Successful dissemination of HIV-1 in infected individuals depends on efficient transmission of viral particles from infected (producer) to uninfected (target) cells. In vitro propagation studies have established that HIV-1 particles are most effectively transmitted to target cells if they bud into the cleft of the so-called virological synapse (VS) that forms between producer and target cells. The events leading to the formation, maintenance and disassembly of this synapse are poorly understood. Previously, we and other laboratories have established that HIV-1 particles exit from cells at sites that are enriched in tetraspanins. These cellular membrane proteins normally function as organizers of plasma membrane-based processes, including cell-cell fusion and adhesion. Our preliminary data suggest that individual members of the tetraspanin family are not required for virus release, but they point to a role of these proteins in regulating virus transfer to target cells. We thus propose to evaluate if tetraspanins in producer cells are regulatory cofactors necessary for efficient cell-to-cell transmission of HIV-1 particles. We will also analyze the effects of virus-mediated downregulation of tetraspanins. Altogether, these studies will provide further insight into the molecular mechanisms underlying HIV-1 spread and thus pathogenesis. In the Specific Aims of this proposal we propose: 1) To test the hypothesis that tetraspanins inhibit HIV-1-induced membrane fusion, thus allowing cell-to-cell transfer without fusion of producer and target cell. 2) To determine if tetraspanins in HIV-1 producer cells promote efficient transmission of viral particles to target cells by supporting the formation, the organization and the disassembly of the VS. 3) To examine the kinetics, determinants and potential consequences of HIV-1-induced tetraspanin downregulation in infected cells.

Public Health Relevance

The proposed analyses are aimed at elucidating HIV-1 transmission from cell-to-cell, a step in the viral replication cycle that remains poorly understood. Hence, the results may reveal novel targets for intervention with HIV-1 spread in infected individuals.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Vermont & St Agric College
Schools of Medicine
United States
Zip Code
Symeonides, Menelaos; Lambelé, Marie; Roy, Nathan H et al. (2014) Evidence showing that tetraspanins inhibit HIV-1-induced cell-cell fusion at a post-hemifusion stage. Viruses 6:1078-90
Roy, Nathan H; Lambelé, Marie; Chan, Jany et al. (2014) Ezrin is a component of the HIV-1 virological presynapse and contributes to the inhibition of cell-cell fusion. J Virol 88:7645-58
Roy, Nathan H; Chan, Jany; Lambele, Marie et al. (2013) Clustering and mobility of HIV-1 Env at viral assembly sites predict its propensity to induce cell-cell fusion. J Virol 87:7516-25
Wesley, Cedric S; Guo, Heng; Chaudhry, Kanita A et al. (2011) Loss of PTB or negative regulation of Notch mRNA reveals distinct zones of Notch and actin protein accumulation in Drosophila embryo. PLoS One 6:e21876
Thali, Markus (2011) Tetraspanin functions during HIV-1 and influenza virus replication. Biochem Soc Trans 39:529-31
Dillingham, Mark S (2011) Superfamily I helicases as modular components of DNA-processing machines. Biochem Soc Trans 39:413-23
Thali, Markus (2011) For HIV, it's never too late to grow up. Cell Host Microbe 10:527-8
Krementsov, Dimitry N; Rassam, Patrice; Margeat, Emmanuel et al. (2010) HIV-1 assembly differentially alters dynamics and partitioning of tetraspanins and raft components. Traffic 11:1401-14
Weng, Jia; Krementsov, Dimitry N; Khurana, Sandhya et al. (2009) Formation of syncytia is repressed by tetraspanins in human immunodeficiency virus type 1-producing cells. J Virol 83:7467-74
Singethan, Katrin; Muller, Nora; Schubert, Sabine et al. (2008) CD9 clustering and formation of microvilli zippers between contacting cells regulates virus-induced cell fusion. Traffic 9:924-35