in a pathogen. Protein evolution on the other hand has been found to be useful after a period of time, through a response to single pathogen efficiency in replication of other pathogen elements.
In conclusion, differences that were contained in a mouse and human CRM1 was demonstrated by the scientists, which is a protein functions as the medium of transport of macromolecules from the nucleus to the cytoplasm. They demonstrated that murine CRM1 fails can not support the function of the HIV-1 Rev protein, a factor that has a role of transporting viral RNAs to the cytoplasm. The main differences between amino acids of a human and mouse CRM1 proteins were given. It was also revealed in the experiment that there exists a unique pattern in human that would have been seen in from ancient evolutionary pressures. The CRM1 element demonstrated where pathogens can freely interact in order to avoid infections.
It is from the findings that we get to realize that humans have turned to be more susceptible to HIV-1 as per the reasons given above as evolution. Replication process in the human body has been catalyzed by virus evolution. Other non-humans like primates; their evolution has taken place for quite some time now hence introducing certain specific factors, that inhibit the process of replication of HIV-1. Finally, the experiment based its findings on the post-transcriptional movement of HIV-1 genomic RNAs from the nucleus to several sites in which the virus assemble at the plasma membrane. This demonstrated that the virus can replicate at a vey high rate in a human body. On the other hand, replications of this type are dependent on the strength of cellular factors to enhance replication of the virus.
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