scholarly journals Human immunodeficiency virus type 1 (HIV-1) protease inhibitors block cell-to-cell HIV-1 endocytosis in dendritic cells

2009 ◽  
Vol 90 (11) ◽  
pp. 2777-2787 ◽  
Author(s):  
Claudia Muratori ◽  
Eliana Ruggiero ◽  
Antonella Sistigu ◽  
Roberta Bona ◽  
Maurizio Federico
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Hiv Protease ◽  
Donor Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

Sexual transmission is now the most frequent means of diffusion of human immunodeficiency virus type 1 (HIV-1). Even if the underlying mechanism is still largely unknown, there is a consensus regarding the key role played by mucosal dendritic cells (DCs) in capturing HIV through contact with infected subepithelial lymphocytes, and their capacity to spread HIV by trans-infection. We found that HIV protease inhibitors (PIs) reduced virion endocytosis strongly in monocyte-derived immature (i) DCs contacting HIV-1-infected cells, and that this phenomenon led to dramatically impaired trans-infection activity. This inhibitory effect was not mediated by the block of viral protease activity, as it was also operative when donor cells were infected with a PI-resistant HIV-1 strain. The block of virus maturation imposed by PIs did not correlate with significant variations in the levels of virus expression in donor cells or of Gag/Env virion incorporation. Also, PIs did not affect the endocytosis activity of DCs. In contrast, we noticed that PI treatment inhibited the formation of cell–cell conjugates whilst reducing the expression of ICAM-1 in target iDCs. Our results contribute to a better delineation of the mechanisms underlying HIV-1 trans-infection activity in DCs, whilst having implications for the development of new anti-HIV microbicide strategies.

scholarly journals Differential Transmission of Human Immunodeficiency Virus Type 1 by Distinct Subsets of Effector Dendritic Cells

2002 ◽  
Vol 76 (15) ◽  
pp. 7812-7821 ◽  
Author(s):  
Rogier W. Sanders ◽  
Esther C. de Jong ◽  
Christopher E. Baldwin ◽  
Joost H. N. Schuitemaker ◽  
Martien L. Kapsenberg ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Virus Transmission ◽  
Viral Envelope ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Dendritic cells (DC) support human immunodeficiency virus type 1 (HIV-1) transmission by capture of the virus particle in the mucosa and subsequent transport to the draining lymph node, where HIV-1 is presented to CD4+ Th cells. Virus transmission involves a high-affinity interaction between the DC-specific surface molecule DC-SIGN and the viral envelope glycoprotein gp120 and subsequent internalization of the virus, which remains infectious. The mechanism of viral transmission from DC to T cells is currently unknown. Sentinel immature DC (iDC) develop into Th1-promoting effector DC1 or Th2-promoting DC2, depending on the activation signals. We studied the ability of these effector DC subsets to support HIV-1 transmission in vitro. Compared with iDC, virus transmission is greatly upregulated for the DC1 subset, whereas DC2 cells are inactive. Increased transmission by DC1 correlates with increased expression of ICAM-1, and blocking studies confirm that ICAM-1 expression on DC is important for HIV transmission. The ICAM-1-LFA-1 interaction is known to be important for immunological cross talk between DC and T cells, and our results indicate that this cell-cell contact is exploited by HIV-1 for efficient transmission.

scholarly journals CD4 Binding Affinity Determines Human Immunodeficiency Virus Type 1-Induced Alpha Interferon Production in Plasmacytoid Dendritic Cells

2008 ◽  
Vol 82 (17) ◽  
pp. 8900-8905 ◽  
Author(s):  
Sabrina Haupt ◽  
Norbert Donhauser ◽  
Chawaree Chaipan ◽  
Philipp Schuster ◽  
Bridget Puffer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Binding Affinity ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Plasmacytoid dendritic cells (PDC) are major producers of type I interferons (IFN) in response to human immunodeficiency virus type 1 (HIV-1) infection. To better define the underlying mechanisms, we studied the magnitude of alpha IFN (IFN-α) induction by recombinant viruses containing changes in the Env protein that impair or disrupt CD4 binding or expressing primary env alleles with differential coreceptor tropism. We found that the CD4 binding affinity but not the viral coreceptor usage is critical for the attachment of autofluorescing HIV-1 to PDC and for subsequent IFN-α induction. Our results illustrate the importance of the gp120-CD4 interaction in determining HIV-1-induced immune stimulation via IFN-α production.

scholarly journals Human Immunodeficiency Virus Type 1 Derived from Cocultures of Immature Dendritic Cells with Autologous T Cells Carries T-Cell-Specific Molecules on Its Surface and Is Highly Infectious

