Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers

Martín‐Gayo, Enrique; Buzón, María J.; Ouyang, Zhengyu; Hickman, Taylor; Cronin, Jacqueline; Pimenova, Dina; Walker, Bruce D.; Lichterfeld, Mathias; Yu, Xu G.

doi:10.1371/journal.ppat.1004930

Cited by 73 publications

(89 citation statements)

References 70 publications

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“…Previous studies with peripheral blood myeloid MDDCs and MDDCs from HIV-1 elite controllers have shown that these cells may be critical for viral control, acting to capture the virus and enhance T cell-specific immunity to HIV-1 while being less susceptible to HIV-1 infection than MDDCs from healthy controls (108,109). Understanding the mechanisms that control HIV-1 replication in MDDCs, which are overcome by Vpr, might lead to new insights into viral dissemination and persistence in vivo and the development of novel anti-HIV-1 therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells

Miller

Akiyama

Agosto

et al. 2017

J Virol

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Viral protein R (Vpr) is an HIV-1 accessory protein whose function remains poorly understood. In this report, we sought to determine the requirement of Vpr for facilitating HIV-1 infection of monocyte-derived dendritic cells (MDDCs), one of the first cell types to encounter virus in the peripheral mucosal tissues. In this report, we characterize a significant restriction of Vpr-deficient virus replication and spread in MDDCs alone and in cell-to-cell spread in MDDC-CD4 ϩ T cell cocultures. This restriction of HIV-1 replication in MDDCs was observed in a single round of virus replication and was rescued by the expression of Vpr in trans in the incoming virion. Interestingly, infections of MDDCs with viruses that encode Vpr mutants unable to interact with either the DCAF1/DDB1 E3 ubiquitin ligase complex or a host factor hypothesized to be targeted for degradation by Vpr also displayed a significant replication defect. While the extent of proviral integration in HIV-1-infected MDDCs was unaffected by the absence of Vpr, the transcriptional activity of the viral long terminal repeat (LTR) from Vpr-deficient proviruses was significantly reduced. Together, these results characterize a novel postintegration restriction of HIV-1 replication in MDDCs and show that the interaction of Vpr with the DCAF1/DDB1 E3 ubiquitin ligase complex and the yet-to-be-identified host factor might alleviate this restriction by inducing transcription from the viral LTR. Taken together, these findings identify a robust in vitro cell culture system that is amenable to addressing mechanisms underlying Vpr-mediated enhancement of HIV-1 replication.IMPORTANCE Despite decades of work, the function of the HIV-1 protein Vpr remains poorly understood, primarily due to the lack of an in vitro cell culture system that demonstrates a deficit in replication upon infection with viruses in the absence of Vpr. In this report, we describe a novel cell infection system that utilizes primary human dendritic cells, which display a robust decrease in viral replication upon infection with Vpr-deficient HIV-1. We show that this replication difference occurs in a single round of infection and is due to decreased transcriptional output from the integrated viral genome. Viral transcription could be rescued by virion-associated Vpr. Using mutational analysis, we show that domains of Vpr involved in binding to the DCAF1/DDB1/E3 ubiquitin ligase complex and prevention of cell cycle progression into mitosis are required for LTR-mediated viral expression, suggesting that the evolutionarily conserved G 2 cell cycle arrest function of Vpr is essential for HIV-1 replication.

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Section: Discussionmentioning

confidence: 99%

Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells

Miller

Akiyama

Agosto

et al. 2017

J Virol

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“…While suppression of mDC-mediated stimulation of IFN-γ release from CD4 T cells was not statistically significant, addition of IL-12 strongly enhanced the capacity for mDC to drive cytokine production from T cells. Increased recruitment of mDC to lymphoid tissues is associated with disease progression in SIV-infected macaques (27), and in HIV infection, mDC from the blood of elite controllers but not individuals with chronic progressive infection stimulate CD4 T cell proliferation and IFN-γ release from HIV-specific CTL (17). Collectively these data are suggestive of a generalized defect in mDC T cell-stimulating function in HIV and SIV infection that reduces immune control of virus thereby promoting disease development.…”

Section: Discussionmentioning

confidence: 99%

“…Many groups have examined the impact of HIV and SIV infection on production of pro-inflammatory cytokines by isolated DC and macrophages (3, 9–15) as well as the effect of HIV exposure in vitro on the IFN response (16). However, studies exploring the T-cell stimulating function of myeloid DC (mDC) and plasmacytoid DC (pDC) in HIV or SIV infection have been limited (11, 13, 14, 17), and virtually nothing is known about the APC function of macrophages in these infections.…”

Section: Introductionmentioning

confidence: 99%

Macrophages and Myeloid Dendritic Cells Lose T Cell–Stimulating Function in Simian Immunodeficiency Virus Infection Associated with Diminished IL-12 and IFN-α Production

Wonderlich

Normolle

et al. 2015

The Journal of Immunology

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Impaired T cell responses are a defining characteristic of HIV infection but the extent to which altered mononuclear phagocyte function contributes to this defect is unclear. We show that mononuclear phagocytes enriched from rhesus macaque lymph nodes have suppressed ability to stimulate CD4 T cell proliferation and IFN-γ release after acute SIV infection. When individual populations were isolated, myeloid dendritic cells (mDC) and macrophages but not plasmacytoid dendritic cells (pDC) had suppressed capacity to stimulate CD4 T cell proliferation, with macrophage function declining as infection progressed. Macrophages but not pDC or mDC had suppressed capacity to induce IFN-γ release from CD4 T cells in acute infection, even after stimulation with virus-encoded TLR7/8 ligand. Changes in expression of costimulatory molecules did not explain loss of function after infection. Conversely, pDC and mDC had marked loss of IFN-α and IL-12 production, respectively, and macrophages lost production of both cytokines. In T cell co-cultures without TLR7/8 ligand macrophages were the primary source of IL-12 which was profoundly suppressed after infection and correlated with loss of IFN-γ release by T cells. TLR7/8-stimulated pDC, mDC and macrophages all produced IL-12 in T cell co-cultures which was suppressed in chronic infection. Supplementing IL-12 enhanced mDC-driven IFN-γ release from T cells, and IL-12 and IFN-α together restored function in TLR7/8-activated macrophages. These findings reveal loss of macrophage and mDC T cell-stimulating function in lymph nodes of SIV-infected rhesus macaques associated with diminished IL-12 and IFN-α production that may be a factor in AIDS immunopathogenesis.

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“…Here, we used HIV-1 controllers, a group of patients widely used for investigation of HIV-1 immune defense mechanisms in previous studies (43)(44)(45) DCs in HIV-1 controllers seem to have a distinct functional and phenotypic profile that can contribute to the induction of highly functional HIV-1-specific T cell responses. These abilities have been associated with an altered expression profile of immunoregulatory receptors (46) and with enhanced abilities for HIV sensing and innate immune recognition (47). However, the impact of DCs from these patients on Tfh development is still unclear, and investigations of DCs on induction of Tfh have mostly been limited to animal studies (11,48,49) or experiments with in vitro generated monocyte-derived DCs (MDDCs) (25,33), rather than primary DCs.…”

Section: Cxcr3mentioning

confidence: 99%

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

et al. 2017

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Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers

Cited by 73 publications

References 70 publications

Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells

Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells

Macrophages and Myeloid Dendritic Cells Lose T Cell–Stimulating Function in Simian Immunodeficiency Virus Infection Associated with Diminished IL-12 and IFN-α Production

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

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