Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral Nef protein

ABSTRACT The intrinsic immunity factor CD317 (BST-2/HM1.24/tetherin) imposes a barrier to HIV-1 release at the cell surface that can be overcome by the viral protein Vpu. Expression of Vpu results in a reduction of CD317 surface levels; however, the mechanism of this Vpu activity and its contribution to the virological antagonism are incompletely understood. Here, we characterized the influence of Vpu on major CD317 trafficking pathways using quantitative antibody-based endocytosis and recycling assays as well as a microinjection/microscopy-based kineticde novoexpression approach. We report that HIV-1 Vpu inhibited both the anterograde transport of newly synthesized CD317 and the recycling of CD317 to the cell surface, while the kinetics of CD317 endocytosis remained unaffected. Vpu trapped trafficking CD317 molecules at thetrans-Golgi network, where the two molecules colocalized. The subversion of both CD317 transport pathways was dependent on the highly conserved diserine S52/S56 motif of Vpu; however, it did not require recruitment of the diserine motif interactor and substrate adaptor of the SCF-E3 ubiquitin ligase complex, β-TrCP. Treatment of cells with the malaria drug primaquine resulted in a CD317 trafficking defect that mirrored that induced by Vpu. Importantly, primaquine could functionally replace Vpu as a CD317 antagonist and rescue HIV-1 particle release.IMPORTANCEHIV efficiently replicates in the human host and induces the life-threatening immunodeficiency AIDS. Mammalian genomes encode proteins such as CD317 that can inhibit viral replication at the cellular level. As a countermeasure, HIV has evolved genes likevputhat can antagonize these intrinsic immunity factors. Investigating the mechanism by which Vpu overcomes the virion release restriction imposed by CD317, we find that Vpu subverts recycling and anterograde trafficking pathways of CD317, resulting in surface levels of the restriction factor insufficient to block HIV-1 spread. This describes a novel mechanism of immune evasion by HIV.

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HIV-1 gp120 induces CD4 association with several molecules on the T cell surface and modulates T cell interaction with endothelium and homing

Immunology Letters ◽

10.1016/s0165-2478(97)86948-9 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 29

Author(s):

M Bragardo

Keyword(s):

T Cell ◽

Cell Surface ◽

Cell Interaction ◽

Hiv 1

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Cell surface expression of the HIV-1 envelope glycoproteins is directed from intracellular CTLA-4-containing regulated secretory granules

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.122696599 ◽

2002 ◽

Vol 99 (12) ◽

pp. 8031-8036 ◽

Cited By ~ 32

Author(s):

L. R. Miranda ◽

B. C. Schaefer ◽

A. Kupfer ◽

Z. Hu ◽

A. Franzusoff

Keyword(s):

Cell Surface ◽

Secretory Granules ◽

Surface Expression ◽

Cell Surface Expression ◽

Envelope Glycoproteins ◽

Hiv 1

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Identification of a novel cell attachment domain in the HIV-1 Tat protein and its 90-kDa cell surface binding protein.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)53530-4 ◽

1993 ◽

Vol 268 (7) ◽

pp. 5279-5284

Author(s):

B.S. Weeks ◽

K. Desai ◽

P.M. Loewenstein ◽

M.E. Klotman ◽

P.E. Klotman ◽

...

Keyword(s):

Cell Surface ◽

Cell Attachment ◽

Binding Protein ◽

Tat Protein ◽

Surface Binding ◽

Cell Surface Binding ◽

Hiv 1

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Human Mucosal Mast Cells Capture HIV-1 and Mediate Viraltrans-Infection of CD4+T Cells

Journal of Virology ◽

10.1128/jvi.03008-15 ◽

2015 ◽

Vol 90 (6) ◽

pp. 2928-2937 ◽

Cited By ~ 16

Author(s):

Ai-Ping Jiang ◽

Jin-Feng Jiang ◽

Ji-Fu Wei ◽

Ming-Gao Guo ◽

Yan Qin ◽

...

Keyword(s):

T Cells ◽

Mast Cells ◽

Cell Surface ◽

Bacterial Infections ◽

Mucosal Mast Cells ◽

Mucosal Tissues ◽

Viral Particles ◽

Molecular Patterns ◽

Hiv 1

ABSTRACTThe gastrointestinal mucosa is the primary site where human immunodeficiency virus type 1 (HIV-1) invades, amplifies, and becomes persistently established, and cell-to-cell transmission of HIV-1 plays a pivotal role in mucosal viral dissemination. Mast cells are widely distributed in the gastrointestinal tract and are early targets for invasive pathogens, and they have been shown to have increased density in the genital mucosa in HIV-infected women. Intestinal mast cells express numerous pathogen-associated molecular patterns (PAMPs) and have been shown to combat various viral, parasitic, and bacterial infections. However, the role of mast cells in HIV-1 infection is poorly defined. In this study, we investigated their potential contributions to HIV-1 transmission. Mast cells isolated from gut mucosal tissues were found to express a variety of HIV-1 attachment factors (HAFs), such as DC-SIGN, heparan sulfate proteoglycan (HSPG), and α4β7 integrin, which mediate capture of HIV-1 on the cell surface. Intriguingly, following coculture with CD4+T cells, mast cell surface-bound viruses were efficiently transferred to target T cells. Prior blocking with anti-HAF antibody or mannan before coculture impaired viraltrans-infection. Cell-cell conjunctions formed between mast cells and T cells, to which viral particles were recruited, and these were required for efficient cell-to-cell HIV-1 transmission. Our results reveal a potential function of gut mucosal mast cells in HIV-1 dissemination in tissues. Strategies aimed at preventing viral capture and transfer mediated by mast cells could be beneficial in combating primary HIV-1 infection.IMPORTANCEIn this study, we demonstrate the role of human mast cells isolated from mucosal tissues in mediating HIV-1trans-infection of CD4+T cells. This finding facilitates our understanding of HIV-1 mucosal infection and will benefit the development of strategies to combat primary HIV-1 dissemination.

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