1999 ◽  
Vol 73 (4) ◽  
pp. 3449-3454 ◽  
Author(s):  
Ines Frank ◽  
Laco Kacani ◽  
Heribert Stoiber ◽  
Hella Stössel ◽  
Martin Spruth ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Surface ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT During the budding process, human immunodeficiency virus type 1 (HIV-1) acquires cell surface molecules; thus, the viral surface of HIV-1 reflects the antigenic pattern of the host cell. To determine the source of HIV-1 released from cocultures of dendritic cells (DC) with T cells, immature DC (imDC), mature DC (mDC), T cells, and their cocultures were infected with different HIV-1 isolates. The macrophage-tropic HIV-1 isolate Ba-L allowed viral replication in both imDC and mDC, whereas the T-cell-line-tropic primary isolate PI21 replicated in mDC only. By a virus capture assay, HIV-1 was shown to carry a T-cell- or DC-specific cell surface pattern after production by T cells or DC, respectively. Upon cocultivation of HIV-1-pulsed DC with T cells, HIV-1 exclusively displayed a typical T-cell pattern. Additionally, functional analysis revealed that HIV-1 released from imDC–T-cell cocultures was more infectious than HIV-1 derived from mDC–T-cell cocultures and from cultures of DC, T cells, or peripheral blood mononuclear cells alone. Therefore, we conclude that the interaction of HIV-1-pulsed imDC with T cells in vivo might generate highly infectious virus which primarily originates from T cells.

scholarly journals Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis

2004 ◽  
Vol 78 (18) ◽  
pp. 9763-9772 ◽  
Author(s):  
Laura Fantuzzi ◽  
Cristina Purificato ◽  
Karim Donato ◽  
Filippo Belardelli ◽  
Sandra Gessani
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Interleukin 12 ◽  
Activation Markers ◽  
Antigen Uptake ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Dendritic cells (DCs) play a crucial role in bridging innate and acquired immune responses to pathogens. In human immunodeficiency virus type 1 (HIV-1) infection, immature DCs (iDCs) are also main targets for HIV-1 at the mucosal level. In this study, we evaluated the effects of HIV-1-DC interactions on the maturation and functional activity of these cells. Exposure of human monocyte-derived iDCs to either aldrithiol-2-inactivated HIV-1 or gp120 led to an upmodulation of activation markers indicative of functional maturation. Despite their phenotype, these cells retained antigen uptake capacity and showed an impaired ability to secrete cytokines or chemokines and to induce T-cell proliferation. Although gp120 did not interfere with DC differentiation, the capacity of these cells to produce interleukin-12 (IL-12) upon maturation was markedly reduced. Likewise, iDCs stimulated by classical maturation factors in the presence of gp120 lacked allostimulatory capacity and did not produce IL-12, in spite of their phenotype typical of activated DCs. Exogenous addition of IL-12 restores the allostimulatory capacity of gp120-exposed DCs. The finding that gp120 induces abnormal maturation of DCs linked to profound suppression of their activities unravels a novel mechanism by which HIV can lead to immune dysfunction in AIDS patients.

scholarly journals Human Immunodeficiency Virus Type 1 Activates Plasmacytoid Dendritic Cells and Concomitantly Induces the Bystander Maturation of Myeloid Dendritic Cells

2004 ◽  
Vol 78 (10) ◽  
pp. 5223-5232 ◽  
Author(s):  
Jean-François Fonteneau ◽  
Marie Larsson ◽  
Anne-Sophie Beignon ◽  
Kelli McKenna ◽  
Ida Dasilva ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Plasmacytoid Dendritic Cells ◽  
Myeloid Dendritic Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT In this study, we analyzed the phenotypic and physiological consequences of the interaction of plasmacytoid dendritic cells (pDCs) with human immunodeficiency virus type 1 (HIV-1). pDCs are one cellular target of HIV-1 and respond to the virus by producing alpha/beta interferon (IFN-α/β) and chemokines. The outcome of this interaction, notably on the function of bystander myeloid DC (CD11c+ DCs), remains unclear. We therefore evaluated the effects of HIV-1 exposure on these two DC subsets under various conditions. Blood-purified pDCs and CD11c+ DCs were exposed in vitro to HIV-1, after which maturation markers, cytokine production, migratory capacity, and CD4 T-cell stimulatory capacity were analyzed. pDCs exposed to different strains of infectious or even chemically inactivated, nonreplicating HIV-1 strongly upregulated the expression of maturation markers, such as CD83 and functional CCR7, analogous to exposure to R-848, a synthetic agonist of toll-like receptor-7 and -8. In addition, HIV-1-activated pDCs produced cytokines (IFN-α and tumor necrosis factor alpha), migrated in response to CCL19 and, in coculture, matured CD11c+ DCs, which are not directly activated by HIV. pDCs also acquired the ability to stimulate naïve CD4+ T cells, albeit less efficiently than CD11c+ DCs. This HIV-1-induced maturation of both DC subsets may explain their disappearance from the blood of patients with high viral loads and may have important consequences on HIV-1 cellular transmission and HIV-1-specific T-cell responses.

scholarly journals Heterologous Human Immunodeficiency Virus Type 1 Lentiviral Vectors Packaging a Simian Immunodeficiency Virus-Derived Genome Display a Specific Postentry Transduction Defect in Dendritic Cells

