TRIM5A Proteins Reduce Replication Of Herpes Simplex Virus Biology Essay

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Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as Human herpes virus 1 and 2 (HHV-1 and -2), are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and -2 are ubiquitous and contagious (Shors, 409). They can be spread when an infected person is producing and shedding the virus. This virus has been interest of all scientists for many years and many studies have been done. The article titled "Simian TRIM5α proteins reduce replication of herpes simplex virus" sets out to show that TRIM5α proteins can inhibit the HSV replication with assists of TRIM5α protein of rhesus macaques.

Herpes simplex virus has a broad host range because it has around 12 envelope surface which can facilitate entry to the cell, uses lots of moiety of cell surface and has many mechanisms to manipulate intracellular blocks to replication (Reszka et al. 243). Rhesus macaques are used in this article because it is an excellent model for HIV. TRIM5α belongs to the TRIM protein family. It is a retrovirus restriction factor, which mediates species-specific, early block to retrovirus infection. The TRIM protein family is involved in many different processes in the cell. For instance, TRIM19/PML interferes with the replication of several DNA and RNA viruses such as HSV-1.

TRIM19/PLM and TRIM5α protein have structural and functional similarities, so based by this information Natalia Reszka et al. asked if TRIM5α might manipulate HSV replication. They hypothesize that TRIM5α protein could show effects that inhibit viruses outside of the retrovirus family. "These antiviral effects may be countered in some cases, such as late times in cells infected with HSV, by down regulation of TRIM5α levels during the late phase of infection" (Reszka et al. 244).


This article uses many researches and experiments to support their hypothesis. These are the few experiments that been used.

HSV-1 and HSV-2 replication is reduced in rhesus macaque fibroblasts;

The replication of HSV-1 and 2 in rhesus monkey fibroblast were investigated and compared to with the replication of these viruses in Hela cells. Both cell lines were infected with HSV-1and HSV-2 at an MOI of 3 PFU/cell. As a result, HSV-1 and HSV-2 from rhesus monkey fibroblast were reduced significantly compared to Hela calls.

Rhesus TRIM5α proteins restricts HSV infection;

In this experiment, they used H-L and H-R which is the empty pLPCX and rhesus TRIM5α respectively. The H-R and H-L were infected with HSV-1 KOS and HSV-2 186. The reduction of HSV was shown at low MOI =30. In addition, the HSV-1 KOS virus which infected H-R cells were reduced by 2 folds and the HSV-2 186 replication was reduced by 5 folds compared to infection of H-L cells.

Effects of other primates TRIM5α molecules on HSV infection;

The effects of TRIM5a protein on retrovirus infection depend on the animal of origin, so the effects of TRIM5α protein sources were investigating in this experiment. Therefore, the effects of TRIM5α protein on viral replication was compared between different HeLa cell lines; H-AGM cells, H-Sq cell, H-R cells, H-H cells, and H-L cells. As a result of all the TRIM5a primate molecules observed, NWM only moderately inhibited HSV-2 replication. OWM TRIM5a proteins displayed the highest levels of inhibitory activity on HSV-2 replication.

Effects of rhesus TRIM5a proteins on HSV-1 and HSV-2 protein synthesis;

Based by the theory that the TRIM5α protein's restrictive activity has an effect at early stage of infection, so the rhesus monkey TRIM5α protein's restrictive activity was examined. It was measured with Western blots. The cells were harvested at the time s indicated, and viral protein expression was analyzed by Western blotting using anti-ICP4, ICP27 and ICP8 antibodies. As a result the HSV-2 infected cells had a greater reduction compared to HSV-1. Therefore, the reduction in HSV-2 replication in H-R cells could be clarified by a similar reduction in IE and E genes expression.

Effects of rhesus TRIM5a on different HSV strains;

The H-R and the H-L cells were infected with the low passage HSV-2 clinical isolate SD90-3P. Also, in the second set of experiments the H-R and H-L cells were infected with HSV-1 low passage laboratory strain 17 syn+. As a result, both HSV-1 and Hsv-2 strains were inhibited by TRIM5a, but the inhibition of HSV-2 were greater than HSV-1. In other words, the "inhibition of HSV replication in TRIM5 expressing cells appeared to be more viral strain-specific than species-specific" (Reszka et al. 245).

Effects of TRIM5a on HSV ICPO distribution;

ICP is an infected cell protein, which made by HSV during the earlier stage of infection. Also, ICPO activates transcription of several viral genes. McNally et al. reported that PML, another protein in the TRIM family, retained ICPO in the cytoplasm resulting in less viral replication (protein needs to reach nucleus to affect gene transcription), so the scientists of this article wanted to know if TRIM5α had a similar effect on ICPO. They used immunohistochemistry to visualize the amount and location of ICPO in HSV infected H-L, H-R, and H-H cells. Also, they performed a mock infection of each of the 3 cell types. As a result, More H-R cells showed cytoplasmic ICPO at 4 hours past infection. At 8 hours past infection, they showed decreased nuclear ICPO and increased cytoplasmic ICPO. This shows that TRIM5α's ability to reduce replication of HSV in old world monkeys may be due to its ability to sequester high-levels of ICPO in the cytoplasm, preventing it from activating viral gene transcription in the nucleus.

Effect of TRIM5a on HSV-1 ICPO- mutant replication;

The H-L and H-R cells were infected with ICPO null and rescued viruses and were measured at 24hpi. Based by the table 1, it shows that the TRIM5α inhibition of HSV replication is most likely not dependant on ICPO.


In conclusion, this research article did support their hypotheses which indicate specific forms of simian TRIM5α proteins can restrict herpes simplex virus infection. They examined on HSV infection in HeLa cell lines. They showed that several TRIM5α proteins can limit HSV replication with the TRIM5α proteins of rhesus macaques which was the strongest inhibition of HSV infection. Also, they determine that the inhibition of virus replication was viral strain-specific. Also, they conclude TRIM5α is inhibiting the HSV at early stage of infection.

Furthermore, TRIM5α might sequester ICP0 in the cytoplasm, preventing its nuclear functions, and thereby inhibiting HSV replication. The absence of ICP0 did not affect the restriction of HSV-1 by TRIM5α. Data shows the level of TRIM5α inhibition in HSV-infected cells is independent of the presence of ICP0. Because all forms of TRIM5α were reduced in HSV-infected cells regardless of their level of restrictive activity, the level of reduction seems to not be the primary determinant of activity. In addition, ICP0 was not required for the loss of TRIM5α from infected cells (not shown); thus, the reduction in levels of TRIM5α appears to occur by a different mechanism from the mechanism of PML degradation promoted by ICP0.

The data in this experiment did support their hypotheses. There were many methods and data which were used in this article such as western blotting and immunohistochemistry. In general, the data was precious and accurate and it was a detail oriented report on the data. This research can go for further investigation on HSV vaccines. In addition, usage of human cells instead of rhesus macaques cell and have a better explanation on the effect of TRIM5α proteins in other retroviruses.