Abstract
In vitro, dendritic cells (DCs) bind and transfer intact, infectious HIV to CD4 T cells without first becoming infected, a process known as trans-infection. trans-infection is accomplished by recruitment of HIV and its receptors to the site of DC–T cell contact and transfer of virions at a structure known as the infectious synapse. In this study, we used fluorescent microscopy to track individual HIV particles trafficking in DCs during virus uptake and trans-infection. Mature DCs rapidly concentrated HIV into an apparently intracellular compartment that lacked markers characteristic of early endosomes, lysosomes, or antigen-processing vesicles. Live cell microscopy demonstrated that the HIV-containing compartment was rapidly polarized toward the infectious synapse after contact with a T cell; however, the bulk of the concentrated virus remained in the DCs after T cell engagement. Individual virions were observed emerging from the compartment and fusing with the T cell membrane at the infectious synapse. The compartmentalized HIV, although engulfed by the cytoplasm, was fully accessible to HIV envelope-specific inhibitors and other membrane-impermeable probes that were delivered to the cell surface. These results demonstrate that HIV resides in an invaginated domain within DCs that is both contiguous with the plasma membrane and distinct from endocytic vesicles. We conclude that HIV virions are routed through this specialized compartment, which allows individual particles to be delivered to T cells during trans-infection.
Highlights
Cell-to-cell transmission of viral infections is an important mechanism that enables HIV to establish systemic infections in the face of a strong immune response
HIV-1 has appropriated this feature of the immune system to better establish and maintain infection of its primary target–CD4-positive T cells
We report that mature Dendritic cells (DCs) concentrate infectious HIV into a pocket-like compartment that resides within the cell but remains physically connected to the cell surface
Summary
Cell-to-cell transmission of viral infections is an important mechanism that enables HIV to establish systemic infections in the face of a strong immune response. DCs greatly enhance infection of T cells by binding and concentrating HIV at sites of T cell contact. Recruitment of CD4 and chemokine co-receptors CCR5 and CXCR4 to the contact site on the T cell surface provides a receptor-rich environment for HIV entry. This structure is referred to as the infectious synapse, due to its similarity to the immunological synapse [3]. Because DCs can bind and sequester HIV without becoming infected, they can potentially harbor infectious virus despite ongoing antiviral therapy. A better understanding of how DCs effect trans-infection might yield better strategies for control of HIV infections
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