Findings from a small study funded by the National Institutes of Health show that myeloid cells, a subset of white blood cells, can contain HIV in persons who have been virally suppressed for years on antiretroviral medication. Researchers demonstrated in the study that HIV can be reactivated and infect new cells in certain myeloid cells—short-lived monocytes and longer-lived monocyte-derived macrophages. Myeloid cells are an important but underutilized target in attempts to eradicate HIV, according to the findings, which were published in Nature Microbiology(link is external).
According to study author Rebecca Veenhuis, Ph.D.(link is external), an assistant professor of molecular and comparative pathobiology and of neurology at Johns Hopkins University School of Medicine, Baltimore, "our findings challenge the prevailing narrative that monocytes are too short-lived to be important in cure efforts." Indeed, the cells are transient, but our follow-up results indicate that in individuals with viral suppression, HIV can survive in monocytes for a number of years. Given how long we can detect HIV in these cells, it is likely that something is sustaining the myeloid reservoir.
The National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, and the National Institute on Drug Abuse—all divisions of the NIH—all provided funding for the study, which was headed by Veenhuis and coworkers at Johns Hopkins University School of Medicine.
Because they stop the virus from replicating and infecting new cells, antiretroviral drugs are effective in treating HIV. Nonetheless, cells that are dormant or latent may still harbor HIV, forming an HIV reservoir. The most extensively researched HIV reservoir is a subset of white blood cells called CD4 T cells. Since latent HIV can become active again if people stop taking antiretroviral drugs, finding HIV reservoirs is essential to efforts to treat the disease.
Monocytes are immune cells that circulate in the blood for about 3 days before traveling to tissue in various parts of the body, including the brain, where they can mature into macrophages. To date, it has not been apparent if latent HIV in these cells can become active again and infect other cells.
Understanding how monocytes contribute to the tissue macrophage reservoir is crucial in the long run, according to senior author of the study and professor of molecular and comparative pathobiology at Johns Hopkins University School of Medicine Janice Clements, Ph.D. (link is external). "That's a real problem if resident macrophages that are self-renewing and live almost indefinitely can be infected by virus carried by monocytes to the brain, lung, or another part of the body."
A sample of 30 HIV-positive individuals who were all virally suppressed and had received antiretroviral therapy for at least five years were used in the study. Veenhuis, Clements, and colleagues first assessed the HIV DNA in myeloid cells of these participants. Monocytes and macrophages contained detectable amounts of HIV genetic material, but at considerably lower concentrations than CD4 T cells. In some participants, the HIV genetic material found in monocytes was intact, which suggests it may be capable of infecting other cells if reactivated.
Then, they directly measured viral propagation from HIV discovered in myeloid cells using the novel quantitative technique they created. To mimic the individuals' initial physical condition, the researchers extracted monocytes from blood samples taken from 10 patients and raised the monocytes in cultures containing antiretroviral medications. The researchers added an immune-activating substance after the monocytes had transformed into macrophages then added fresh white blood cells thereafter to allow the virus to propagate to other cells.
Over the course of the following 12 days, the researchers repeatedly took samples from the cell cultures. To ensure that infected CD4 T cells did not affect their measurements, they built checkpoints into the process.
The results demonstrated that cultures from five of the 10 people had detectable HIV genetic material in monocyte-derived macrophages that could be reactivated to infect other cells and produce additional virus. There were larger amounts of HIV DNA overall in the patients who had these reactivatable reservoirs of HIV in macrophages originating from monocytes.
Three participants' follow-up data revealed that this reservoir can be long-lived and can harbor latent HIV for a number of years. These reservoirs were persistent and capable of activation over time, suggesting that monocyte-derived macrophages may be involved in viral rebound in the event that antiretroviral therapy is stopped.
The study's limitations, according to the researchers, make additional studies with a wider range of participants necessary in order to determine the precise percentage of patients harboring latent HIV in myeloid cells. Investigating the mechanisms that replenish the monocyte reservoir over time is a critical next step in this research.
The head of the National Institute of Mental Health, Joshua A. Gordon, M.D., Ph.D., remarked that these findings "underscore the necessity of widening the scope of HIV cure efforts." "The research will move toward more promising approaches for eliminating HIV if it shifts away from a pure focus on CD4 T cells and toward thinking about CD 4 T cells and myeloid cells together, in context."
