According to the study, individuals who have been virally suppressed for years with antiretroviral drugs may harbor HIV in a subpopulation of white blood cells known as myeloid cells. In the study, the researchers showed that HIV can be reactivated and infect new cells in certain myeloid cells short-lived monocytes and longer-lived monocyte-derived macrophages.
The results, which were published in Nature Microbiology, suggest that myeloid cells contribute to the long-term reservoir of HIV, making them a crucial but underutilized target in HIV eradication efforts.
“Our findings challenge the prevailing narrative that monocytes are too short-lived to be important in treatment efforts,” said study author Rebecca Veenhuis, Ph.D., assistant professor of molecular and comparative pathobiology and neurology at the Johns Hopkins University School of Medicine, Baltimore.
“Yes, the cells are short-lived, but our follow-up data show that HIV can persist in monocytes for several years in people who are virally suppressed.” The fact that we can detect HIV in these cells for such a long time suggests that something is keeping the myeloid reservoir going.”
The study, led by Veenhuis and colleagues at the Johns Hopkins University School of Medicine, was supported by the National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, and the National Institute on Drug Abuse, all of which are part of the NIH.
Antiretroviral drugs are effective in treating HIV because they prevent the virus from infecting new cells and multiplying. However, HIV can still exist in cells that are in a resting or latent state, creating an HIV reservoir. CD4 T cells, a type of white blood cell, are the best-studied reservoir of HIV.
Monocytes are immune cells that circulate in the blood for about 3 days before traveling to tissues in various parts of the body, including the brain, where they can mature into macrophages. Until now, it was not clear whether latent HIV in these cells could reactivate and infect other cells.
“Long-term, it’s really important to understand how monocytes contribute to the tissue macrophage reservoir,” explained Janice Clements, Ph.D., lead author of the study and professor of molecular and comparative pathobiology at Johns Hopkins University School of Medicine.
Detectable levels of HIV genetic material
In the study, Veenhuis, Clements and colleagues first measured HIV DNA in myeloid cells in a sample of 30 participants with HIV, all of whom were virally suppressed and had been on antiretroviral therapy for at least 5 years.
They found detectable levels of HIV genetic material in monocytes and macrophages, although the levels were much lower than those seen in CD4 T cells. In some participants, the HIV genetic material found in monocytes was intact, suggesting that it may be able to infect other cells if reactivated.
They then used a new quantitative method they developed to directly measure the spread of the HIV virus found in myeloid cells. The researchers isolated monocytes from blood samples taken from 10 participants and cultured the monocytes in cultures that contained antiretroviral drugs to replicate the participants’ baseline physical condition.
After the monocytes differentiated into macrophages, the researchers introduced an immune-activating agent and then added fresh white blood cells to allow the virus to spread to the new cells.
The researchers took samples from the cell cultures several times over the next 12 days. They included checkpoints throughout the process to ensure that infected CD4 T cells did not interfere with their measurements.
The results showed that cultures from five of the 10 participants had detectable HIV genetic material in monocyte-derived macrophages that could be reactivated to infect other cells and produce more virus. Participants who had these reactivable reservoirs of HIV in monocyte-derived macrophages had higher levels of HIV DNA material overall.
Follow-up data from three participants showed that this reservoir can be long-lived, harboring latent HIV for months to several years. These reservoirs were stable and could be reactivated over time, suggesting that monocyte-derived macrophages could contribute to viral rebound when antiretroviral therapy is discontinued.
The researchers note that this study is small, and larger studies with more diverse groups of participants will be necessary to accurately estimate the proportion of people who have latent HIV in their myeloid cells. Investigating the mechanisms that replenish the monocyte reservoir over time is a critical next step in this research.
