scholarly journals Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

2008 ◽  
Vol 83 (2) ◽  
pp. 884-895 ◽  
Author(s):  
Susanna Trapp ◽  
Nina R. Derby ◽  
Rachel Singer ◽  
Andrew Shaw ◽  
Vennansha G. Williams ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Hiv Infection ◽  
Molecular Mass ◽  
Type I Interferon ◽  
Poly I:C ◽  
Interleukin 12 ◽  
Type I ◽  
Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus (HIV) is taken up by and replicates in immature dendritic cells (imDCs), which can then transfer virus to T cells, amplifying the infection. Strategies known to boost DC function were tested for their ability to overcome this exploitation when added after HIV exposure. Poly(I:C), but not single-stranded RNA (ssRNA) or a standard DC maturation cocktail, elicited type I interferon (IFN) and interleukin-12 (IL-12) p70 production and the appearance of unique small (15- to 20-kDa) fragments of APOBEC3G (A3G) and impeded HIVBal replication in imDCs when added up to 60 h after virus exposure. Comparable effects were mediated by recombinant alpha/beta IFN (IFN-α/β). Neutralizing the anti-IFN-α/β receptor reversed poly(I:C)-induced inhibition of HIV replication and blocked the appearance of the small A3G proteins. The poly(I:C)-induced appearance of small A3G proteins was not accompanied by significant differences in A3G mRNA or A3G monomer expression. Small interfering RNA (siRNA) knockdown of A3G could not be used to reverse the poly(I:C)-induced protective effect, since siRNAs nonspecifically activated the DCs, inducing the appearance of the small A3G proteins and inhibiting HIV infection. Notably, the appearance of small A3G proteins coincided with the shift of high-molecular-mass inactive A3G complexes to the low-molecular-mass (LMM) active A3G complexes. The unique immune stimulation by poly(I:C) with its antiviral effects on imDCs marked by the expression of IFN-α/β and active LMM A3G renders poly(I:C) a promising novel strategy to combat early HIV infection in vivo.

scholarly journals Type I Interferon Upregulates Bak and Contributes to T Cell Loss during Human Immunodeficiency Virus (HIV) Infection

2013 ◽  
Vol 9 (10) ◽  
pp. e1003658 ◽  
Author(s):  
Joseph A. Fraietta ◽  
Yvonne M. Mueller ◽  
Guibin Yang ◽  
Alina C. Boesteanu ◽  
Donald T. Gracias ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Hiv Infection ◽  
Type I Interferon ◽  
Cell Loss ◽  
Type I ◽  
Immunodeficiency Virus

Zidovudine and Didanosine Combination Therapy in Children With Human Immunodeficiency Virus Infection

PEDIATRICS ◽  
1994 ◽  
Vol 93 (2) ◽  
pp. 316-322 ◽  
Author(s):  
Robert N. Husson ◽  
Brigitta U. Mueller ◽  
Maureen Farley ◽  
Linda L. Lewis ◽  
Frank M. Balis ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Combination Therapy ◽  
Antiviral Activity ◽  
Hiv Infection ◽  
Geometric Mean ◽  
Single Agent ◽  
Nucleoside Analogues ◽  
Hematologic Toxicity ◽  
Immunodeficiency Virus

