scholarly journals HIV-1 and HIV-2 differentially regulate NF-κB activity during the late stages of the replication cycle through BST-2/tetherin antagonism

2020 ◽  
Author(s):  
François E. Dufrasne ◽  
Géraldine Dessilly ◽  
Mara Lucchetti ◽  
Kate Soumillion ◽  
Eléonore Ngyuvula ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Replication ◽  
Signaling Pathway ◽  
Replication Cycle ◽  
Immune Control ◽  
Antiviral Immune Response ◽  
Late Stages ◽  
Hiv 1 ◽  
Tetherin Antagonism

ABSTRACTHIV-2 is the second causative agent of AIDS and is commonly considered as an attenuated form of retroviral infection. Most of HIV-2-infected individuals display a slow-progressing disease, lower viral loads and a stronger immunological control of viral infection as compared with HIV-1-infected patients. The main hypothesis that could explain the difference of disease progression between HIV-1 and HIV-2 implies a more efficient T cell–mediated immunity in the control of HIV-2 infection. Herein, we investigate the effects of the HIV-2 envelope glycoprotein (Env) and its antitetherin function in the NF-κB signaling pathway during single-round infection of CD4+ T cells. First, we report an essential role of the Env cytoplasmic tail (CT) in the activation of this signaling pathway and we also demonstrate that the HIV-2 Env CT activates NF-κB in a TRAF6-dependent but TAK1-independent manner. Further, we show that HIV-2 reference strains and clinical isolates are unable to completely inhibit NF-κB mainly via the Env-mediated BST-2/tetherin antagonism in the late stages of the viral replication cycle in CD4+ T cells, in striking contrast to the HIV-1 Vpu-mediated counteraction of tetherin. We observe that this inability of HIV-2 to suppress NF-κB signaling pathway promotes stimulation of numerous genes involved in the antiviral immune response, such as il-6, il-21 and ifn-β genes. Therefore, HIV-1 and HIV-2 differentially regulate the NF-κB-induced antiviral immune response mainly through the BST-2/tetherin antagonism. These new insights highlight molecular mechanisms determining, at least partly, the distinct immune control and disease outcomes of HIV-1 and HIV-2 infections.IMPORTANCEThis study explores how HIV-1 and HIV-2 diverge in their regulation of the NF-κB signaling pathway. We revealed that HIV-2 fails to completely inhibit NF-κB activity, thereby inducing a stronger antiviral response than HIV-1. We demonstrated that the ability to antagonize the cellular restriction factor BST-2/tetherin largely governs the regulation of the NF-κB pathway: at the late stages of the viral replication cycle, HIV-1 Vpu blocks this pathway whereas HIV-2 Env does not. We also demonstrated that several NF-κB-targeted genes are upregulated in CD4+ T cells infected with HIV-2, but not with HIV-1. This stronger NF-κB-induced antiviral response may explain the better immune control of HIV-2 infection and the differences between HIV-1 and HIV-2 pathogenesis. Moreover, we observed in this study that non-pathogenic isolates of HIV-2 have an impaired NF-κB inhibitory capacity compared to pathogenic ones.

scholarly journals Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B

Virology ◽  
2007 ◽  
Vol 361 (1) ◽  
pp. 141-148 ◽  
Author(s):  
Jeroen N. Stoop ◽  
Renate G. van der Molen ◽  
Ernst J. Kuipers ◽  
Johannes G. Kusters ◽  
Harry L.A. Janssen
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Regulatory T Cells ◽  
Viral Replication ◽  
Chronic Hepatitis B ◽  
Antiviral Immune Response

scholarly journals Notwithstanding Circumstantial Alibis, Cytotoxic T Cells Can Be Major Killers of HIV-1-Infected Cells

2016 ◽  
Vol 90 (16) ◽  
pp. 7066-7083 ◽  
Author(s):  
Saikrishna Gadhamsetty ◽  
Tim Coorens ◽  
Rob J. de Boer
Keyword(s):  
T Cells ◽  
Viral Replication ◽  
Cytotoxic T Cells ◽  
Chronic Phase ◽  
Replication Rate ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Eclipse Phase ◽  
Hiv 1

