La Jolla, California (January 18, 2020). A new study published in the Journal of Clinical Investigation enrolled people with HIV who also happened to have a terminal illness to study where HIV hides in the human body so doctors can better treat and maybe even cure HIV.
Selfless Terminally Ill Persons Join Doctors To Study HIV
Despite understanding that HIV exists throughout the human body, researchers working toward a cure of HIV do not understand how HIV populates deep tissues. "Unfortunately, we simply cannot know the answer until a person is deceased and subject to an autopsy. Delays between death and when tissues are collected means the virus degrades, obscuring where HIV really hides," said Davey Smith, MD, the senior author and Chief of Infectious Diseases and Global Public Health at UC San Diego.
To fill this gap, the team turned to terminally ill persons who happened to have HIV, and with their consent, the team serially collected blood while the person was alive, and then performed a rapid autopsy at the time of their death. "This donation at the end of one's life is the first of its kind in HIV research, and allowed us to discover all the places HIV hides, even during treatment where the virus is difficult to detect in standard blood tests."
Terminally ill volunteers were eager to support this groundbreaking work. "Our participants have HIV but are dying of something else, like cancer. They are going through a lot, but they still want to leave a larger legacy behind and help find a cure for HIV," said Sara Gianella, MD, assistant professor at UC San Diego Health and study coauthor. Study participants were either self-referred from hearing about the study or referred from their primary HIV providers. "Only one potential volunteer decided ultimately not to participate," added Dr. Gianella."It is an amazing gift from both the participants and their families."
Where does HIV hide?
Study investigators found HIV in every one of the 30 organ sites they studied, even when the deceased participant was taking modern HIV therapy . When the virus was sequenced, some of the virus had genetic defects, which meant that it was nonfunctional or likely 'dead', but most of the virus seemed to be intact and able to grow.
"As expected, most of the HIV was in the blood, gut and lymph nodes," said Antoine Chaillon, MD, PhD, assistant professor in the Division of Infectious Diseases and Global Public Health at UC San Diego and the study's lead author. "But, intact HIV was also found in the brain, liver, spleen, kidney, basically everywhere."
It seems that having HIV in all these tissues can cause problems, even when someone is taking HIV therapy, and active HIV growth is 'undetectable' in blood. Being 'undetectable' in blood means that a person's HIV therapy has basically stopped the growth of HIV in the blood. Although antiretroviral therapy can keep HIV from replicating, it does not stop all of the problems associated with HIV. Persons with HIV have more inflammation-related diseases, like heart attacks, stroke and cancer, than people who do not have HIV. "We do not fully know why," Dr. Gianella said. "We think that when HIV tries to regrow in each of these tissues where it was lying dormant, it can cause an inflammatory response. Even though the antiretroviral therapy keeps it from fully replicating, it still causes local damage."
"Yes," Dr. Smith added. "For example, half of persons with HIV have neurocognitive impairment even when taking the very best HIV therapy. How HIV causes local inflammation in the brain, even during therapy, may explain this."
"Further improving the health of people with HIV likely means we need to figure out how to clear HIV from its hiding places," Dr. Chaillon said. "This means new therapies."
How HIV moves in the body?
Two of the study's participants had stopped taking their HIV therapy, leading to even more new insights. "Sometimes when people have a terminal illness they don't want to keep taking their medicines anymore," Dr. Gianella explained. "This gave us a unique opportunity to study how the virus replicated and moved in the body while the virus was untreated. We collected the participant's blood before and after stopping their therapy, while they were alive, and then we collected all the tissues after they died. Since HIV evolves quickly within a person, we were able to identify the same viruses that restarted replicating in the blood after the person stopped their therapy in all their tissues after death."
"We expected the replicating virus to seed blood cells and cells in the gut and lymph nodes," added Dr. Chaillon, "but we were surprised at how quickly the virus was everywhere!" The team used new analytical methods, to find that the virus moved between tissues in the body. Cells in the blood and the gut seemed to be the source of most HIV in the rest of the body, and most HIV was trafficked through the body by the blood.
What does this mean for curing HIV?
Developing a way to keep HIV from replicating when therapy is stopped, often called 'therapy free remission', is a major goal for HIV researchers. Two people seem to have achieved this goal through treatments with special bone marrow transplants. "But even in these patients they still have intact virus throughout their body, even if it cannot get to the bloodstream," said Dr. Smith. "Our study found that HIV was mainly trafficked through the body in the blood. This might explain why we saw therapy-free remission in the two persons with bone marrow transplants," Dr. Smith explained. "After the transplants, their blood cells were protected and could no longer carry HIV. They still have intact virus throughout their body, but it can't get to the bloodstream to start replicating."
"But, HIV in these tissues still likely cause local inflammation and damage," Dr. Chaillon added. "We need new ways to clear those places and extensions of our work can some day answer how."
Journal of Clinical Investigation