In vivo, HIV-1 infects cells that express CD4, such as macrophages and CD4+ T cells, but in vitro infection of macrophages by HIV-1 is inefficient owing to their low expression of viral entry receptors. Therefore, the mechanism by which macrophages become infected with HIV-1 in vivo has been unclear. Now, Baxter et al. show that primary monocyte-derived macrophages selectively capture HIV-1-infected CD4+ T cells, which leads to efficient HIV-1 cell-to-cell spread and macrophage infection.
The authors co-cultured monocyte-derived macrophages with CD4+ T cells infected with HIV-1 isolates that use either the CC-chemokine receptor 5 or the CXC-chemokine receptor 4 viral co-receptor for entry, or with uninfected CD4+ T cells. Live-cell imaging showed that CD4+ T cells infected with either type of virus were engulfed by macrophages, whereas uninfected CD4+ T cells were not. Using multispectral flow cytometry — which measures the amount and location of multiple markers inside cells and quantifies morphologically distinct cell subpopulations — the authors quantified selective macrophage uptake of different CD4+ T cell subsets that had been labelled with markers of apoptosis or necrosis. They found that both cell death and HIV-1 infection of CD4+ T cells promoted their uptake by macrophages, and together they generated a stronger uptake signal. Thus, macrophages efficiently capture HIV-1-infected CD4+ T cells independently of the co-receptor specificity of the HIV-1 isolate.
more infectious HIV-1 was released from macrophages
Uptake of HIV-1-infected CD4+ T cells by macrophages could either lead to infection of the macrophages or phagolysosomal elimination of the infected cells. Macrophages and HIV-1-infected CD4+ T cells were co-cultured in the presence or absence of azidothymidine — a drug that inhibits replicating HIV-1 — which showed that the viral DNA content of macrophages increased more in the absence of azidothymidine than in the presence of the drug, indicating that HIV-1 is replicating in macrophages. Furthermore, the authors found that more infectious HIV-1 was released from macrophages exposed to infected CD4+ T cells than from macrophages exposed to cell-free virus. Exposing co-cultures of macrophages and HIV-1-infected CD4+ T cells to inhibitors of HIV-1 T cell entry reduced macrophage infection, although infected CD4+ T cells were still taken up by the macrophages. Moreover, despite the avid macrophage capture of T cells infected with non-macrophage-tropic HIV-1, these viruses were unable to infect the macrophages. Together, these results demonstrate that infected T cells are captured by macrophages and this results in subsequent macrophage infection.
Finally, the authors investigated the mechanisms of macrophage uptake of infected CD4+ T cells. HIV-1 is known to spread between CD4+ T cells by forming a supramolecular structure called the 'virological synapse' and this is dependent on the expression of the viral envelope glycoprotein. However, experiments using a large set of inhibitors or a virus without the envelope glycoprotein showed that macrophage uptake of infected T cells was independent of HIV-1 envelope glycoprotein–receptor interactions; thus, the uptake and spread of HIV-1 in macrophages is not mediated by conventional virological synapse signals.
In summary, these data show that macrophages capture HIV-1-infected CD4+ T cells, which leads to efficient macrophage infection. This can have important implications for the spread of viruses to macrophages in vivo.
References
Baxter, A. E. et al. Macrophage infection via selective capture of HIV-1-infected CD4+ T cells. Cell Host Microbe http://dx.doi.org/10.1016/j.chom.2014.10.010 (2014)
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Kugelberg, E. Capturing HIV-infected T cells. Nat Rev Immunol 15, 3 (2015). https://doi.org/10.1038/nri3794
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DOI: https://doi.org/10.1038/nri3794
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