2003 ◽  
Vol 77 (17) ◽  
pp. 9295-9304 ◽  
Author(s):  
Caroline Goujon ◽  
Loraine Jarrosson-Wuilleme ◽  
Jeanine Bernaud ◽  
Dominique Rigal ◽  
Jean-Luc Darlix ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Types ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Heterologous lentiviral vectors (LVs) represent a way to address safety concerns in the field of gene therapy by decreasing the possibility of genetic recombination between vector and packaging constructs and the generation of replication-competent viruses. Using described LVs based on human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus MAC251 (SIVMAC251), we asked whether heterologous virion particles in which trans-acting factors belonged to HIV-1 and cis elements belonged to SIVMAC251 (HIV-siv) would behave as parental homologous vectors in all cell types. To our surprise, we found that although the heterologous HIV-siv vector was as infectious as its homologous counterpart in most human cells, it was defective in the transduction of dendritic cells (DCs) and, to a lesser extent, macrophages. In DCs, the main postentry defect was observed in the formation of two-long-terminal-repeat circles, despite the fact that full-length proviral DNA was being synthesized and was associated with the nucleus. Taken together, our data suggest that heterologous HIV-siv vectors display a cell-dependent infectivity defect, most probably at a post-nuclear entry migration step. As homologous HIV and SIV vectors do transduce DCs, we believe that these results underscore the importance of a conserved interaction between cis elements and trans-acting viral factors that is lost or suboptimal in heterologous vectors and essential only in the transduction of certain cell types. For gene therapy purposes, these findings indicate that the cellular tropism of LVs can be modulated not only through the use of distinct envelope proteins or tissue-specific promoters but also through the specific combinatorial use of packaging and transfer vector constructs.

Effects of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Reverse Transcriptase Processing, Activity, and Drug Sensitivity

1999 ◽  
Vol 73 (4) ◽  
pp. 3455-3459 ◽  
Author(s):  
Laurence Carron de la Carrière ◽  
Sylvie Paulous ◽  
François Clavel ◽  
Fabrizio Mammano
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Rt Inhibitors ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease inhibitors often display a reduced replicative capacity as a result of an impairment of protease function. Such fitness-impaired viruses display Gag precursor maturation defects. Here, we report that some protease inhibitor-resistant viruses also display abnormalities in the processing of reverse transcriptase (RT) by the protease. In three recombinant viruses carrying resistant protease sequences from patient plasma, we observed a marked decrease in the amount of mature RT subunits and of particle-associated RT activity compared to their parental pretherapy counterparts. We investigated the possibility that a decrease in the amount of particle-associated mature RT could affect the sensitivity of the corresponding virus to RT inhibitors. We observed a twofold increase of sensitivity to zidovudine (AZT) when a virus which carried AZT mutations was processed by a resistant protease. Interestingly, the presence of AZT-resistance mutations partially rescued the replication defect associated with the mutated protease. The interplay between resistance to protease inhibitors and to RT inhibitors described here may be relevant to the therapeutic control of HIV-1 infection.

scholarly journals Maturation of Blood-Derived Dendritic Cells Enhances Human Immunodeficiency Virus Type 1 Capture and Transmission

2007 ◽  
Vol 81 (14) ◽  
pp. 7559-7570 ◽  
Author(s):  
Nuria Izquierdo-Useros ◽  
Julià Blanco ◽  
Itziar Erkizia ◽  
Maria Teresa Fernández-Figueras ◽  
Francesc E. Borràs ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Target Cells ◽  
Capture Process ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Dendritic cells (DCs) are specialized antigen-presenting cells. However, DCs exposed to human immunodeficiency virus type 1 (HIV-1) are also able to transmit a vigorous cytopathic infection to CD4+ T cells, a process that has been frequently related to the ability of DC-SIGN to bind HIV-1 envelope glycoproteins. The maturation of DCs can increase the efficiency of HIV-1 transmission through trans infection. We aimed to comparatively study the effect of maturation in monocyte-derived DCs (MDDCs) and blood-derived myeloid DCs during the HIV-1 capture process. In vitro capture and transmission of envelope-pseudotyped HIV-1 and its homologous replication-competent virus to susceptible target cells were assessed by p24gag detection, luciferase activity, and both confocal and electron microscopy. Maturation of MDDCs or myeloid DCs enhanced the active capture of HIV-1 in a DC-SIGN- and viral envelope glycoprotein-independent manner, increasing the life span of trapped virus. Moreover, higher viral transmission of mature DCs to CD4+ T cells was highly dependent on active viral capture, a process mediated through cholesterol-enriched domains. Mature DCs concentrated captured virus in a single large vesicle staining for CD81 and CD63 tetraspanins, while immature DCs lacked these structures, suggesting different intracellular trafficking processes. These observations help to explain the greater ability of mature DCs to transfer HIV-1 to T lymphocytes, a process that can potentially contribute to the viral dissemination at lymph nodes in vivo, where viral replication takes place and there is a continuous interaction between susceptible T cells and mature DCs.

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