New research shows HIV can lie dormant in the brain

As part of its life cycle, human immunodeficiency virus-1 (HIV) inserts a copy of its DNA into human immune cells. Some of these newly infected immune cells can then transition into an inactive and latent state for long periods of time, which is known as HIV latency.

While current therapies, such as current antiretroviral therapy (ART), can successfully block further viral replication, they cannot eradicate latent HIV. If treatment is stopped, the virus can recover from latency and restart the progression of HIV infection to AIDS.

Scientists from the HIV Cure Center at UNC School of Medicine, University of California San Diego, Emory University, and University of Pennsylvania have been looking for exactly where these latent cells lurk in the body. New research published in Journal of Clinical Investigation confirmed that microglial cells – which are specialized immune cells with a decade-long lifespan in the brain – could serve as a stable viral reservoir for latent HIV.

“We now know that microglial cells serve as a persistent brain reservoir,” said first author Yuyang Tang, PhD, assistant professor of medicine in the Division of Infectious Diseases and a member of UNC’s HIV Treatment Center. “This has been suspected in the past, but evidence in humans has been lacking. Our method for isolating viable brain cells provides a new framework for future studies in the central nervous system reservoir, and, ultimately, efforts towards eradicating HIV.”

latent HIV

HIV is a complex and unique virus to study. During infection, the virus specifically targets key coordinators of the immune response, called CD4+ lymphocytes. Over time, the virus kills enough CD4+ cells to cause immune deficiency. .

Previous research has shown that latent HIV can hide in some surviving CD4+ T cells throughout the body and bloodstream. However, another viral reservoir is thought to be lurking within the central nervous system (CNS) in people with HIV who are receiving effective HAART.

Unlike peripheral blood cells, it is very difficult to access and analyze brain tissue to study the HIV reservoir. Because these cell types cannot be sampled safely in people on ART, the potential reservoir of the virus in the brain has remained an enigma for many years.

Pure Brain Tissue Extraction

The team first studied the brains of monkeys with simian immunodeficiency virus (SIV), a virus closely related to HIV, from the Yerkes National Primate Research Center at Emory University to gain a better understanding of how to extract and purify viable cells from primate brain tissue.

Researchers used physical separation techniques and antibodies to selectively remove cells expressing microglial surface markers. Then, they isolated and separated highly purified brain myeloid cells from CD4+ cells that passed through brain tissue.

Using this technique, the researchers then obtained samples donated by HIV+ people enrolled in The Last Gift Study at the University of California San Diego (UCSD). As part of this unique and important effort, altruistic HIV+ people, who are on ART but suffer from other terminal illnesses, want their bodies to continue the HIV research project.

“The sample came from people living with HIV, who are on therapy but dealing with fatal disease,” said co-author David Margolis, MD, Sarah Kenan Professor of Medicine, Microbiology & Immunology, and Epidemiology. “They were willing not only to donate their bodies to science, but also to participate in research programs in the months leading up to their deaths. This is an amazing program that makes this critical research possible.”

Future Projects

Now that researchers know that latent HIV can take refuge in microglial cells in the brain, they are now considering plans to target this type of reservoir. Because latent HIV in the brain is radically different from the virus in the periphery, researchers believe that HIV has adapted special characteristics to replicate in the brain.

“HIV is very smart,” says senior author Guochun Jiang, PhD, an assistant professor in the UNC Department of Biochemistry and Biophysics and a member of the UNC Center for HIV Treatment. “Over time, it has evolved to have epigenetic control over its expression, silencing the virus to hide in the brain from immune clearance. We are beginning to unravel the unique mechanisms that enable HIV latency in brain microglia.”

NF-κB signaling is one of the important signaling pathways that controls HIV expression elsewhere in the body. When NF-κB signaling is “turned off”, HIV enters latency in the peripheral blood. However, latent HIV in the brain is not affected by activation of NF-κB signaling. Researchers aren’t sure why this is, but once an answer is found, they will be one step closer to figuring out how to selectively target and eradicate the virus in the brain or peripheral blood. In addition to understanding the inner workings of the brain reservoir, researchers are also trying to determine the true size of the latent HIV brain reservoir.

“It’s very hard to know how big the reservoir is,” said Margolis, who is also the director of the UNC HIV Treatment Center. “The problem with trying to eradicate HIV is like trying to eradicate cancer. You want to be able to get it all, so it’s not coming back.