ABSTRACTSeveral experiments suggest that in the chronic phase of human immunodeficiency virus type 1 (HIV-1) infection, CD8+cytotoxic T lymphocytes (CTL) contribute very little to the death of productively infected cells. First, the expected life span of productively infected cells is fairly long, i.e., about 1 day. Second, this life span is hardly affected by the depletion of CD8+T cells. Third, the rate at which mutants escaping a CTL response take over the viral population tends to be slow. Our main result is that all these observations are perfectly compatible with killing rates that are much faster than one per day once we invoke the fact that infected cells proceed through an eclipse phase of about 1 day before they start producing virus. Assuming that the major protective effect of CTL is cytolytic, we demonstrate that mathematical models with an eclipse phase account for the data when the killing is fast and when it varies over the life cycle of infected cells. Considering the steady state corresponding to the chronic phase of the infection, we find that the rate of immune escape and the rate at which the viral load increases following CD8+T cell depletion should reflect the viral replication rate, ρ. A meta-analysis of previous data shows that viral replication rates during chronic infection vary between 0.5 ≤ ρ ≤ 1 day−1. Balancing such fast viral replication requires killing rates that are several times larger than ρ, implying that most productively infected cells would die by cytolytic effects.IMPORTANCEMost current data suggest that cytotoxic T cells (CTL) mediate their control of human immunodeficiency virus type 1 (HIV-1) infection by nonlytic mechanisms; i.e., the data suggest that CTL hardly kill. This interpretation of these data has been based upon the general mathematical model for HIV infection. Because this model ignores the eclipse phase between the infection of a target cell and the start of viral production by that cell, we reanalyze the same data sets with novel models that do account for the eclipse phase. We find that the data are perfectly consistent with lytic control by CTL and predict that most productively infected cells are killed by CTL. Because the killing rate should balance the viral replication rate, we estimate both parameters from a large set of published experiments in which CD8+T cells were depleted in simian immunodeficiency virus (SIV)-infected monkeys. This confirms that the killing rate can be much faster than is currently appreciated.

scholarly journals Dendritic Cell Precursors Are Permissive to Dengue Virus and Human Immunodeficiency Virus Infection

2005 ◽  
Vol 79 (12) ◽  
pp. 7291-7299 ◽  
Author(s):  
Wing-Hong Kwan ◽  
Anna-Marija Helt ◽  
Concepción Marañón ◽  
Jean-Baptiste Barbaroux ◽  
Anne Hosmalin ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Immunodeficiency Virus ◽  
Virus Infection ◽  
Dengue Virus ◽  
Blood Monocytes ◽  
Dengue Virus Infection ◽  
Differentiation Potential ◽  
Antiviral Immune Response ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT CD14+ interstitial cells reside beneath the epidermis of skin and mucosal tissue and may therefore play an important role in viral infections and the shaping of an antiviral immune response. However, in contrast to dendritic cells (DC) or blood monocytes, these antigen-presenting cells (APC) have not been well studied. We have previously described long-lived CD14+ cells generated from CD34+ hematopoietic progenitors, which may represent model cells for interstitial CD14+ APC. Here, we show that these cells carry DC-SIGN and differentiate into immature DC in the presence of granulocyte-macrophage colony-stimulating factor. We have compared the CD14+ cells and the DC derived from these cells with respect to dengue virus and human immunodeficiency virus type 1 (HIV-1) infection. Both cell types are permissive to dengue virus infection, but the CD14+ cells secrete the anti-inflammatory cytokine interleukin 10 and no tumor necrosis factor alpha. Regarding HIV, the CD14+ cells are permissive to HIV-1, release higher p24 levels than the derived DC, and more efficiently activate HIV Pol-specific CD8+ memory T cells. The CD14+ DC precursors infected with either virus retain their DC differentiation potential. The results suggest that interstitial CD14+ APC may contribute to HIV-1 and dengue virus infection and the shaping of an antiviral immune response.

scholarly journals Human Papillomavirus Type 16 E7 Peptide-Directed CD8+ T Cells from Patients with Cervical Cancer Are Cross-Reactive with the Coronavirus NS2 Protein

2003 ◽  
Vol 77 (9) ◽  
pp. 5464-5474 ◽  
Author(s):  
Katja Nilges ◽  
Hanni Höhn ◽  
Henryk Pilch ◽  
Claudia Neukirch ◽  
Kirsten Freitag ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Immune Response ◽  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
T Cell Responses ◽  
Cross Reactivity ◽  
Antiviral Immune Response ◽  
Human Papillomavirus Type 16 ◽  
Cell Responses