Findings from a small study funded by the National Institutes of Health show that myeloid cells, a subset of white blood cells, can contain HIV in persons who have been virally suppressed for years on antiretroviral medication. Researchers demonstrated in the study that HIV can be reactivated and infect new cells in certain myeloid cells—short-lived monocytes and longer-lived monocyte-derived macrophages. Myeloid cells are an important but underutilized target in attempts to eradicate HIV, according to the findings, which were published in Nature Microbiology(link is external).
According to study author Rebecca Veenhuis, Ph.D.(link is external), an assistant professor of molecular and comparative pathobiology and of neurology at Johns Hopkins University School of Medicine, Baltimore, "our findings challenge the prevailing narrative that monocytes are too short-lived to be important in cure efforts." Indeed, the cells are transient, but our follow-up results indicate that in individuals with viral suppression, HIV can survive in monocytes for a number of years. Given how long we can detect HIV in these cells, it is likely that something is sustaining the myeloid reservoir.
The National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, and the National Institute on Drug Abuse—all divisions of the NIH—all provided funding for the study, which was headed by Veenhuis and coworkers at Johns Hopkins University School of Medicine.
Because they stop the virus from replicating and infecting new cells, antiretroviral drugs are effective in treating HIV. Nonetheless, cells that are dormant or latent may still harbor HIV, forming an HIV reservoir. The most extensively researched HIV reservoir is a subset of white blood cells called CD4 T cells. Since latent HIV can become active again if people stop taking antiretroviral drugs, finding HIV reservoirs is essential to efforts to treat the disease.
Monocytes are immune cells that circulate in the blood for about 3 days before traveling to tissue in various parts of the body, including the brain, where they can mature into macrophages. To date, it has not been apparent if latent HIV in these cells can become active again and infect other cells.
Understanding how monocytes contribute to the tissue macrophage reservoir is crucial in the long run, according to senior author of the study and professor of molecular and comparative pathobiology at Johns Hopkins University School of Medicine Janice Clements, Ph.D. (link is external). "That's a real problem if resident macrophages that are self-renewing and live almost indefinitely can be infected by virus carried by monocytes to the brain, lung, or another part of the body."
A sample of 30 HIV-positive individuals who were all virally suppressed and had received antiretroviral therapy for at least five years were used in the study. Veenhuis, Clements, and colleagues first assessed the HIV DNA in myeloid cells of these participants. Monocytes and macrophages contained detectable amounts of HIV genetic material, but at considerably lower concentrations than CD4 T cells. In some participants, the HIV genetic material found in monocytes was intact, which suggests it may be capable of infecting other cells if reactivated.
Then, they directly measured viral propagation from HIV discovered in myeloid cells using the novel quantitative technique they created. To mimic the individuals' initial physical condition, the researchers extracted monocytes from blood samples taken from 10 patients and raised the monocytes in cultures containing antiretroviral medications. The researchers added an immune-activating substance after the monocytes had transformed into macrophages then added fresh white blood cells thereafter to allow the virus to propagate to other cells.
Over the course of the following 12 days, the researchers repeatedly took samples from the cell cultures. To ensure that infected CD4 T cells did not affect their measurements, they built checkpoints into the process.
The results demonstrated that cultures from five of the 10 people had detectable HIV genetic material in monocyte-derived macrophages that could be reactivated to infect other cells and produce additional virus. There were larger amounts of HIV DNA overall in the patients who had these reactivatable reservoirs of HIV in macrophages originating from monocytes.
Three participants' follow-up data revealed that this reservoir can be long-lived and can harbor latent HIV for a number of years. These reservoirs were persistent and capable of activation over time, suggesting that monocyte-derived macrophages may be involved in viral rebound in the event that antiretroviral therapy is stopped.
The study's limitations, according to the researchers, make additional studies with a wider range of participants necessary in order to determine the precise percentage of patients harboring latent HIV in myeloid cells. Investigating the mechanisms that replenish the monocyte reservoir over time is a critical next step in this research.
The head of the National Institute of Mental Health, Joshua A. Gordon, M.D., Ph.D., remarked that these findings "underscore the necessity of widening the scope of HIV cure efforts." "The research will move toward more promising approaches for eliminating HIV if it shifts away from a pure focus on CD4 T cells and toward thinking about CD 4 T cells and myeloid cells together, in context."
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