It all started about two years ago, when a patient of Jean-Pierre Routy with HIV wanted to undergo a sex change. The individual was planning to go to GRS (for ‘Gender Reassignment Surgery’) Montreal, a center that facilitates over 400 such surgeries a year. At the time, it was the only center in Canada to offer the procedure, also known as gender affirmation surgery. According to Routy, an infectious disease clinician and researcher at McGill University in Montreal, getting human testicular tissue for study is extremely difficult, so after he received consent from the individual to obtain samples of the man’s discarded testes for research once they were removed during surgery, Routy reached out to GRS Montreal. “I was probably the first person to ask GRS to share tissue,” Routy says. The tissue from the patient was delivered to his lab, and since then, Routy has received close to 100 such testicular tissue samples from GRS Montreal, of which a tenth have come specifically from people who are HIV positive.
Routy’s main research focus is on how and why viruses like HIV persist in the body. With the testicular tissue from the HIV-positive man, he was hoping to get closer to understanding this persistence. Testes (or testicles) are what are known as an ‘immune-privileged’ site, which allows sperm cells within testicles to be protected from the body’s immune system. Most cells in the body are recognized by the immune system as ‘self,’ but mature sperm are a notable exception. Since sperm cells don’t mature until puberty, the immune system doesn’t recognize sperm as ‘self,’ but rather as a foreign agent. Immune privilege prevents molecular triggers, called antigens, expressed by sperm from inciting an autoimmune attack against them. Some 20 percent of male infertility is thought to be a result of a breakdown of immune privilege, in which sperm cells are attacked and destroyed by the body.
On the flip side, immune privilege allows foreign invaders, including viruses, to find protection from the immune system within the testes. This is because antigens from invaders also do not seem to set off an inflammatory response, unlike elsewhere in the body. Routy and his team observed this to be the case when they examined testicular tissue and blood samples of six patients who were HIV positive and receiving antiretroviral therapy. All six, despite being treated with anti-HIV medication with such success that the virus was undetectable in their blood, had lingering viral DNA in at least one testicle. The result indicated the virus could evade drug treatment by finding a home in the testes.
Exactly how HIV and other viruses manage to gain entry into the testes and stay, often for years on end, without being detected by the immune system is still being worked out by scientists. The recent Zika and Ebola epidemics brought further urgency to the issue of immune privilege. Reports emerged of patients who had these viruses in their semen months after they were originally infected even though the viruses had been cleared from elsewhere in their bodies. In one of the most extreme cases, Zika virus was detected in the semen of a man in Italy at least 134 days after symptoms of the disease (mainly a fever) first emerged, even though blood and saliva samples showed no trace of the virus. A semen test done at day 188 still showed the presence of virus (his blood and saliva weren’t tested).
The testes seem to be a particularly understudied area among immune-privileged sites, which also include the eye and the brain. Human testes are less readily available than other tissue types donated to research, making it tough to validate findings in animal studies. But the dedicated few scientists in the field working with testicular tissue say that the reach of insights gleaned from studying infectious diseases that affect the testes could also help treat diseases affecting other organs, including cancer and diabetes. For now, though, much of the focus is on viruses. “If we don’t learn how [viruses] persist in the testes, then patients will continue to transmit the virus to others and put people at risk,” Routy says. Read more via Scientific America