ABSTRACT Human papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are required for cellular transformation and represent candidate targets for HPV-specific and major histocompatibility complex class I-restricted CD8+-T-cell responses in patients with cervical cancer. Recent evidence suggests that cross-reactivity represents the inherent nature of the T-cell repertoire. We identified HLA-A2 binding HPV16 E7 variant peptides from human, bacterial, or viral origin which are able to drive CD8+-T-cell responses directed against wild-type HPV16 E7 amino acid 11 to 19/20 (E711-19/20) epitope YMLDLQPET(T) in vitro. CD8+ T cells reacting to the HLA-A2-presented peptide from HPV16 E711-19(20) recognized also the HLA-A2 binding peptide TMLDIQPED (amino acids 52 to 60) from the human coronavirus OC43 NS2 gene product. Establishment of coronavirus NS2-specific, HLA-A2-restricted CD8+-T-cell clones and ex vivo analysis of HPV16 E7 specific T cells obtained by HLA-A2 tetramer-guided sorting from PBL or tumor-infiltrating lymphocytes obtained from patients with cervical cancer showed that cross-reactivity with HPV16 E711-19(20) and coronavirus NS252-60 represents a common feature of this antiviral immune response defined by cytokine production. Zero of 10 patients with carcinoma in situ neoplasia and 3 of 18 patients with cervical cancer showed ≥0.1% HPV16 E7-reactive T cells in CD8+ peripheral blood lymphocytes. In vivo priming with HPV16 was confirmed in patients with cervical cancer or preinvasive HPV16-positive lesions using HLA-A2 tetramer complexes loaded with the E6-derived epitope KLPQLCTEL. In contrast, we could not detect E6-reactive T cells in healthy individuals. These data imply that the measurement of the HPV16 E711-19(20) CD8+-T-cell response may reflect cross-reactivity with a common pathogen and that variant peptides may be employed to drive an effective cellular immune response against HPV.

scholarly journals Variants in Host Viral Replication Cycle Genes Are Associated With Heterosexual HIV-1 Acquisition in Africans

2014 ◽  
Vol 66 (2) ◽  
pp. 127-134 ◽  
Author(s):  
Abigail W. Bigham ◽  
Romel D. Mackelprang ◽  
Connie Celum ◽  
Guy De Bruyn ◽  
Kristin Beima-Sofie ◽  
...  
Keyword(s):  
Viral Replication ◽  
Replication Cycle ◽  
Hiv 1

A Janus Kinase in the JAK/STAT signaling pathway from Litopenaeus vannamei is involved in antiviral immune response

2015 ◽  
Vol 44 (2) ◽  
pp. 662-673 ◽  
Author(s):  
Xuan Song ◽  
Zijian Zhang ◽  
Sheng Wang ◽  
Haoyang Li ◽  
Hongliang Zuo ◽  
...  
Keyword(s):  
Immune Response ◽  
Signaling Pathway ◽  
Litopenaeus Vannamei ◽  
Janus Kinase ◽  
Antiviral Immune Response ◽  
Stat Signaling

CCCH‐type zinc finger antiviral protein mediates antiviral immune response by activating T cells

2020 ◽  
Vol 107 (2) ◽  
pp. 299-307 ◽  
Author(s):  
Mingjun Zhu ◽  
Jing Zhou ◽  
Yanfei Liang ◽  
Venugopal Nair ◽  
Yongxiu Yao ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Zinc Finger ◽  
Antiviral Protein ◽  
Antiviral Immune Response

scholarly journals Race between Retroviral Spread and CD4+ T-Cell Response Determines the Outcome of Acute Friend Virus Infection

2009 ◽  
Vol 83 (21) ◽  
pp. 11211-11222 ◽  
Author(s):  
Rebecca Pike ◽  
Andrew Filby ◽  
Mickaël J.-Y. Ploquin ◽  
Urszula Eksmond ◽  
Rute Marques ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Acute Infection ◽  
T Cell Response ◽  
Friend Virus ◽  
Antiviral Immune Response ◽  
Ultimate Failure ◽  
Necessary And Sufficient

