Rat experiments revealed infertility caused by herpes virus

There are eight known herpes viruses that infect humans. Of these, Herpes Simplex Virus Type 1 affects areas around the lips and on the genitals. It has been estimated that 70 – 80% of the total Japanese population has the Type 1 virus. Herpes Simplex Virus Type 2 is generally responsible for genital herpes outbreaks, and it has been estimated almost 10% of the population has the Type 2 virus. Hence, we can say these viruses are very common. People infected by herpes virus do not always immediately develop symptoms. The virus remains latent in ganglia and spinal nerves, causing symptoms in times such as when the body’s immune system is weakened. The relationship between herpes virus infection and infertility has been mentioned and investigated, but conclusive elucidation has yet to be obtained.

To study regulation of hormone gene expression in the pituitary gland, we produced a transgenic rat (an experimental animal which expresses a foreign gene that has been deliberately introduced), which carries a gene encoding an enzyme called the human herpes virus 1 thymidine kinase. The thymidine kinase is required for viral genes to synthesize DNA. There are also therapies for viral infectious, targeting thymidine kinase of herpes virus origin. In conducting the animal experiments, we noticed that many male rats had become infertile. Therefore, we studied their testes, and found the thymidine kinase of herpes virus origin was ectopically expressed in the testis. We also observed abnormal sperm generation. In female rats, the thymidine kinase of herpes virus origin was only expressed in the pituitary. Herpes virus is known to take up residence in ganglia and spinal nerves and has not been expected to exist in the testis. The finding, however, revealed that the testis also has a mechanism for thymidine kinase gene of herpes virus origin to function. Further investigation revealed that rats expressing this enzyme gene in the testis start to have abnormal sperm at around three months old, and gradually become unable to generate sperm.

Clues to understand infertility mechanisms

The rat experiments revealed that thymidine kinase of herpes virus origin disrupts spermiogenesis and triggers male infertility. But we did not know how it applies to humans. Through collaboration with obstetricians and gynecologists in China, we were able to obtain and study samples from male infertile patients. We found that thymidine kinase of herpes virus origin is expressed in the testis in some cases. Herpes virus infection, however, does not automatically cause infertility of the carrier. When certain factors cause the herpes virus gene to be expressed in the testis, spermiogenesis becomes abnormal. We do not know what factors cause this expression. Also, we have not resolved how the expression of a herpes virus gene, particularly the thymidine kinase gene of herpes virus origin, results in inablity to generate sperm. The puzzle even deepens as we see no change in the cells surrounding the pituitary gland, where the enzyme gene is expressed. Far more research is required to identify what affects spermiogenesis.

If herpes virus infection was proved to be one etiology for male infertility, and the underlying mechanism is uncovered in the future, this research could advance into the development of diagnostic and therapeutic methods and medicines. If this research reveals the fundamental mechanism of sperm generation, it can also help develop a method to make spermiogenesis more stable, leading to enhanced reproduction capability. Expression of thymidine kinase of herpes virus origin in round spermatid cells during spermiogenesis causes abnormality or disruption of spermiogenesis. Elucidation of this mechanism might also lead to development of a male contraceptive, which temporarily disturbs spermiogenesis only when administered, without permanently shutting down spermiogenesis. In this way, one result from basic research can grow into various applications.

Solid basic research generates new applications

My primary focus is actually on basic research, including regulation of pituitary hormone gene expression and pituitary organogenesis and differentiation. As a common method used in this type of research, we produced transgenic rats. And in the process, we discovered that a thymidine kinase gene of herpes virus origin was expressed in the testis, and noticed abnormal spermiogenesis in male rats. In basic research, we first need to understand and identify what condition is normal before starting further experiments. This effort sharpens our sensitivity to notice abnormality. As a result, we think out how normal condition becomes abnormal, which, in turn, leads to better understanding of what is normal. As outcomes of applied research directly link to our lives, they often attract a great deal of public attention. Basic research, though it may appear quieter, can also be meaningful.

A single researcher would find it a huge burden to handle all the basic and applied research by him/herself. Realistically, it would be impossible in most cases. Hence, the communication between researchers in basic and applied research is necessary and important. This research on herpes virus and infertility started when a simple question emerged during our untiring experiments for a different theme. The research found its way and has developed through collaboration with obstetricians and gynecologists in China. I hope the students who are currently learning about various kinds of research remember to value basic research, and not be swayed only by the outcomes of applied research.

* The information contained herein is current as of June 2016.
* The contents of articles on M’s Opinion are based on the personal ideas and opinions of the author and do not indicate the official opinion of Meiji University.

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