Objective. Zidovudine and didanosine are both beneficial for the treatment of human immunodeficiency virus (HIV) infection in children. Because disease progression and toxicity often limit their long-term use as single agents, new approaches to using nucleoside analogues are necessary to improve current antiretroviral therapy. Design. We conducted a phase I-II study to evaluate the tolerance, pharmacokinetics, and antiviral activity of the combination of zidovudine and didanosine in children with HIV infection. Sixty-eight children who were either previously untreated or who had manifested hematologic toxicity on full-dose zidovudine were enrolled. Eight dose combinations were studied in the previously untreated children, with doses of zidovudine ranging from 90 to 180 mg/m2 every 6 hours and doses of didanosine ranging from 90 to 180 mg/m2 every 12 hours. Results. Fifty-four previously untreated HIV-infected children were enrolled in this part of the study, of whom 49 remained in the study for a minimum of 24 weeks. For children with previous zidovudine-related hematologic toxicity, three dose levels with zidovudine at 60 mg/m2 every 6 hours orally and didanosine ranging from 90 to 180 mg/m2 every 12 hours orally were used. A total of 14 children were enrolled in this part of the study, and 12 remained on therapy for at least 24 weeks. No evidence of new or enhanced toxicity was observed in either group. After 24 weeks, the median CD4 cell count for all patients increased from 331 to 556 cells/mm3 (P = .01). For the previously untreated group, the median increase in CD4 counts was from 386 to 726 cells/mm3 (P = .003). The median p24 antigen concentration (in those with a detectable level at baseline) decreased from 95 to <31 pg/mL (P < .001). The geometric mean titer of HIV in plasma decreased from 83.1 to 2.7 tissue culture infectious doses/mL (P = .001). Conclusions. The combination of zidovudine and didanosine was well-tolerated at doses as high as those used in single agent therapy. Potent in vivo antiviral activity was observed. Combination therapy with nucleoside analogues may be an important approach to optimizing the use of these agents in the treatment of HIV infection.

scholarly journals Potent activity of 2'-beta-fluoro-2',3'-dideoxyadenosine against human immunodeficiency virus type 1 infection in hu-PBL-SCID mice.

1996 ◽  
Vol 40 (10) ◽  
pp. 2369-2374 ◽  
Author(s):  
K Ruxrungtham ◽  
E Boone ◽  
H Ford ◽  
J S Driscoll ◽  
R T Davey ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Hiv Infection ◽  
Infection Rate ◽  
Cd4 T Cells ◽  
Scid Mice ◽  
Immunodeficiency Virus ◽  
Anti Hiv

A new antiretroviral agent, 2'-beta-fluoro-2',3'-dideoxyadenosine (FddA), is an acid-stable compound whose triphosphate form is a potent reverse transcriptase inhibitor with in vitro anti-human immunodeficiency virus (HIV) activity and a favorable pharmacokinetic profile. Severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice) provide a useful small-animal model for HIV research. In the present study we utilized this experimental system for the in vivo evaluation of the anti-HIV activity of this new compound when administered prior to infection. Initial studies revealed that, following a challenge with 50 100% tissue culture infective doses of HIV type 1 lymphadenopathy-associated virus, 39 of 42 (93%) control mice developed HIV infection, as evidenced by positive coculture or positive PCR. Administration of zidovudine decreased the infection rate to 5 of 16 (31%), while administration of FddA decreased the infection rate to 0 of 44 (0%). In follow-up controlled studies, the anti-HIV activity of FddA was confirmed, with 18 of 20 control mice showing evidence of HIV infection, compared with 4 of 20 FddA-treated mice. In addition to having direct anti-HIV effects, FddA was found to have a protective effect on human CD4+ T cells in the face of HIV infection. Mice treated with FddA were found to have a significantly higher percentage of CD4+ T cells than controls (10.3% +/- 3.4% versus 0.27% +/- 0.21%; P = 0.01). Thus, FddA, with its potent anti-HIV activity in vivo, high oral bioavailability, long intracellular half-life, and ability to preserve CD4+ cells in the presence of HIV, appears to be a promising agent for clinical investigation.

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 gp120 Inhibits Interleukin-12 Secretion by Human Monocytes: An Indirect Interleukin-10–Mediated Effect

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2842-2848 ◽  
Author(s):  
Y. Taoufik ◽  
O. Lantz ◽  
C. Wallon ◽  
A. Charles ◽  
E. Dussaix ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Aureus Strain ◽  
Interleukin 12 ◽  
Similar Data ◽  
Human Monocytes ◽  
Mrna Accumulation ◽  
Immunodeficiency Virus ◽  
Monocytes And Macrophages ◽  
Hiv Gp120

Abstract Interleukin-12 (IL-12), a cytokine with in vitro and in vivo immunomodulatory effects, is produced mostly by activated monocytes and macrophages. To study the effect of human immunodeficiency virus (HIV) infection on IL-12 production, we investigated the expression of IL-12 at mRNA and protein levels by human monocytes preincubated with HIV-gp120. In these conditions, we show that monocytes have a decreased ability to express IL-12 mRNA subunits and to produce IL-12 p40 and bioactive p70 proteins in response to Staphylococcus aureus strain cowan I (SAC). We showed that in human monocyte cultures, HIV-gp120 induces a significant IL-10 synthesis, which in turn inhibits IL-12 subunits mRNA accumulation and protein secretion after SAC-activation. Similar data were obtained with human macrophages. These results suggest that, during HIV infection, gp120 induces in uninfected monocytes and macrophages IL-10/IL-12 disregulation, which can alter immune response.

