Universität zu Köln

Bayliss, Rebecca ORCID: 0000-0002-3324-957X, Wheeldon, James, Caucheteux, Stephan M., Niessen, Carien M. and Piguet, Vincent (2020). Identification of Host Trafficking Genes Required for HIV-1 Virological Synapse Formation in Dendritic Cells. J. Virol., 94 (9). WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 1098-5514

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Abstract

Dendritic cells (DCs) are one of the earliest targets of HIV-1 infection acting as a Trojan horse, concealing the virus from the innate immune system and delivering it to T cells via virological synapses (VS). To explicate how the virus is trafficked through the cell to the VS and evades degradation, a high-throughput small interfering RNA screen targeting membrane trafficking proteins was performed in monocyte-derived DCs. We identified several proteins including BIN-1 and RAB7L1 that share common roles in transport from endosomal compartments. Depletion of target proteins resulted in an accumulation of virus in intracellular compartments and significantly reduced viral trans-infection via the VS. By targeting endocytic trafficking and retromer recycling to the plasma membrane, we were able to reduce the virus's ability to accumulate at budding microdomains and the VS. Thus, we identify key genes involved in a pathway within DCs that is exploited by HIV-1 to traffic to the VS. IMPORTANCE The lentivirus human immunodeficiency virus (HIV) targets and destroys CD4(+) T cells, leaving the host vulnerable to life-threatening opportunistic infections associated with AIDS. Dendritic cells (DCs) form a virological synapse (VS) with CD4(+) T cells, enabling the efficient transfer of virus between the two cells. We have identified cellular factors that are critical in the induction of the VS. We show that ADP-ribosylation factor 1 (ARF1), bridging integrator 1 (BIN1), and Rab GTPases RAB7L1 and RAB8A are important regulators of HIV-1 trafficking to the VS and therefore the infection of CD4(+) T cells. We found these cellular factors were essential for endosomal protein trafficking and formation of the VS and that depletion of target proteins prevented virus trafficking to the plasma membrane by retaining virus in intracellular vesicles. Identification of key regulators in HIV-1 trans-infection between DC and CD4(+) T cells has the potential for the development of targeted therapy to reduce trans-infection of HIV-1 in vivo.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bayliss, Rebecca UNSPECIFIED orcid.org/0000-0002-3324-957X UNSPECIFIED Wheeldon, James UNSPECIFIED UNSPECIFIED UNSPECIFIED Caucheteux, Stephan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Niessen, Carien M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Piguet, Vincent UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-335925
DOI:	10.1128/JVI.01597-19
Journal or Publication Title:	J. Virol.
Volume:	94
Number:	9
Date:	2020
Publisher:	AMER SOC MICROBIOLOGY
Place of Publication:	WASHINGTON
ISSN:	1098-5514
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELLS; DC-SIGN; CD4(+) T; RETROGRADE TRANSPORT; ANTIGEN PRESENTATION; INFECTIOUS SYNAPSE; MEDIATED TRANSFER; DOWN-REGULATION; TRANSMISSION Multiple languages Virology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33592