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The Herpes simplex virus (HSV) is a highly adaptable, unique human DNA virus. The virus has the functions to create a multitude of progeny in many various cell types of different species. The wide host range allows HSV to infect cultured cells from species that are different than the natural host cells. The distinctive extensive host range HSV has can be explained by three unique traits:
The virion of HSV has 12 envelope surfaces glycoproteins that allow entry into a broad number of cell types.
A wide assortment of heparin moiety of cell surface glycosaminoglycans (for attachment) and three various receptors for entry are released by HSV. This can boast an increase in the probability for the virus to be able to get into the cell for uncoating and replication.
Because the cell has intracellular functions to prevent replication, HSV has many ways to overcome these objections:
In order to repel the constraint of the HSV infection, HSV can interfere with the nuclear domain 10 nuclear bodies along with breaking down the TRIM19/PML protein.
To allow active lytic gene transcription, HSV blocks the host cell's chromatin-silencing activities.
Disrupting the interferon stimulation.
HSV infections do not necessarily always become diseases in specific animal species; the rhesus macaques are an example of this fact. However, the reason why these primates do not receive the disease is a mystery. The rhesus macaques have provided studies with an exceptional primate model for simian immunodeficiency virus and acquired immunodeficiency syndrome (AIDS). Studies involving the rhesus macaques have provided a relevant measure of the efficiency of various AIDS vaccine vectors.
TRIM5a is a protein that includes RING domain, B-box domains, and a coil. It has the function to intervene in retroviral control. There have been found to be 69 different proteins of the TRIM family in the human genome. Their homologs have been determined to be various primates as well. Some these members in the TRIM family perform different cell functions such as differentiation, oncogenesis, and apoptosis. TRIM19/PML, specifically has the ability to disrupt the replication of many RNA and DNA viruses. TRIM19/PML has connections with other proteins that can perform transcription, mRNA stability, chromatin remodeling, and DNA repair. The control of retroviral infections has been identified by many host characteristics. Determined to have a big impact in restricting the HIV-1 infection in Old World monkey cells, TRIM5a, prevents infections at an early stage. TRIM5a accomplishes this by selecting the capsid and promoting an early disassembly. Experiments involved with TRIM5a illustrate how it hampers retroviral infection in certain species. The main question behind this study is "does TRIMa possess the ability to control HSV replication?" The data illustrates that TRIM5 proteins in Old World monkeys can limit HSV infection but this restriction is specific depending on the viral strain. The study hypothesizes that TRIM5 protein could demonstrate antiviral consequences that restrict viruses other than the ones from the retrovirus group. If there is a cell component decrease of TRIM5a levels during the late period of the infection, the antiviral results could be offset.
In order to measure if rhesus TRIM5a did indeed play a role in the limitation of the HIV infection, the researchers analyzed the HSV infection of HeLa cells that allowed the rhesus monkey TRIM5a protein (H-R cells). Not only have H-R cells been used to examine the limiting activity of TRIM5a on various retroviruses, but also these cells have illustrated virus-selective reduced functions. The HSV-1 KOS virus quantity after the infection of H-R cells was lessened by 2-fold and the HSV-2 was decreased by 5-fold in contrast to the infection of H-L cells. This data suggest that rhesus monkey TRIM5a is fully capable of inhibiting HSV replication at a low multiplicity of infection (MOI) but rhesus TRIM5a protein is a nonfactor when there is a higher MOI.
The data in the results illustrate HSV-1 and HSV-2 replication was inhibited in the rhesus macaque fibroblasts. Since little is known as to why macaques are less vulnerable to HSV infection, this study tested the how the HSV would grow in rhesus cells. The progeny created by HSV-1 and HSV-2 in rhesus monkey fibroblasts determined the results. This replication was then analyzed compared to viruses in the tolerant HeLa cells. Infected cells were produced at different periods during late infections, and the yields of replicated viruses were measured on Vero cells. Compared to the HeLa cells, the HSV-1 and HSV-2 produced from monkey fibroblasts were substantially less. With the results this experiment gave the study, the researchers then tried to determine if the rhesus TRIM5a protein influenced the diminished tolerance.
