HIV Discriminates Amongst Cells

May 11, 1998

Researchers at Johns Hopkins have discovered that the human immunodeficiency virus (HIV) depends on the moving parts of a cell's surface in order to enter the cell. "The white blood cell has an intricate semi-rigid structural framework that is both pliable and mobile. It can assemble and disassemble rapidly in response to internal and external signals. This allows the cell to migrate across blood vessel walls and squeeze through small spaces," said David H. Schwartz, MD, PhD, associate professor, Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, who co-authored the paper with Sujatha Iyengar, PhD, research associate, and James E.K. Hildreth, MD, PhD, associate professor, Hopkins School of Medicine. Their study appeared in the current issue of the Journal of Virology.

The implications could be significant. "The clustering transmits signals to the cell that could be important for HIV replication," said Dr. Iyengar. She said that the findings could be relevant to many other kinds of viruses that use specific cell receptors. "A requirement for contracting actin in the target cell could also be a mechanism that prevents HIV from entering inactive cells, or cells in the early stages of cell death. We know that these are poor host cells for viral replication, and they don't have an active actin filament network to pull surface molecules together," Dr. Schwartz added. Dr. Hildreth and his colleagues cautioned that speculations about the role of receptor signaling in virus replication and the selective advantage to HIV of entering cells with intact actin remain unproven at this time. However, these roles are being tested.

Actin, a protein also used in muscles, is organized in a lattice just under the surface of the cell. Many protein molecules on the surface of the cell have tails that pass through the cell membrane and project into the cell. Through additional connecting proteins, actin can pull together the tails of proteins projecting through the cell membrane so that they cluster together on the outer surface of the cell. Two of these surface proteins, CD4 and fusin, also serve as receptors for HIV by binding the envelope spikes sticking out from the virus. The Hopkins investigators showed that HIV envelope binding to CD4 and fusin causes them to be concentrated by the actin network to one end of the cell.

To visualize the movement of cell surface receptors in response to HIV envelope, the team labeled the receptors with fluorescent antibody tags and took photographs through a specially designed microscope. Cytochalasin D, a compound that prevents actin filaments from forming, was used to inhibit the movement of CD4 and fusin. It also blocked viral entry.

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This work was supported in part by the National Institutes of Health and The American Cancer Society.
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Johns Hopkins University Bloomberg School of Public Health

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