This research paper is mainly focus on Human herpes simplex virus (HSV) which is a human nuclear DNA virus that is able to replicate in different types of cells of many species. The virus has 12 envelope surface glycoprotein which leads entry to wide range of host. Unlike many other viruses, HSV has three different receptors, and it uses broadly distributed heparan moiety of cell surface glycosaminoglycans for attachment. However HSV encounters several obstacles that blocks replication within the host cell. In order to prevent the obstacles HSV has adopted several mechanisms. For example, blocking host cell chromatin-silencing mechanism and interferon induction. Despite these strategies, studies reported that HSV infection does not lead to disease in specific animals such as rhesus macaques. Study shows the expression of SIV protein in rhesus macaques when HSV-based vaccine is used as a vector. Based o this indication researcher questioned if rhesus macaques are less susceptible when it compares to other primates. This result leads them also to investigate whether TRIM5α protein contributed to the reduced permissiveness. Studies have shown that TRIM5α protein is the main factor that blocks the replication of HIV in old world monkey.
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In order to show the less susceptibility of HSV in rhesus macaques, experiment is done to see the growth rate of progeny obtained from HSV-1 and HSV-2 infection. Replication of HSV-1 and HSV-2 is investigated. At different time of post-infection, viral replication is compared between rhesus monkey fibroblast and permissive HeLa cells. According to the result 100 fold lower progeny obtained in rhesus monkey fibroblast compared to the progeny obtained from HeLa cells. This indicates that rhesus monkey is less susceptible to HSV infection compares to other primates.
Further studies have done to investigate if TRIM5α is a factor that contributes to the restriction of HSV-1 and 2 in rhesus cell. Infection which is caused by HSV on HeLa cells that expresses rhesus monkey TRIM5α protein (H-R cells) is examined. Researchers infected Rhesus monkey (H-R cells) with HSV-1 and 2, they and compare the result with a control group (H-L) cells. The infected cells were collected within 24 hpi, and titration on vero cells is done to determine yields of HSV. The result indicates there is a significant reduction of viral yields in H-R cells for both HSV-1 and 2 when it compared to the control group (H-L) cells. However this significant reduction is obtained at low MOIs. The result indicates the viral yield at high MOIs in H-R cells is equal to the control group H-L cells. This indicates the viral have overcome the effect of TRIM5α protein at higher MOIs .
Studies have shown that the effect if TRIMα5 protein on retrovirus infection depends on species origin of the TRIM5α and protein. Therefore researchers questioned if the source of TRIM5α protein determines the effect of HSV infection in order to answer this question experiment is done on different species. This method allows researchers to compare the effect of TRIMα5 protein by comparing the level of HSV-2 replicate. Result from this experiment shows that HSV-2 replicate in H-H cells which express human TRIM5α was the same compared to control H-L cells. The level of the TRIM5α protein was reduced by 3.6 fold in H-AGM (African Green Monkey) cell and 4.5 fold lowers in (rhesus) cells. Unlikely there was only 35% TRIM5α reduce in H-sq (squirrel monkey) cell. This result indicates there is a strong restriction of HSV replication in H-R (rhesus) cell expressing TRIM5α compared to human AGM and squirrel monkey.
According to the study the effect rhesus monkeyTRIM5α protein in restriction HSV-infection is effective at early stage. Based on this result researchers want to investigate the effect of rhesus TRIM5α protein on HSV-1and 2 protein synthesis. Therefore they hypothesized there will be more inhibition of HSV infection at an early stage. This means in rhesus monkey the HSV IE viral protein synthesis would be decrease that express TRIM5α protein. Experiment is done by infecting HSV-1 and 2 H-R cells that express TRIM5α protein and compare its protein synthesis using western blot analysis. The result indicates viral protein (ICP4) and ICP8 of HSV-1infection is lowered by 2 fold and 8 fold at different time interval in H-R cells respectively of ICP and ICP27 decreased by 5-7 fold. This indicates that viral protein synthesis is highly reduced in cells infection with HSV-2.
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Researchers have done an experiment to test the effect of the rhesus TRIM5α on diff HSV strains. In order to do this, they infected H-R cell and the control group (H-L) cell with low passage HSV-2 clinical isolate SDPO-3P or low passage laboratory stain. The result indicates reduction of HSV-2 infection. Based on the result HSV-2 strain G yields and SD90-3P clinical isolate the viral yields reduced in HR cell by 12 fold, 4 fold and 2.5 fold respectively. On the other hand, they infect both H-R cell and H-L cell with HSV-1 low passage laboratory strain F or the laboratory strain 17 syn+. The result also indicates reduction of viral yields in H-R cell by 3.6 fold of HSV-1 strain F compares to H-L. However, there was no significant replication inhibition of strain 17syn+ in rhesus- TRIM5α cells. Based on this result, it is conducted that the effect of TRIMα5 protein is more viral strain specific than species-specific.
Studies have reported that an Infected Cell Protein 0 (ICP0) present in the cytoplasm of HSV infected cell promotes reduction of HSV replication. Based on this result, researchers were questioned if TRIMα5 also act similarly. Therefore they infected HSV-1 KOS virus to (H-L) cell, (H-H) human cell and (H-R) rhesus cell. They conduct time interval distribution of ICP0 in each cell. The result indicates at 1 hpi, there is no ICP0 distribution in (H-L) cell and (H-H) cell. Later by 4hpi increase number of nuclear ICP0 and small number of cytoplamic ICP0 distribution observed in H-L and H-H bells in contrast the number of cytoplamic ICP0 increased in (H-R) cell. In contrast at 8 hpi more cytoplasmic ICP0 observed in (H-L) and (H-H) cells. On the other hand in (H-R) cell increased number of cytoplasmic ICP0 distribution is observed. However at 8 hpi, the number of nuclear ICP0 distribution decrease in contrast to cytoplasm ICP0 distribution. Based on this result, researchers determined that TRIM5α might block ICP0 in the cytoplasm; therefore ICP0 distribution in the nucleus decrease which leads to inhibit HSV replication.
An experiment conducted to see if viral replication is dependent on cytoplasmic retention of ICP0 distribution at early stage. The experiment is done on H-R and H-L cell by mutating ICP0, and compared the effect on viral replication with ICP0 null mutant. The result indicates 1.9 fold reductions of viral yields in H-R cells compared to H-L cells. Therefore the researchers concluded that the difference is not significant to state the reduction of HSV-1 replication by TRIMα5 is dependent of ICP0 distribution.
In general, this research explains the reason why HSV are not able to replicate in rhesus monkey. Researchers conducted several experiment to indicate that TRIMα5 protein plays a major role in restricting the replication of HSV in rhesus monkey. Based on the result, Researchers questioned if rhesus monkey TRIM5α can also inhibit HIV-1 replication in human. They tested different TRIM5α orthologs from Old World and New World monkey, and human to see the viral replication in HeLa cells. However the result indicates a strong inhibitory effect on Old World Monkey (rhesus). In contrast, human TRIM5α had the least effect on viral inhibition. Therefore researchers concluded that rhesus monkey TRIM5α protein function in species specific manner.
I think the data collected to determine the effect of rhesus TRIM5α protein on HSV-1 and HSV-2 protein synthesis might contribute to find antiviral mechanism for treatment. The data indicates more inhibition of HSV infection at early stage, therefore viral protein synthesis decrease in rhesus monkey. Even though rhesus monkey TRIM5α protein does not have significant effect in treating HSV infection in human, the same mechanism can be applied to create antiviral drugs. If the antiviral drug inhibit the viral replication at early stage, it is possible to inhibit the viral protein synthesis thereby restrict its replication.