Researchers identify new behavior for the human macrophage

Researchers at the Institute of Human Virology of the University of Maryland School of Medicine have identified a new behavior for the human macrophage that provides new explanations for several features of HIV biology, including how the virus persists within the body indefinitely, how quiescently infected CD4+ T-cells arise, and how the infection leads to depletion of CD4+ T-cells. The research team found that macrophages cultured from human blood can function as "nurse cells" and in this capacity, generate and release newly formed cells. The new cells released include a previously unknown small cell, termed "self-renewing monocytoid cell" (SRMC) that is highly susceptible to infection with HIV. This small cell can develop into another nurse macrophage that can, in turn, produce another small cell. This nurse macrophage/small cell developmental cycle can continue in culture for several generations, even during continuous production of HIV. Current anti-HIV drugs cannot inhibit HIV maintained through this process, because they act to prevent new infection. The nurse macrophage/small cell cycle does not require infection of new cells and for this reason, it may help to explain, along with latently infected long-lived cells, how "wildtype" HIV strains -- those lacking drug resistance mutations -- are maintained within the body during years of uninterrupted anti-HIV therapy. The researchers emphasize that although working with HIV led them to recognize nurse macrophage behavior, all of the phenomena observed can be seen in uninfected, as well as HIV-infected macrophage cultures.    

Amazingly, nurse macrophages can also produce CD4+ T-cells, which are released as resting cells. These cells are a specific subtype of CD4+ T-cells, the subtype preferentially targeted by HIV. The researchers observed a dramatic decline in T-cell production in HIV-infected macrophage cultures, as well as release of resting CD4+ T-cells that contained HIV DNA, but were not producing the virus. These findings suggest that nurse macrophages may represent a source of latently infected CD4+ T-cells, and that compromise of nurse macrophage production of CD4+ T-cells, brought about by HIV infection, may contribute to the CD4+ T-cell decline that characterizes AIDS. Dr. Suzanne Gartner, the leader of the Institute's stem cell research team, notes, "Thus far, the experiments have been performed using macrophages obtained from blood, and then cultured in the laboratory. We are now trying to determine if these phenomena are operational in vivo -- within the human body." Dr. Robert C. Gallo, Director of the Institute of Human Virology adds, "The concept that a cell can be produced within another cell, a 'mother' cell, is new -- at least in human biology -- and thought-provoking, and it makes sense that a virus would exploit this process as a survival strategy. Of course, the phenomena must be documented directly in patients, but it is likely that these concepts will ultimately impact several fields. In fact, this observation in vitro does demonstrate that at least some macrophages have a capacity never before described." Gartner and her coauthors at the Institute, Drs. Yiling Liu and Senthilkumar Natesan, began this work while they were members of the Department of Neurology at Johns Hopkins University.

Source: PLoS ONE