Another study that was done was to examine the effects rhesus TRIM5a protein has on HSV-1 and 2 protein syntheses. The study predicted that rhesus monkey TRIM5a might force its inhibitory mechanisms on HSV infections at early phase. This prediction was made because the inhibitory effect of TRIM5a has on retroviruses has been considered to happen at a beginning phase of infection. In order to examine if the hypothesis was correct, the experiment involved has H-L control cells and H-R cells conveying TRIM5a being infected with HSV-1 and 2. Following this procedure, Western blot analysis was used for viral protein synthesis assay. The decline in HSV-1 progeny in H-R cells was at the level of IE gene expression. In comparison, in the HSV-2 infected cells, the decline of viral protein synthesis in H-R cells was a lot more. The decrease in HSV-2 replication in H-R cells is be clarified by a similar reduction in E gene expression and IE.
After determining the effects of TRIM5a protein on retrovirus infections were influenced by the type origin of the TRIM5a protein, the basis of TRIM5a control of the effects on HSV infection were researched. Analysis was done analyzing the effects of TRIM5a proteins from squirrel monkey, rhesus monkey, human, and the African green monkey. The data on this study compared the viral replication in H-R cells and the expression of the TRIM5a. The results concluded that TRIM5a proteins from Old World Monkeys illustrated the strongest reducing mechanism on HSV replication.
The effects of rhesus TRIM5a on various HSV strains were also analyzed. Rhesus TRIM5a inhibited the replication of HSV-1 strain KOS and HSV-2 strain. This caused for an examination of how the inhibition passed to other HSV strains. In H-R cells, there was a 3.6 fold decrease of HSV-1 strain F in H-R cells in contrast to H-L control cells. However, the production of progeny of HSV-1 strain 17syn+ was not substantially restricted (pN0.05) in rhesus-TRIM5a cells. Consequentially, TRIM5a, and the restriction of HSV replication in TRIM5 expressing cells looked to be more viral strain particular instead of species exact. This means that the viral strain was the cause of the restricted HSV-1 and 2 strains.
One interesting note is that a cytoplasmic PML can preserve the HSV infected cell protein in the cytoplasm, thus inhibiting HSV-1 replication. The data suggest that TRIM5a is probable to react in the same way. In order to truly test this assumption, the distributions of ICP0 in HSV-1 KOS virus infected H-L, H-R, and H-H cells were analyzed. It appeared rhesus TRIM5a increased the number of ICP0 in the cytoplasm. In the conclusion of this study, TRIM5a was found to seize ICP0 in the cytoplasm. This in effect, restricted ICP0's nuclear function, restricting HSV replication.
In order to receive a better comprehension of the interactions between TRIM5a and HSV, a Western blot analysis on lusates from mock- or HSV infected H-R and H-L cells was done to measure how HSV infection affected TRIM5a levels. The results illustrated that HSV-1 and 2 both resulted in decreased levels of TRIM5a. For all TRIM5a variants examined, the kinetics of TRIM5a loss was measured. The viral gene expression found in by ICP8 expression was different for the cell lines. The key data that results present is that the level of TRIM5-s intervened in inhibiting the replication of HSV by the various TRIM5a proteins was not affected mainly by TRIM5a protein levels in the infected cells. This means the function of HSV to stimulate the loss of TRIM5a in infected cells could decrease the overall effect of all of the TRIM5a molecules. The absences of ICP0 did not affect the inhibition of HSV-1 by TRIM5a. The amount of TRIM5a restriction in HSV-infected cells seemed to be free of the existence of ICP0.
It appeared that the viral IE gene expression is inhibited in cells showing signs of rhesus monkey TRIM5a. In affect, TRIM5a activates at the beginning in a HSV infection. The nuclear targeting of the nucleocapsid, uncoating at the nuclear pores, viral entry, and other functions are all affected because TRIM5a is positioned in the cytoplasm. The data also suggests that rhesus monkey TRIM5a could restrict the VP16 virion transactivator from contacting the nucleus. Rhesus monkey may also restrict HSV ICP0 from passing into the nucleus. This was evident by a cytoplasmic PML isoform that illustrated that cytoplasmic PML forces its antiviral mechanism by inhibiting viral gene expression through the cytoplasmic theft of ICP0. The ICP0 provided a viral protein that was capable of performing a variety of functions such as the transformation of viral chromatin or the interference of PML bodies. It was proven that the TRIM5a inhibition of HSV replication does not need ICP0 so it is still a mystery why the ICP0 co localizes with the rhesus monkey TRIM5a. To find out more about the relationship between TRIM5a and the development of the HSV infection, the HSV major capsid protein loops would be an interesting site for studies. The ICP0 also provides an important transport system between the nucleus and the cytoplasm late after the infection as occurred. An important discovery was found through our immunofluorescence analysis; since cytoplasmic ICP0 seems to follow along with the location of rhesus monkey TRIM5a, this suggest that there may be some type of interaction between the ICP0 and the TRIm5a molecule.