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.

Detection and characterization of apoptotic peripheral blood lymphocytes in human immunodeficiency virus infection and cancer chemotherapy by a novel flow immunocytometric method

Blood ◽  
1994 ◽  
Vol 83 (5) ◽  
pp. 1268-1277 ◽  
Author(s):  
M Carbonari ◽  
M Cibati ◽  
M Cherchi ◽  
D Sbarigia ◽  
AM Pesce ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Hiv Infection ◽  
Peripheral Blood ◽  
Peripheral Blood Leukocytes ◽  
Blood Leukocytes ◽  
Cell Counts ◽  
Immunodeficiency Virus

We have developed a quantitative and sensitive flow cytometric method for the detection of human apoptotic lymphocytes that, unlike previously described assays, allows their identification in mixed populations of peripheral blood leukocytes as well as their immunophenotyping. Apoptotic lymphocytes are identified on the basis of peculiar light scatter changes, reflecting their smaller size and their modified nucleus/cytoplasm organization, and of the decreased expression of surface CD45 molecules. Based on these criteria, apoptotic lymphocytes generated by exposure to ionizing radiation can be easily distinguished from viable cells and from necrotic lymphocytes generated by treatment with antibody and complement. Using this assay, we reappraised the phenomenon of the in vitro apoptosis of lymphocytes from patients with human immunodeficiency virus (HIV) infection. Lymphocytes from HIV patients, unlike those from normal HIV-negative subjects, undergo apoptosis upon simple in vitro culture. We found that the percentages of lymphocytes undergoing apoptosis were significantly higher in patients with low CD4 cell counts (< 400/microL) than in patients at earlier stages (> 400 CD4 cells/microL). However, phenotypic analysis disclosed that apoptotic lymphocytes generated in these cultures were mostly CD8+ T cells and CD19+ B cells. Thus, in contrast to what has been previously suggested, the phenomenon of in vitro lymphocyte apoptosis might not be pathogenetically related to the depletion of CD4+ T cells in acquired immunodeficiency syndrome. Nevertheless, it might represent an useful marker of disease progression. Our assay allows the analysis of unfractionated peripheral blood leukocytes and thus the identification of apoptotic lymphocytes circulating in vivo. Apoptotic lymphocytes could indeed be detected in the circulation of a patient with cancer shortly after high-dose cytotoxic chemotherapy. By contrast, no apoptotic lymphocytes could be detected in vivo in patients with early or advanced HIV infection.

scholarly journals In Vitro Evaluation of Nonnucleoside Reverse Transcriptase Inhibitors UC-781 and TMC120-R147681 as Human Immunodeficiency Virus Microbicides

2004 ◽  
Vol 48 (1) ◽  
pp. 337-339 ◽  
Author(s):  
Yven Van Herrewege ◽  
Jo Michiels ◽  
Jens Van Roey ◽  
Katrien Fransen ◽  
Luc Kestens ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Hiv Infection ◽  
Reverse Transcriptase ◽  
Sexual Transmission ◽  
Therapeutic Index ◽  
Reverse Transcriptase Inhibitors ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Immunodeficiency Virus

ABSTRACT The nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 (Dapivirine) effectively prevented human immunodeficiency virus (HIV) infection in cocultures of monocyte-derived dendritic cells and T cells, representing primary targets in sexual transmission. Both drugs had a favorable therapeutic index. A 24-h treatment with 1,000 nM UC-781 or 100 nM TMC120-R147681 prevented cell-free HIV infection, whereas 10-fold-higher concentrations blocked cell-associated HIV.

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