The presence of the tetraspanins CD9, CD63, CD81 and CD82 at HIV-1 budding sites, at the virological synapse (VS), and their enrichment in HIV-1 virions has been well-documented, but it remained unclear if these proteins play a role in the late phase of the viral replication cycle. Here we used overexpression and knockdown approaches to address this question.
Neither ablation of CD9, CD63 and/or CD81, nor overexpression of these tetraspanins was found to affect the efficiency of virus release. However, confirming recently reported data, tetraspanin overexpression in virus-producing cells resulted in the release of virions with substantially reduced infectivity. We also investigated the roles of these tetraspanins in cell-to-cell transmission of HIV-1. Overexpression of CD9 and CD63 led to reduced cell-to-cell transmission of this virus. Interestingly, in knockdown experiments we found that ablation of CD63, CD9 and/or CD81 had no effect on cell-free infectivity. However, knockdown of CD81, but not CD9 and CD63, enhanced productive particle transmission to target cells, suggesting additional roles for tetraspanins in the transmission process. Finally, tetraspanins were found to be downregulated in HIV-1-infected T lymphocytes, suggesting that HIV-1 modulates the levels of these proteins in order to maximize the efficiency of its transmission within the host.
Altogether, these results establish an active role of tetraspanins in HIV-1 producer cells.
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"Several tetraspanins are recruited to the budding site of HIV (Krementsov et al., 2010) and are incorporated into the viral membrane (Monk and Partridge, 2012). Furthermore, the presence of tetraspanins at exit sites and in viral particles inhibits, to some extent, virus infection at a post-attachment step, as well as the formation of syncytium induced by the virus (Gordón- Alonso et al., 2006; Krementsov et al., 2009; Sato et al., 2008). Takeda et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Tetraspanins are a family of proteins with four transmembrane domains that play a role in many aspects of cell biology and physiology; they are also used by several pathogens for infection and regulate cancer progression. Many tetraspanins associate specifically and directly with a limited number of proteins, and also with other tetraspanins, thereby generating a hierarchical network of interactions. Through these interactions, tetraspanins are believed to have a role in cell and membrane compartmentalization. In this Cell Science at a Glance article and the accompanying poster, we describe the basic principles underlying tetraspanin-based assemblies and highlight examples of how tetraspanins regulate the trafficking and function of their partner proteins that are required for the normal development and function of several organs, including, in humans, the eye, the kidney and the immune system.
"Furthermore, tetraspanins may serve as markers for the subcellular localization and traf fi cking of HIV-1, rather than possessing a functional role in DC-mediated HIV-1 transmission to CD4 + T cells (Garcia et al. 2005; Izquierdo-Useros et al. 2009). A study using HeLa cells as donor cells to transmit HIV-1 to the CD4 + CEM T cell line has suggested that CD9 and CD63 promote HIV-1 cell-to-cell transmission and CD81 inhibits HIV-1 cell-to-cell transmission without affecting the infectivity of the cell-free virus (Krementsov et al. 2009). However, tetraspanin-mediated HIV-1 transmission to CD4 + T cells has not been demonstrated in DCs. "
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DCs) play a key role in the initial infection and cell-to-cell transmission events that occur upon HIV-1 infection. DCs interact closely with CD4(+) T cells, the main target of HIV-1 replication. HIV-1 challenged DCs and target CD4(+) T cells form a virological synapse that allows highly efficient transmission of HIV-1 to the target CD4(+) T cells, in the absence of productive HIV-1 replication in the DCs. Immature and subsets of mature DCs show distinct patterns of HIV-1 replication and cell-to-cell transmission, depending upon the maturation stimulus that is used. The cellular and viral mechanisms that promote formation of the virological synapse have been the subject of intense study and the most recent progress is discussed here. Characterizing the cellular and viral factors that affect DC-mediated cell-to-cell transmission of HIV-1 to CD4(+) T cells is vitally important to understanding, and potentially blocking, the initial dissemination of HIV-1 in vivo.
Advances in Experimental Medicine and Biology 01/2013; 762:109-30. DOI:10.1007/978-1-4614-4433-6_4 · 1.96 Impact Factor
"In addition to cytoskeleton, lipid rafts and TEMs are implicated in VS formation as well. Markers for both microdomains accumulate to VS [110, 146, 159, 160]. Consistent with a role for lipid rafts in VS formation, cholesterol depletion was observed to diminish formation of VS, as defined by the accumulation of CD4 (on the target cell) and HIV antigens (in the donor cell) at the cell-cell interface . "
[Show abstract][Hide abstract] ABSTRACT: HIV-1 particle assembly is driven by the structural protein Gag. Gag binds to and multimerizes on the inner leaflet of the plasma membrane, eventually resulting in formation of spherical particles. During virus spread among T cells, Gag accumulates to the plasma membrane domain that, together with target cell membrane, forms a cell junction known as the virological synapse. While Gag association with plasma membrane microdomains has been implicated in virus assembly and cell-to-cell transmission, recent studies suggest that, rather than merely accumulating to pre-existing microdomains, Gag plays an active role in reorganizing the microdomains via its multimerization activity. In this paper, we will discuss this emerging view of Gag microdomain interactions. Relationships between Gag multimerization and microdomain association will be further discussed in the context of Gag localization to T-cell uropods and virological synapses.