ABSTRACT Retroviruses can establish persistent infection despite induction of a multipartite antiviral immune response. Whether collective failure of all parts of the immune response or selective deficiency in one crucial part underlies the inability of the host to clear retroviral infections is currently uncertain. We examine here the contribution of virus-specific CD4+ T cells in resistance against Friend virus (FV) infection in the murine host. We show that the magnitude and duration of the FV-specific CD4+ T-cell response is directly proportional to resistance against acute FV infection and subsequent disease. Notably, significant protection against FV-induced disease is afforded by FV-specific CD4+ T cells in the absence of a virus-specific CD8+ T-cell or B-cell response. Enhanced spread of FV infection in hosts with increased genetic susceptibility or coinfection with Lactate dehydrogenase-elevating virus (LDV) causes a proportional increase in the number of FV-specific CD4+ T cells required to control FV-induced disease. Furthermore, ultimate failure of FV/LDV coinfected hosts to control FV-induced disease is accompanied by accelerated contraction of the FV-specific CD4+ T-cell response. Conversely, an increased frequency or continuous supply of FV-specific CD4+ T cells is both necessary and sufficient to effectively contain acute infection and prevent disease, even in the presence of coinfection. Thus, these results suggest that FV-specific CD4+ T cells provide significant direct protection against acute FV infection, the extent of which critically depends on the ratio of FV-infected cells to FV-specific CD4+ T cells.

scholarly journals HIV-1 Vpr Accelerates Viral Replication during Acute Infection by Exploitation of Proliferating CD4+ T Cells In Vivo

2013 ◽  
Vol 9 (12) ◽  
pp. e1003812 ◽  
Author(s):  
Kei Sato ◽  
Naoko Misawa ◽  
Shingo Iwami ◽  
Yorifumi Satou ◽  
Masao Matsuoka ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Replication ◽  
Cd4 T Cells ◽  
Acute Infection ◽  
Hiv 1

scholarly journals Thymic HIV-2 Infection Uncovers Posttranscriptional Control of Viral Replication in Human Thymocytes

2014 ◽  
Vol 89 (4) ◽  
pp. 2201-2208 ◽  
Author(s):  
Helena Nunes-Cabaço ◽  
Paula Matoso ◽  
Russell B. Foxall ◽  
Rita Tendeiro ◽  
Ana R. Pires ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Cell Loss ◽  
Replication Cycle ◽  
Cd4 T Cell ◽  
Mrna Levels ◽  
Thymic Tissue ◽  
Cell Production ◽  
Human Thymus ◽  
Hiv 1

ABSTRACTA unique HIV-host equilibrium exists in untreated HIV-2-infected individuals. This equilibrium is characterized by low to undetectable levels of viremia throughout the disease course, despite the establishment of disseminated HIV-2 reservoirs at levels comparable to those observed in untreated HIV-1 infection. Although the clinical spectrum is similar in the two infections, HIV-2 infection is associated with a much lower rate of CD4 T-cell decline and has a limited impact on the mortality of infected adults. Here we investigated HIV-2 infection of the human thymus, the primary organ for T-cell production. Human thymic tissue and suspensions of total or purified CD4 single-positive thymocytes were infected with HIV-2 or HIV-1 primary isolates using either CCR5 or CXCR4 coreceptors. We found that HIV-2 infected both thymic organ cultures and thymocyte suspensions, as attested to by the total HIV DNA and cell-associated viral mRNA levels. Nevertheless, thymocytes featured reduced levels of intracellular Gag viral protein, irrespective of HIV-2 coreceptor tropism and cell differentiation stage, in agreement with the low viral load in culture supernatants. Our data show that HIV-2 is able to infect the human thymus, but the HIV-2 replication cycle in thymocytes is impaired, providing a new model to identify therapeutic targets for viral replication control.IMPORTANCEHIV-1 infects the thymus, leading to a decrease in CD4 T-cell production that contributes to the characteristic CD4 T-cell loss. HIV-2 infection is associated with a very low rate of progression to AIDS and is therefore considered a unique naturally occurring model of attenuated HIV disease. HIV-2-infected individuals feature low to undetectable plasma viral loads, in spite of the numbers of circulating infected T cells being similar to those found in patients infected with HIV-1. We assessed, for the first time, the direct impact of HIV-2 infection on the human thymus. We show that HIV-2 is able to infect the thymus but that the HIV-2 replication cycle in thymocytes is impaired. We propose that this system will be important to devise immunotherapies that target viral production, aiding the design of future therapeutic strategies for HIV control.

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