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Nipping HIV Transfer from Monocyte Derived Dendritic Cells in the Bud

Jul 4, 2016 1:00:15 PM / by Steffen Porwollik

HIV - stock-photo-digital-illustration-of-hiv-virus-in-blood-stream-in-color-background-165731567-207167-edited.jpgDuring HIV infection, the virus is taken up by dendritic cell populations (modeled in vitro by monocyte derived dendritic cells, MDDC), which subsequently transfer the virus to T lymphocytes. Scientists identified MDDC processes that affect transfer success – revealing ways to prevent early virus dissemination.

Dendritic cells are the human body’s border patrol. Many of these cells circulate in body areas that are in contact with the outer world, such as the linings of the stomach and nose or in the skin. When they encounter a foreign (and possibly dangerous) object, they swiftly scoop it up and present its characteristics to the authorities, the cell-mediated immune system in the form of T cells. Once the T cells have received the invader's footprint, they spring into action by replicating and secreting cytokines that shape the body’s immune response, eventually neutralizing the intruder.

Vexingly, the human immunodeficiency virus (HIV) has found a way to use this mechanism to get a free shuttle ride to the CD4+ T helper cells it prefers as replication vessels (the virus can also replicate in macrophages). Dendritic cells are the first cells that encounter and bind HIV during viral transmission in the body, and the virus has developed strategies to make sure that it gets presented very efficiently to the CD4+ T helper cells. Once docked, it stays close to the cell surface and is not migrating inside the dendritic cells, to avoid lysis and alarm. Small numbers of HIV can therefore wreak havoc and infect many CD4+ T cells. New York scientists recently investigated the molecular details of this process (called trans-enhancement), and their results reveal novel genes with vital impact on virus transfer. [1]

The researchers used a technique called small hairpin RNA (shRNA) gene knockdown, where a collection of shRNA molecules is transduced into cells. These shRNAs turn off expression of genes that contain corresponding sequences. When the monocyte derived dendritic cells (MDDCs) were transduced with shRNAs representing 455 genes involved in vesicular and membrane trafficking, molecules representing 43 genes reduced successful HIV transmission onto T lymphocytes by at least 30%. Two of these genes, TSPAN7 and DMN2, were examined further.

Preventing expression of TSPAN7 resulted in the inability of the monocyte derived dendritic cells to form their characteristic dendrite structures, and the emergence of so-called bleb structures, bulging buds of the plasma membrane. HIV particles, which would usually reside in dendrites, now relocated to intracellular cytosolic compartments, formed via macropinocytosis through bleb retraction. In contrast to lowering TSPAN7, reducing expression of DMN2 had no effect on dendrite formation – but the virus still relocated to cytosolic compartments in the MDDCs. Both of these genes were necessary to form a stable actin barrier in the monocyte derived dendritic cells, to limit intracellular HIV uptake. When actomyosin contraction – a process needed for bleb formation - was inhibited, virus-filled dendrites re-appeared, and HIV transfer from monocyte derived dendritic cells to T cells was restored to wild type levels, for both genes. In conclusion, the researchers suggested that “[e]ffectors of actin nucleation and stabilization [such as TSPAN7 and DMN2] are critical regulators of the transfer of HIV-1 particles from human dendritic cells to T cells and may serve as potential targets to limit viral propagation.

At HemaCare, we think research efforts like these are of immense importance in our fight against HIV. We offer monocyte derived dendritic cells, CD4+ T helper cells and HIV-relevant cell populations and blood components - and customize any cell population or product you desire, to cost-effectively further your research. Please contact us at (877) 397-3087, and tell us how we can be of assistance to you.

Reference

[1] Ménager MM & Littman DR. Actin Dynamics Regulates Dendritic Cell-Mediated Transfer of HIV-1 to T Cells. Cell 2016 Feb 11;164(4):695-709.

Topics: Dendritic Cells, T Cells, Infectious Disease

Steffen Porwollik

Written by Steffen Porwollik

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