922 HIV-1 trans-infection of T-cells via dendritic cells requires endosomal sorting and polarized trafficking to the virological synapse

Abstract The dynamic interplay between dendritic cells (DCs) and human immunodeficiency virus type-1 (HIV-1) is thought to result in viral dissemination and evasion of antiviral immunity. Although initial observations suggested that the C-type lectin receptor (CLR) DC-SIGN was responsible for the trans-infection function of the virus, subsequent studies demonstrated that trans-infection of CD4+ T cells with HIV-1 can also occur through DC-SIGN–independent mechanisms. We demonstrate that a cell surface molecule designated DCIR (for DCimmunoreceptor), a member of a recently described family of DC-expressing CLRs, can participate in the capture of HIV-1 and promote infection in trans and in cis of autologous CD4+ T cells from human immature monocyte-derived DCs. The contribution of DCIR to these processes was revealed using DCIR-specific siRNAs and a polyclonal antibody specific for the carbohydrate recognition domain of DCIR. Data from transfection experiments indicated that DCIR acts as a ligand for HIV-1 and is involved in events leading to productive virus infection. Finally, we show that the neck domain of DCIR is important for the DCIR-mediated effect on virus binding and infection. These results point to a possible role for DCIR in HIV-1 pathogenesis by supporting the productive infection of DCs and promoting virus propagation.

Download Full-text

Penicillium marneffei-Stimulated Dendritic Cells Enhance HIV-1 Trans-Infection and Promote Viral Infection by Activating Primary CD4+ T Cells

PLoS ONE ◽

10.1371/journal.pone.0027609 ◽

2011 ◽

Vol 6 (11) ◽

pp. e27609 ◽

Cited By ~ 10

Author(s):

Yan Qin ◽

Yuye Li ◽

Wan Liu ◽

Renrong Tian ◽

Qianqian Guo ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Viral Infection ◽

Cd4 T Cells ◽

Penicillium Marneffei ◽

Trans Infection ◽

Hiv 1

Download Full-text

Slit2N Inhibits Transmission Of HIV-1 From Dendritic Cells To T-Cells By Modulating Novel Cytoskeletal Elements

Blood ◽

10.1182/blood.v122.21.2285.2285 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2285-2285

Author(s):

Ashutosh Shrivastava ◽

Anil Prasad ◽

Paula Kuzontkoski ◽

Jinlong Yu ◽

Jerome E. Groopman

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Conflicts Of Interest ◽

Target Cells ◽

Dependent Manner ◽

Trans Infection ◽

Intact Virus ◽

Cell Transmission ◽

Cytoskeletal Elements ◽

Hiv 1

Abstract During sexual contact, HIV-1 can enter the mucous membranes of the vagina, throat, or rectum. There, the virus encounters potential target cells, including antigen-presenting cells such as dermal dendritic cells (DC), Langerhans cells, and plasmacytoid DCs, which play pivotal roles in both innate and adaptive immunity. All DC subsets are susceptible to HIV-1 infection or internalization of intact virus, and appear to facilitate cell-mediated transmission of HIV-1 in the mucosa and lymphatic tissues. Once internalized, HIV-1 can be transmitted from DCs to T-cells at a specialized junction termed the infectious synapse (IS). Recent studies reveal that several actin-rich DC membrane extensions, including actin filopodia, membrane sheets, cytonemes, and nanotubes, establish direct contact between cells at the IS and facilitate HIV-1 transmission. Although the virus can infect T-cells directly (cis-infection), transmission of HIV-1 from DCs to T-cells at IS (trans-infection and de novo trans-infection) appears to be some 10 to 100 times more efficient than direct infection; therefore, cell-to-cell transmission is an attractive target for novel HIV therapeutics. We evaluated the effects of Slit2N, a ligand for the Roundabout (Robo) receptors, on the transmission of HIV-1 from DCs to T-cells. Slit2N inhibits HIV-1 transmission to T-cells and its replication. Binding of HIV-1 to DC-SIGN on the surface of DCs initiates signaling through cellular-Src (c-Src) and cell division control protein 42 (Cdc42), which modulates actin polymerization and filopodia formation via the actin-related protein 2/3 (Arp2/3) complex and mammalian Diaphanous 2 (mDia2). Slit2N inhibited HIV-1-induced signaling through both Arp2/3 and mDia2, decreased filopodial extensions on virus-infected DCs, and inhibited cell-to-cell transmission of HIV-1 at the IS in a Robo1-dependent manner. Of particular note, we identified Flightless-1 (Fli1) as a novel, Robo1-interacting protein, and demonstrated that it is required for efficient cell-to-cell transmission of HIV-1. These results suggest that targeting the Slit/Robo pathway involves the modulation of previously unrecognized cytoskeletal elements in HIV-1 transmission, and thus, offers an innovative strategy to limit viral infection in the host. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