Since the data resulted in TRIM5a protein being absent when the HSV infection occurred, this suggests that HSV may have evolved to limit the inhibiting ability of TRIM5a. Surprisingly, the level of decrease of TRIM5a in HSV-infected cells did not affect the level of inhibiting activity. The decrease of TRIM5a did not depend on the activity of the PML degradation (which was stimulated by ICP0).
Another discovery is that PML protein adds to the antiviral activities that prevent HSV replication. As PML decreases, viral gene expression increases; however, over expression of PML does not influence HSV replication at all. Because TRIM5a does not impact the nuclear processes directly, the mechanisms of inhibition of HSV by PML and TRIM5a may vary.
The data for the inhibition of the specific host species discovered that different Old World monkeys TRIM5a proteins partially influenced the restriction of replication of HSV in the cells. The Old World monkey TRIM5a proteins also limit HIV replication. The TRIM5a is observed to be an essential piece in the antiviral resistance activity that evolved in much earlier for restricting thwarting the viruses from jumping to different host species.
The HSV studies in rhesus macaques suggest that HSV vaccines with vaccine vectors in rhesus macaques may be effective. Because rhesus macaques are the best nonhuman primate models for AIDs, the studies tested HSV vectors expressing SIV proteins as AIDS vaccines in rhesus macaques. The data observed from this illustrated that these vectors stimulated cellular and humoral reactions. These reactions decreased the SIV challenge viral loads and disease. The data from this experiment clearly express how ineffective HSV infects rhesus monkey cells and the TRIM5a protein heavily influences the key component of the inhibition in rhesus monkey cells.
There is lack of knowledge behind what make rhesus macaques immune to HSV as well as the method of avirulence that takes place. A possible reason for the absence of disease in HSV-infected creatures is because HSV-1 and 2 grew weakly in the rhesus monkey fibroblast cells. After it was known that rhesus monkey TRIM5a could restrict HIV-1 replication, the influence that TRIM5a proteins had on HSV replication were further investigated. Various orthologs from Old World monkeys, New World monkeys, and humans were examined for how they impact HSV replication in HeLa cells. The TRIM5a from the Old World monkeys, specifically rhesus macaques, illustrated the best restricting effect of HSV replication and protein expression. On the other hand, the TRIM5a expressed a poor effect on HSV growth in the squirrel monkey. Unsurprisingly, the human TRIM5a had little to no impact on HSV replication. This data is great measure of how much of an influence the TRIM5a protein has on the growth of HSV. We can conclude with this data that TRIM5a is expressed in rhesus monkeys a greater degree compared to how it is expressed in humans. I think it is important that the data of this study is not understated. Fighting viral infections is an on-going battle and scientist need to keep finding ways to slow the infections of viral diseases. I like the fact that the study addressed all the questions in the introduction and answered all of them in a detailed manner. The background knowledge on HSV also enabled me to understand better of how HSV's host range is so extensive. Because of the definite potential and the plague that are viral infections, it is essential that the data in this experiment should be analyzed. Based on the data and how rhesus macaques TRIM5a protein restricts HSV replication, this could unlock great potential in the quest for finding ways fight off virus infections. Although, the Old World monkeys are one of the species that are immune to HSV, they may present a solution to other species. Unlocking the mystery behind how exactly these TRIM5a proteins are inhibiting HSV replication should be the direction of the follow-up experiment. Since there is a dire need slow down the AIDs epidemic, more studies can be done to see how well the rhesus macaques TRIM5a proteins inhibit this retroviral's growth. They could also pursue at examining if it possible to produce a drug that could enhance the expression of human TRIM5a proteins. This could inhibit and prevent the viral growth of HSV. Studies could also aim at what other benefits an overexpressing TRIM5a protein may have. The protein could restrict other viral infections as well.