Simian TRIM5a proteins reduce replication of herpes simplex virus

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Introduction:

Herpes simplex virus has many virulence factors that enable it to replicate in various types of cells within different species. Some of the factors include wide range of surface glycoprotein's and receptors that aids in attachment and entry in various cell types. Additionally, this virus uses mechanisms such as degradation of host TRIM19/PML protein, disruption of nuclear bodies and blocks host cell chromatin-silencing mechanisms, which allows them to overcome any kind of intracellular obstacles that might interfere with viral replication. Even though, HSV can infect many species but sometimes it fails to cause disease in some species like rhesus macaques. TRIM5α is a protein that showed antiviral affects on HIV-1 infection of old world monkey cells. TRIM19/PML is a family of TRIM protein that is involved in many cellular functions including transcription, DNA repair, and act as an antiviral agent in innate immunity. Observing the structural and functional similarities between TRIM 19/PML and TRIM 5, the authors of the journal focused their interest on the function of TRIM5α to see if it can serve as an antiviral agent during HSV replication. It was hypothesized that TRIM5 protein may show antiviral effects that inhibit viruses outside of the retrovirus family (Reszka et al., 2010).

TRIM5α as an antiviral agent during HSV infection

First experiment was done to check the ability of the HSV to grow in rhesus cells. To do so rhesus monkey fibroblasts and HeLa cells lines were infected with both HSV-1 and HSV -2; the yield of the virus growth was measured at various times after the infection. It was found out that HSV-1 and HSV-2 replication is reduced in rhesus macaque fibroblasts which led to further investigation of whether the rhesus TRIM5α protein contributed to the reduced replication. To investigate, a vector was used to integrate TRIM5α gene into HeLa cells named H-R cells. H-R cells and H-L (control) were infected with both HSV-1 and HSV-2 at various MOI's. H-R cells with TRIM5α protein showed reduction in viral yield. It was observed that at low MOI, TRIM5α is able to reduce HSV replication but it cannot overcome higher MOI. Next question that arose following the experiment was to see if the origin of the TRIM5α has any effect on HSV infection. Thus, TRIM5α of various monkey origins such as African green monkey, squirrel monkey, rhesus monkey and human were compared with their effect on HSV infection. Out of all the different origins, OWM TRIM5α had the strongest antiviral activity on HSV replication while the squirrel monkey showed only little antiviral activity. On the other hand human TRIM5α had only a very little or no effect (Reszka et al., 2010).

Effects of rhesus TRIM5α protein on HSV-1 and HSV-2 protein synthesis

Effects of rhesus TRIM5α protein on HSV-1 and HSV-2 protein synthesis were measured by infecting H-L and H-R expressing rhesus monkey TRIM5α protein with HSV-1 and HSV-2 and assayed with western blot analysis. HSV-2 infected cells had less viral protein synthesis compared to the ones that were infected with HSV-1(Reszka et al., 2010).

Effects of rhesus TRIM5α on different HSV strains

H-R cells were infected with different HSV-1 and HSV-2 strains. For HSV-1, the control H-L cells were infected with HSV-1 strains F and 17syn+ at an MOI of 3. For HSV-2 the control cells were infected with HSV-2 186 syn+, G strains at an MOI of 3, and H-R cells were infected with

HSV 2-G strain, and SD90/3P strain. The infections were grown at 24 hpi and viral replication was measured by plaque assay. It was found out that effect of TRIM5α was more strain specific then species specific (Reszka et al., 2010).

Effect of TRIM5α on HSV ICP0 distribution

It was hypothesized that TRIM5α works similarly to cytoplasmic PML that keeps the infected cell within the cytoplasm and reduce viral replication. For the experiment, ICPO distribution was observed in HSV-1 KOS virus-infected H-L, H-R, and H-H cells. It was observed that rhesus TRIM5α localized with the ICPO in the cytoplasm and TRIM5α mechanism of antiviral activity did not require ICPO (Reszka et al., 2010).

Levels of TRIM5α decrease in HSV-infected cells

It was thought that HSV infection will reduce the amount of TRIM5α levels. H-R and H-L cells were mock infected or infected with HSV-1 KOS strain and HSV-2 186 syn+ strain. The infected cells were harvested at various times and western blot analysis was performed to check the levels of TRIM5α. It was observed that TRIM5α reduces viral replication and viral replication reduces TRIM5α. So it was concluded that HSV may have evolved to reduce the amount of TRIM5α to limit the restrictive ability of TRIM5α (Reszka et al., 2010).

All the experiments were very relevant to the question that was being asked. Presented data were consistent and easy to understand. The figures were very helpful in understanding the results and data. I feel that using this type of investigations, we should move toward development of vaccines using antiviral TRIM5α.

Reference

Reszka ,N., Zhou, C., Song, B., Sodroski, G. J., Knipe, M.D.(2010). Simian TRIM5α proteins

Reduce replication of herpes simplex virus. Journal of Virology.398, 243-250.

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