Differential Regulation of NF-κB-Mediated Proviral and Antiviral Host Gene Expression by Primate Lentiviral Nef and Vpu Proteins

The HIV-1 accessory protein Vpr displays different activities potentially impacting viral replication, including the arrest of the cell cycle in the G 2 phase and the stimulation of apoptosis and DNA damage response pathways. Vpr also modulates cytokine production by infected cells, but this property remains partly characterized. Here, we investigated the effect of Vpr on the production of the proinflammatory cytokine tumor necrosis factor (TNF). We report that Vpr significantly increases TNF secretion by infected lymphocytes. De novo production of Vpr is required for this effect. Vpr mutants known to be defective for G

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Vpr Enhances Tumor Necrosis Factor Production by HIV-1-Infected T Cells

Roesch

Richard

Rua

et al. 2015

“…9D). These findings suggest that primate lentiviruses can, at least to some extent, uncouple the transcriptional activity of the viral LTR promoter from the state of cellular activation, possibly because Nef may support NF-B induction independently of TCR-CD3 signaling (39). However, although similar levels of HIV-1-infected (eGFP ϩ ) cells and only modest differences in eGFP expression levels were detected in RA ϩ RO ϩ Tdp and RA Ϫ RO ϩ Tm cells, only the former produced high levels of infectious HIV-1 (Fig.…”

Section: Cd4mentioning

confidence: 98%

Lentiviral Nef Proteins Manipulate T Cells in a Subset-Specific Manner

Khalid

Heigele

et al. 2015

Self Cite

The role of the accessory viral Nef protein as a multifunctional manipulator of the host cell that is required for effective replication of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) in vivo is well established. It is unknown, however, whether Nef manipulates all or just specific subsets of CD4 ؉ T cells, which are the main targets of virus infection and differ substantially in their state of activation and importance for a functional immune system. Here, we analyzed the effect of Nef proteins differing in their T cell receptor (TCR)-CD3 downmodulation function in HIV-infected human lymphoid aggregate cultures and peripheral blood mononuclear cells. We found that Nef efficiently downmodulates TCR-CD3 in naive and memory CD4؉ T cells and protects the latter against apoptosis. In contrast, highly proliferative CD45RA ؉ CD45RO ؉ CD4 ؉ T cells were main producers of infectious virus but largely refractory to TCR-CD3 downmodulation. Such T cell subset-specific differences were also observed for Nef-mediated modulation of CD4 but not for enhancement of virion infectivity. Our results indicate that Nef predominantly modulates surface receptors on CD4 ؉ T cell subsets that are not already fully permissive for viral replication. As a consequence, Nef-mediated downmodulation of TCR-CD3, which distinguishes most primate lentiviruses from HIV type 1 (HIV-1) and its vpu-containing simian precursors, may promote a selective preservation of central memory CD4؉ T cells, which are critical for the maintenance of a functional immune system. IMPORTANCE The Nef proteins of human and simian immunodeficiency viruses manipulate infected CD4 ؉ T cells in multiple ways to promote viral replication and immune evasion in vivo.Here, we show that some effects of Nef are subset specific. Downmodulation of CD4 and TCR-CD3 is highly effective in central memory CD4؉ T cells, and the latter Nef function protects this T cell subset against apoptosis. In contrast, highly activated/proliferating CD4 ؉ T cells are largely refractory to receptor downmodulation but are main producers of infectious HIV-1. Nef-mediated enhancement of virion infectivity, however, was observed in all T cell subsets examined. Our results provide new insights into how primate lentiviruses manipulate their target cells and suggest that the TCR-CD3 downmodulation function of Nef may promote a selective preservation of memory CD4 ؉ T cells, which are critical for immune function, but has little effect on activated/proliferating CD4 ؉ T cells, which are the main targets for viral replication.

“…These results suggest that HIV NL4.3 Vpu downmodulates NF-B downstream IKK␤. Previous studies reported that Vpu could stabilize the nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha (IB␣), thus inhibiting NF-B activation (12,54). Since TNF-␣ stimulation induces IB␣ rapid degradation (55), we next compared the levels of IB␣ in response to TNF-␣ in 293T expressing Vpu or GFP.…”

Section: Nl43 Vpu Inhibits Nf-b But Not Irf3 Signaling Since the Ifmentioning

confidence: 99%

HIV Vpu Interferes with NF-κB Activity but Not with Interferon Regulatory Factor 3

Manganaro

Castro

Olivieri

et al. 2015

The accessory HIV protein Vpu inhibits a number of cellular pathways that trigger host innate restriction mechanisms. HIV Vpu-mediated degradation of tetherin allows efficient particle release and hampers the activation of the NF-B pathway thereby limiting the expression of proinflammatory genes. In addition, Vpu reduces cell surface expression of several cellular molecules such as newly synthesized CD4. However, the role of HIV Vpu in regulating the type 1 interferon response to viral infection by degradation of the interferon regulatory factor 3 (IRF3) has been subject of conflicting reports. We therefore systematically investigated the expression of IRF3 in primary CD4؉ T cells and macrophages infected with HIV at different time points. In addition, we also tested the ability of Vpu to interfere with innate immune signaling pathways such as the NF-B and the IRF3 pathways. We report here that HIV Vpu failed to degrade IRF3 in infected primary cells. Moreover, we observed that HIV NL4.3 Vpu had no effect on IRF3-dependent gene expression in reporter assays. On the other hand, HIV NL4. T he success of the immediate innate immune response relies on the recognition of conserved pathogen structures, termed pathogen-associated molecular patterns (PAMPs; reviewed in reference 1). PAMPs induce intracellular signaling events, such as activation of the NF-B and interferon (IFN) regulatory factor (IRF) pathways (reviewed in reference 2). The potent, but shortlived, activation of these innate response pathways triggers the induction of cytokines and interferons, which restrict replication of the pathogen (3). In addition, induction of the innate immune system is required for activation of long-lived adaptive immune responses (reviewed in reference 4). Many viruses have adapted to the presence of an innate immune system by specifically counteracting critical components of these pathways (reviewed in reference 5). Our understanding on how HIV efficiently evades immune recognition remains incomplete, despite recent findings describing how HIV can induce activation of the innate immune response in humans (reviewed in reference 6).The accessory HIV protein Vpu antagonizes a number of different host restriction factors (reviewed in reference 7). It counteracts the inhibitory effect of Tetherin on particle release, but it also limits the expression of proinflammatory genes by hampering the activation of the NF-B pathway (8-10). NF-B inhibition is achieved by degradation of tetherin and sequestration of ␤TrCP (10-12). In addition, Vpu reduces the cell surface expression of several cellular molecules, such as the newly synthesized CD4, and the NK T cell and NK cell activating proteins, CD1d and NTB-A (13-15).Reports on the cross talk between Vpu and interferon regulatory factor 3 (IRF3) have been conflicting (10,(16)(17)(18). Doehle et al. reported that HIV NL4.3 Vpu induces IRF3 degradation by a lysosome-dependent pathway, thus blocking type I interferon production in infected cells (16,17). Recently, Park et al. reported...