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Published on: March 8, 2012
Human immunodeficiency virus envelope glycoprotein/CD4-mediated fusion of nonprimate cells with human cells
P A Ashorn1, E A Berger, B Moss
1Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
Insights
Nonhuman cells can fuse with human cells during HIV envelope glycoprotein gp160 binding to CD4 molecules. Fusion is typically blocked by inhibitory factors in nonhuman cells, but can occur under specific conditions.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Human immunodeficiency virus (HIV) uses CD4 molecules and cell membrane fusion for infection.
- Mouse cells expressing CD4 bind HIV but are not infected, suggesting a fusion block.
Purpose of the Study:
- To investigate the mechanisms of CD4/gp160-mediated cell-cell fusion in various cell types.
- To determine the role of nonhuman cell factors in preventing HIV-mediated membrane fusion.
Main Methods:
- Constructed recombinant vaccinia viruses for transient expression of CD4 and HIV envelope glycoprotein gp160.
- Utilized syncytium formation assays to assess cell-cell fusion.
- Performed mixing experiments with human and nonhuman cells expressing CD4 and gp160.
Main Results:
- Human lymphoid and nonlymphoid cells showed membrane fusion mediated by CD4 and gp160.
- 23 nonhuman cell types did not exhibit fusion when expressing both CD4 and gp160.
- Nonhuman cells formed syncytia when mixed with human cells, indicating fusion capability.
- Fusion predominantly required CD4 expression on human cells, with exceptions noted.
Conclusions:
- Nonhuman cells possess intrinsic ability for CD4/gp160-mediated membrane fusion.
- Fusion is typically inhibited by factors present in nonhuman cell membranes.
- Specific conditions, including truncated gp160, can enable fusion in some nonhuman cell lines.
Abstract:
Human immunodeficiency virus (HIV) infects human cells by binding to surface CD4 molecules and directly fusing with the cell membrane. Although mouse cells expressing human CD4 bind HIV, they do not become infected, apparently because of a block in membrane fusion. To study this problem, we constructed a recombinant vaccinia virus that can infect and promote transient expression of full-length CD4 in mammalian cells. This virus, together with another vaccinia recombinant encoding biologically active HIV envelope glycoprotein gp160, allowed us to study CD4/gp160-mediated cell-cell fusion in a wide variety of human and nonhuman cells in the absence of other HIV proteins. By using syncytium formation assays in which a single cell type expressed both CD4 and gp160, we demonstrated membrane fusion in lymphoid and nonlymphoid human cells but not in any of the 23 tested nonhuman cell types, derived from African green monkey, baboon, rabbit, hamster, rat, or mouse. However, in mixing experiments with one cell type expressing CD4 and the other cell type expressing gp160, all of these nonhuman cells could form CD4/gp160-mediated syncytia when mixed with human cells; in 20 of 23 cases, membrane fusion occurred only if the CD4 molecule was expressed on the human cells whereas in the other three cases, CD4 could be expressed on either one of the fusing partners. Interestingly, in one mouse cell line, CD4-dependent syncytia formed without a human partner, but only if a C-terminally truncated form of the HIV envelope glycoprotein was employed. Our results indicate that nonhuman cells are intrinsically capable of undergoing CD4/gp160-mediated membrane fusion, but this fusion is usually prevented by the lack of helper or the presence of inhibitory factors in the nonhuman cell membranes.