077 RNA interference screening for novel cytokine and chemokine factors regulating HIV-1 trans-infection from dendritic cells to CD4+ T-cells

Journal of Investigative Dermatology ◽

10.1016/j.jid.2020.03.079 ◽

2020 ◽

Vol 140 (7) ◽

pp. S9

Author(s):

S. Caucheteux ◽

J. Wheeldon ◽

R. Bayliss ◽

V. Piguet

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Rna Interference ◽

Cd4 T Cells ◽

Trans Infection ◽

Hiv 1

Download Full-text

Identification of Host Trafficking Genes Required for HIV-1 Virological Synapse Formation in Dendritic Cells

Journal of Virology ◽

10.1128/jvi.01597-19 ◽

2020 ◽

Vol 94 (9) ◽

Author(s):

Rebecca Bayliss ◽

James Wheeldon ◽

Stephan M. Caucheteux ◽

Carien M. Niessen ◽

Vincent Piguet

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Plasma Membrane ◽

Membrane Trafficking ◽

Opportunistic Infections ◽

Virological Synapse ◽

Rab Gtpases ◽

Target Proteins ◽

Cellular Factors ◽

Hiv 1

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.

Download Full-text

TLR-4 engagement of dendritic cells confers a BST-2/tetherin-mediated restriction of HIV-1 infection to CD4+ T cells across the virological synapse

Retrovirology ◽

10.1186/1742-4690-10-6 ◽

2013 ◽

Vol 10 (1) ◽

pp. 6 ◽

Cited By ~ 17

Author(s):

Fabien P Blanchet ◽

Romaine Stalder ◽

Magdalena Czubala ◽

Martin Lehmann ◽

Laura Rio ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Virological Synapse ◽

Hiv 1

Download Full-text

094 Cytokine and chemokine factors regulate HIV-1 trans-infection from dendritic cells to CD4+ T-cells

Journal of Investigative Dermatology ◽

10.1016/j.jid.2021.02.112 ◽

2021 ◽

Vol 141 (5) ◽

pp. S17

Author(s):

S. Caucheteux ◽

J. Wheeldon ◽

V. Piguet

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Trans Infection ◽

Hiv 1

Download Full-text

HIV-1 Selection by Epidermal Dendritic Cells during Transmission across Human Skin

Journal of Experimental Medicine ◽

10.1084/jem.187.10.1623 ◽

1998 ◽

Vol 187 (10) ◽

pp. 1623-1631 ◽

Cited By ~ 129

Author(s):

Jeanette C. Reece ◽

Amanda J. Handley ◽

E. John Anstee ◽

Wayne A. Morrison ◽

Suzanne M. Crowe ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Human Skin ◽

Cell Sorting ◽

Virus Entry ◽

Skin Explants ◽

Skin Uptake ◽

Virus Exposure ◽

Epidermal Dendritic Cells ◽

Hiv 1

Macrophage tropic HIV-1 is predominant during the initial viremia after person to person transmission of HIV-1 (Zhu, T., H. Mo, N. Wang, D.S. Nam, Y. Cao, R.A. Koup, and D.D. Ho. 1993. Science. 261:1179–1181.), and this selection may occur during virus entry and carriage to the lymphoid tissue. Human skin explants were used to model HIV-1 selection that may occur at the skin or mucosal surface. Macrophage tropic, but not T cell line tropic strains of HIV-1 applied to the abraded epidermis were recovered from the cells emigrating from the skin explants. Dermis and epidermis were separated by dispase digestion after virus exposure to determine the site of viral selection within the skin. Uptake and transmission to T cells of all HIV-1 isolates was found with the dermal emigrant cells, but only macrophage tropic virus was transferred by emigrants from the epidermis exposed to HIV-1, indicating selection only within the epidermis. CD3+, CD4+ T cells were found in both the dermal and epidermal emigrant cells. After cell sorting to exclude contaminating T cells, macrophage tropic HIV-1 was found in both the dermal emigrant dendritic cells and in dendritic cells sorted from the epidermal emigrants. These observations suggest that selective infection of the immature epidermal dendritic cells represents the cellular mechanism that limits the initial viremia to HIV-1 that can use the CCR5 coreceptor.

Download Full-text