HIV Persistent, but Inert, in Liver Macrophages

New research suggests liver macrophages should not be considered an HIV reservoir, and thus should not be considered a target for HIV therapies.

A new proof-of-concept study finds that although HIV persists in liver macrophages when a patient is taking antiretroviral therapy, the virus is inert in patients on long-term antiretroviral therapy, and thus is unlikely to replicate.

The findings, published in The Journal of Clinical Investigation, suggest that liver macrophages should not be considered HIV reservoirs, since it appears the cells are unable to replicate the virus.

Ashwin Balagopal, MD, an associate professor of medicine at the Johns Hopkins University School of Medicine and the study’s senior author, said his research ought to serve as a signpost for scientists developing new treatment targets for HIV.

Dr. Balagopal noted that the bulk of current research has been targeting resting memory CD4+ T cells (rmT cells), which are the most common HIV reservoirs. Although those are a clear target for scientists, less is known about whether other potential types of cells are worthwhile targets.

“Tissue macrophages have [been] known to be susceptible to HIV infection while also being long lived like rmT cells,” Dr. Balagopal told Contagion®. “Unfortunately, there is a dearth in data on their ability to serve as cellular reservoirs for HIV.”

Dr. Balagopal and colleagues evaluated the potential of liver macrophages using similar experiments to those used to explicate the role of rmT cells. However, in the case of liver macrophages, the results were different.

“Our findings show that current strategies should have a narrower focus on rmT cells,” he explained.

Asked if it would make a significant dent in the time it takes drug developers to create therapies to target HIV reservoirs, Dr. Balagopal said, “[w]hile it may not make it significantly shorter or easier, it serves as encouragement to the scientific community to press on with current strategies.”

The study centered on tissue samples from 9 patients. Of those, 7 had undergone liver transplantation at Johns Hopkins. Eight of the 9 had been taking antiretroviral therapy for a period ranging from 8 months to more than 12 years. After separating out liver macrophages from the liver tissues, the investigators found HIV-1 was still present, even in the patient who had been on antiretroviral therapy for more than a decade. However, the virus in the liver macrophages was found to be inert, meaning it was not a replication threat. Thus, despite the durability of the virus in these cells, it’s unlikely that these cells could pose a major replication threat. Dr. Balagopal said that was even the case for the patient who had been on antiretroviral therapy for less than a year.

“While the person who took antiretroviral therapy for 8 months released infectious virus, it did not replicate exponentially as observed typically from HIV-1 infected rmCD4+ T cells,” he said. “It is possible that this virus would indeed be infectious. However, we infer from our findings that for people who are exposed to antiretroviral therapy for a year or more, it is unlikely that liver macrophage-derived virus would be infectious.”

According to Dr. Balagopal, this study, though small, will hopefully serve as an additional puzzle piece for investigators working to cure HIV once and for all. He said related questions that will need to be answered include whether HIV-infected liver macrophages present viral antigens that could affect an adaptive immune response, and whether HIV infection affects liver macrophage function.