HIV Hides In More Reservoirs In the Body, Researchers
The challenge of developing an HIV cure may have just gotten even more challenging. While most HIV research has focused on finding ways to wipe out the virus from the immune system’s T-cells, a new study has just determined that a new strategy may be in order.
In the study, published in the journal Nature Medicine, researchers from the University of North Carolina’s division of infectious diseases have discovered that HIV persists in macrophages—large white blood cells that reside in the brain, bone marrow, liver and many other tissues all over the body.
Macrophages, like T-cells, are part of the immune system and are found throughout the body, including in the liver, lungs, bone marrow and brain. After other immune cells destroyed foreign invaders, these large white blood cells act as the cleanup crew. They surround and clean up cellular debris, foreign substances, cancer cells and anything else that is not essential to the functioning of healthy cells.
The major obstacle when it comes to developing a cure for HIV is that the virus can remain in reservoirs of infected cells that persist for long periods of time even after the presence of successful highly active antiretroviral therapy (HAART). The virus lies dormant in these reservoirs and can re-emerge and restart an infection at any time, which is why some patients seem to be “cured” of the virus after treatments, only to show signs of the infection again when the treatment ends.
Scientists thought that the virus could only reside in T-cells due to their long life span of several years, and their ability to reactivate upon encounter with their cognate antigen or other stimulation.
Up until this study, researchers around the world focused on new approaches to cure HIV by targeting T-cells. For example, in October, scientists at the University of California at San Francisco announced they have developed a CRISPR gene-editing platform to modify immune cells so they can fight the infection. And a team at Temple University showed they could use CRISPR to eliminate HIV from T-cells.
While research has been dedicated to trying to find ways to eradicate the T-cell reservoir, now they may have to find ways to eliminate HIV from macrophages as well. The discovery that macrophage cells can act as additional viral reservoirs will have significant implications for HIV cure research.
"These results are paradigm-changing because they demonstrate that cells other than T-cells can serve as a reservoir for HIV," said Jenna Honeycutt, Ph.D., lead-author and postdoctoral research associate in the UNC Division of Infectious Diseases. "The fact that HIV-infected macrophages can persist means that any possible therapeutic intervention to eradicate HIV might have to target two very different types of cells."
The discovery builds on previous mouse studies at UNC’s school of medicine that showed the ability of macrophages to foster HIV. Using a mouse model, investigators demonstrated that even in the absence of humanized T-cells, antiretroviral drugs could strongly suppress HIV in macrophages. However, when the therapy was interrupted, the virus rebounded in one-third of the mice. The rebounding of the virus proves that HIV can persist in latent macrophage cells even when no T-cells are present.
Researchers say their work demonstrates that any possible therapies must address macrophages in addition to T-cells to eradicate viral reservoirs. Investigators say they now have more information pointing to the complexity of the virus, and that targeting the viral reservoir in T-cells in the blood will not necessarily work with tackling HIV persistence in macrophages, which reside in tissues and are harder to observe.
It’s also possible that there are additional HIV reservoirs still to be discovered, according to Victor Garcia, the senior author of the study.
"This is the first report demonstrating that tissue macrophages can be infected and that they respond to antiretroviral therapy," Honeycutt said. "In addition, we show that productively infected macrophages can persist despite ART; and most importantly, that they can reinitiate and sustain infection upon therapy interruption even in the absence of T-cells, which are the major target of HIV infection."
Now that Garcia and his team know that HIV does persist in macrophages, the next step is to figure out how the virus does so. Researchers need to determine how HIV is able to persist in macrophages, where in the body infected macrophages tend to reside, and how macrophages will respond to therapy interventions aimed at eradicating HIV from the body.