HIV-1 Glycoprotein 41 Ectodomain Induces Activation of the CD74 Protein-mediated Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway to Enhance Viral Infection

Abstract

Besides mediating the viral entry process, the human immunodeficiency virus (HIV-1) envelope protein gp41 can bind to many host cell components and regulate cell functions. Using a yeast two-hybrid system, we screened a human bone marrow cDNA library and identified a novel gp41-binding protein, CD74 (the MHC class II-associated invariant chain). Here, we report possible biological effects mediated by interaction between gp41 and CD74. We found that HIV-1 gp41 could bind directly to host CD74 in HIV-1-infected cells, and the peptide 6358 derived from gp41 loop region (aa 597-611) could effectively block the gp41-CD74 interaction. As a result of this binding, recombinant soluble gp41 and gp41 peptide 6358 activated the CD74-mediated ERK/MAPK pathway and significantly enhanced HIV-1 infection in vitro. Conversely, the enhancing effect could be suppressed by the recombinant CD74 extracellular domain. These results reveal a novel mechanism underlying gp41 mediation of HIV-1 infection and replication.The human immunodeficiency virus type I (HIV-1) envelope glycoprotein (Env) 4 transmembrane subunit gp41 has been confirmed to play a central role in syncytium formation and HIV infection (1, 2). Its extracellular domain contains four major regions, including fusion peptide, N-terminal heptad repeats, loop, and C-terminal heptad repeats. The gp41 trimer is embedded in the virus membrane and covered by surface protein gp120 (3). In a current membrane fusion model, gp120 first binds to cell surface CD4 and a chemokine receptor (CCR5/CXCR4), resulting in a conformational change of the complex and the exposure of gp41. Then the gp41 trimer ejects and inserts its fusion peptides into the target cell membrane. After that, the N-terminal heptad repeats and the C-terminal heptad repeats of gp41 are rearranged to form a stable six-helix bundle that brings the membranes of both virus and cells into close proximity to finally accomplish the fusion process and infection of the target cells (4, 5).It has been shown that the HIV-1 Env surface subunit gp120 can interact with cell surface receptor CD4 and a coreceptor CCR5 or CXCR4 to induce cascades of cell signals for assisting viral infection (6 -11). Although we know that the HIV-1 gp41 could change conformation triggered by gp120-CD4 interaction and mediate virus-cell fusion, it is unclear whether gp41 itself can interact with the cell surface proteins to trigger cell signals for regulating viral infection and host cell function.We and others have demonstrated that besides its involvement in the viral entry process, gp41 could also regulate cell functions by interacting with a variety of cellular proteins. For instance, the recombinant soluble gp41 (rsgp41) could selectively enhance the surface expression of MHC-1 and ICAM-1 (12), as well as inhibit spontaneous proliferation of human cell lines, including H9, Raji, and U937 (13). A recent study found that gp41 modulates the proliferation of T lymphocytes through its transmembrane region (14). Moreover, gp41 could regulate the expr...

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“…[52] Antigen presentation antagonism HIV-1 gp41 interacts with HLA-associated invariant chain and may have a role in MHC-directed antagonism. [28,53] doi:10.1371/journal.ppat.1003258.t001 , but nine proteins are produced due to editing events in the GP gene. The GP gene primary transcript encodes for a ,110 kDa, dimeric secreted GP (pre-sGP).…”

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