Formation of syncytia is repressed by tetraspanins in human immunodeficiency virus type 1-producing cells.
In vitro propagation studies have established that human immunodeficiency virus type 1 (HIV-1) is most efficiently transmitted at the virological synapse that forms between producer and target cells. Despite the presence of the viral envelope glycoprotein (Env) and CD4 and chemokine receptors at the respective surfaces, producer and target cells usually do not fuse with each other but disengage after the viral particles have been delivered, consistent with the idea that syncytia, at least in vitro, are not required for HIV-1 spread. Here, we tested whether tetraspanins, which are well known regulators of cellular membrane fusion processes that are enriched at HIV-1 exit sites, regulate syncytium formation. We found that overexpression of tetraspanins in producer cells leads to reduced syncytium formation, while downregulation has the opposite effect. Further, we document that repression of Env-induced cell-cell fusion by tetraspanins depends on the presence of viral Gag, and we demonstrate that fusion repression requires the recruitment of Env by Gag to tetraspanin-enriched microdomains (TEMs). However, sensitivity to fusion repression by tetraspanins varied for different viral strains, despite comparable recruitment of their Envs to TEMs. Overall, these data establish tetraspanins as negative regulators of HIV-1-induced cell-cell fusion, and they start delineating the requirements for this regulation.
Weng
Jia
J
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA.
Krementsov
Dimitry N
DN
Khurana
Sandhya
S
Roy
Nathan H
NH
Thali
Markus
M
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002459:Cell Fusion; D002460:Cell Line; D015536:Down-Regulation; D015870:Gene Expression; D015726:Giant Cells / Q000378:metabolism / Q000821:virology*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D060225:Tetraspanin 28; D060245:Tetraspanin 29; D060149:Tetraspanin 30
D015703:Antigens, CD; C554586:CD63 protein, human; C554798:CD81 protein, human; C554869:CD9 protein, human; D008562:Membrane Glycoproteins; D010980:Platelet Membrane Glycoproteins; D060225:Tetraspanin 28; D060245:Tetraspanin 29; D060149:Tetraspanin 30