ARTICLE

What regulates HIV persistence in tissue macrophages

Where in the body persistently infected macrophages reside during HIV treatment

How macrophages respond to possible therapeutic interventions aimed at eradicating HIV from the body

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A good deal of progress has been made in the fight against HIV. Decades ago, when an individual received an HIV diagnosis, it essentially equated to a death sentence, but now, by receiving antiretroviral therapy (ART), these individuals can live longer lives with fewer side effects. Despite this, once an individual is infected, he or she has HIV for life, and the more that researchers learn about the virus, the closer they may come to finding a cure.Now, researchers from the Division of Infectious Diseases at the University of North Carolina, School of Medicine have made another interesting discovery. HIV does not only infect T cells—the virus can also “persist” in macrophages. According to the UNC press release , “The discovery of this additional viral reservoir has significant implications for HIV cure research.” Those who are actively working on a potential cure for HIV can utilize these findings to get a leg-up on the virus.“These results are paradigm changing because they demonstrate that cells other than T cells can serve as a reservoir for HIV,” lead-author Jenna Honeycutt, PhD, post-doctoral research associate in the UNC Division of Infectious Diseases said in the press release. “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.” T cells are white blood cells that are key players in protecting individuals from infection. In fact, when they detect “intruders,” such as HIV, they will elicit signals which will trigger the body’s immune system to respond. However, once an individual is infected with the virus, the virus will then attack the T cells, thus, weakening the immune system. Previous to this discovery, most “cure research” was focused on eliminating the virus from these cells.However, T cells are not the only targets of HIV. Macrophages, myeloid lineage cells, “have been shown to express CD4, CCR5, and CXCR4 and to be susceptible to HIV and [simian immunodeficiency virus] SIV infection in vitro and in vivo.” In fact, just last spring, the research team, led by J. Victor Garcia, PhD, professor of medicine, microbiology and immunology at UNC School of Medicine, was able to actually demonstrate that “tissue macrophages [were able] to support HIV replication in vivo in the total absence of human T cells.” Despite this discovery, there were still a couple of unknowns: How would macrophages respond to ART? After treatment, do macrophages serve as an additional HIV reservoir?In order to answer these questions, the team conducted another study. This study used a “humanized myeloid-only mouse (MoM) model devoid of T cells.” Their findings? ART had a suppressive effect on the virus, preventing it from replicating within the macrophages. However, “viral rebound” was detected in one third of the animals, when treatment was “interrupted.” Therefore, despite treatment, the virus was able to persist in the macrophages. According to the press release, these findings were “consistent with the establishment of persistent infection in tissue macrophages.”This is the first study to show that macrophages are not only capable of being infected with HIV, but that they are also responsive to ART, Dr. Honeycutt said.However, that’s not the only insight that the researchers gleaned from this study.“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—the major target of HIV infection,” Dr. Honeycutt explained.So, what’s next on the agenda for Dr.Garcia and his research team? According to the press release, they are going to further explore:In order to develop an effective therapeutic intervention, researchers should consider targeting this additional HIV reservoir. When thinking large scale, these findings can provide researchers with more information to add to the slowly growing HIV arsenal.