Covert Human Immunodeficiency Virus Replication in Dendritic Cells and in DC-SIGN-Expressing Cells Promotes Long-Term Transmission to Lymphocytes

Institut Pasteur, Groupe Virus et Immunité, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.
Journal of Virology (Impact Factor: 4.44). 06/2005; 79(9):5386-99. DOI: 10.1128/JVI.79.9.5386-5399.2005
Source: PubMed


HIV-1 virions are efficiently captured by monocyte-derived immature dendritic cells (iDCs), as well as by cell lines expressing
the lectin DC-SIGN. Viral infectivity can be retained for several days, and even enhanced, before transmission to CD4+ lymphocytes. The role of DC-SIGN in viral retention and enhancement of infection is not fully understood and varies according
to the cell line expressing the lectin. We studied here the mechanisms underlying this process. We focused our study on X4-tropic
human immunodeficiency virus (HIV) strains, since they were widely believed not to replicate in iDCs. However, we first show
that X4 HIV replicates covertly and slowly in iDCs. This is also the case in Raji-DC-SIGN cells, which are classically used
to study HIV transmission. We used either single-cycle or replicative HIV and measured viral RT and replication to further
demonstrate that transfer of incoming virions from iDCs or DC-SIGN+ cells occurs only on the short-term (i.e., a few hours after viral exposure). There is no long-term storage of original HIV
particles in these cells. A few days after viral exposure, replicative viruses, and not single-cycle virions, are transmitted
to CD4+ cells. The cell-type-dependent activity of DC-SIGN reflects the ability of HIV to replicate covertly in some cells, and not
in others.

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    • "This observation led to the “Trojan horse” hypothesis, which argues that DC-SIGN captures HIV-1 in the mucosa and facilitates its transport to secondary lymphoid organs rich in CD4+ T cells that can be efficiently trans-infected [25]. However, the restricted capacity of iDCs to sustain trans-infection [28], [40] and the limited contribution of DC-SIGN to viral transmission reported in several independent studies [29], [30], [41]–[47] argued against the original “Trojan horse” hypothesis. "
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    ABSTRACT: Dendritic cells (DCs) are essential in order to combat invading viruses and trigger antiviral responses. Paradoxically, in the case of HIV-1, DCs might contribute to viral pathogenesis through trans-infection, a mechanism that promotes viral capture and transmission to target cells, especially after DC maturation. In this review, we highlight recent evidence identifying sialyllactose-containing gangliosides in the viral membrane and the cellular lectin Siglec-1 as critical determinants for HIV-1 capture and storage by mature DCs and for DC-mediated trans-infection of T cells. In contrast, DC-SIGN, long considered to be the main receptor for DC capture of HIV-1, plays a minor role in mature DC-mediated HIV-1 capture and trans-infection.
    PLoS Pathogens 07/2014; 10(7):e1004146. DOI:10.1371/journal.ppat.1004146 · 7.56 Impact Factor
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    • "However, DC lectin receptors are important molecules involved in the presentation of foreign antigens. In fact, the most of the HIV-1 virions captured by DCs were known to be rapidly degraded (Turville et al., 2004; Nobile et al., 2005). Moreover, the interaction of leukocyte-specific protein 1 (LSP-1), a protein directing internalized virus to the proteasome, with the cytoplasmic region of DC-SIGN may further facilitate the degradation of HIV-1 (Smith et al., 2007). "
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    ABSTRACT: Although dendritic cells (DCs) represent a small cell population in the body, they have been recognized as professional antigen presenting cells and key players of both innate and acquired immunity. The recent expansion of basic knowledge concerning differentiation and function of various DC subsets will greatly help to understand the nature of protective immunity required in designing acquired immunodeficiency syndrome (AIDS) vaccines. However, human immunodeficiency virus (HIV) not only targets CD4(+) T cells but also myeloid cells, including macrophages and DC. When HIV infects DC, its replication is highly restricted in DC. Nevertheless, even a low level of HIV production is sufficient to enhance HIV replication in activated CD4(+) T cells, through antigen presentation activity by HIV-infected DC. Considering how antiviral immunity is initiated and memory response is maintained, such efficient DC-T cell transmission of HIV should play an important role in the disturbed immune responses associated with HIV infection. Recently, accessory proteins encoded by HIV have been shown to interact with various proteins in DC, and thereby affect DC-T cell transmission. In this review, we summarize the current understanding about DC biology, antiviral immune responses and DC restriction factors, all of which will be important issues for the development of an effective AIDS vaccine in the future.
    Frontiers in Microbiology 07/2013; 4:178. DOI:10.3389/fmicb.2013.00178 · 3.99 Impact Factor
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    • "In addition to DC-mediated HIV-1 trans-infection, long-term viral transfer to CD4+ T cells by DCs depends on HIV-1 production from infected DCs [6], [7], [50], [51]. Thus, we examined Nef modulation of DC-mediated HIV-1 transmission through de novo production of virus. "
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    ABSTRACT: HIV-1 Nef enhances dendritic cell (DC)-mediated viral transmission to CD4(+) T cells, but the underlying mechanism is not fully understood. It is also unknown whether HIV-1 infected DCs play a role in activating CD4(+) T cells and enhancing DC-mediated viral transmission. Here we investigated the role of HIV-1 Nef in DC-mediated viral transmission and HIV-1 infection of primary CD4(+) T cells using wild-type HIV-1 and Nef-mutated viruses. We show that HIV-1 Nef facilitated DC-mediated viral transmission to activated CD4(+) T cells. HIV-1 expressing wild-type Nef enhanced the activation and proliferation of primary resting CD4(+) T cells. However, when co-cultured with HIV-1-infected autologous DCs, there was no significant trend for infection- or Nef-dependent proliferation of resting CD4(+) T cells. Our results suggest an important role of Nef in DC-mediated transmission of HIV-1 to activated CD4(+) T cells and in the activation and proliferation of resting CD4(+) T cells, which likely contribute to viral pathogenesis.
    PLoS ONE 03/2012; 7(3):e34521. DOI:10.1371/journal.pone.0034521 · 3.23 Impact Factor
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