An Anti‐CD45RO Immunotoxin Kills Latently Infected Human Immunodeficiency Virus (HIV) CD4 T Cells in the Blood of HIV‐Positive Persons

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.

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WFDC1/ps20 Is a Novel Innate Immunomodulatory Signature Protein of Human Immunodeficiency Virus (HIV)-Permissive CD4+ CD45RO+ Memory T Cells That Promotes Infection by Upregulating CD54 Integrin Expression and Is Elevated in HIV Type 1 Infection

Journal of Virology ◽

10.1128/jvi.00939-07 ◽

2007 ◽

Vol 82 (1) ◽

pp. 471-486 ◽

Cited By ~ 19

Author(s):

R. Alvarez ◽

J. Reading ◽

D. F. L. King ◽

M. Hayes ◽

P. Easterbrook ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Cd4 T Cells ◽

Memory T Cells ◽

Ex Vivo ◽

Interleukin 2 ◽

Integrin Expression ◽

Small Interference Rna ◽

Immunodeficiency Virus

ABSTRACT Understanding why human immunodeficiency virus (HIV) preferentially infects some CD4+ CD45RO+ memory T cells has implications for antiviral immunity and pathogenesis. We report that differential expression of a novel secreted factor, ps20, previously implicated in tissue remodeling, may underlie why some CD4 T cells are preferentially targeted. We show that (i) there is a significant positive correlation between endogenous ps20 mRNA in diverse CD4 T-cell populations and in vitro infection, (ii) a ps20+ permissive cell can be made less permissive by antibody blockade- or small-interference RNA-mediated knockdown of endogenous ps20, and (iii) conversely, a ps20low cell can be more permissive by adding ps20 exogenously or engineering stable ps20 expression by retroviral transduction. ps20 expression is normally detectable in CD4 T cells after in vitro activation and interleukin-2 expansion, and such oligoclonal populations comprise ps20positive and ps20low/negative isogenic clones at an early differentiation stage (CD45RO+/CD25+/CD28+/CD57−). This pattern is altered in chronic HIV infection, where ex vivo CD4+ CD45RO+ T cells express elevated ps20. ps20 promoted HIV entry via fusion and augmented CD54 integrin expression; both of these effects were reversed by anti-ps20 antibody. We therefore propose ps20 to be a novel signature of HIV-permissive CD4 T cells that promotes infection in an autocrine and paracrine manner and that HIV has coopted a fundamental role of ps20 in promoting cell adhesion for its benefit. Disrupting the ps20 pathway may therefore provide a novel anti-HIV strategy.

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Cytokine interactions in human immunodeficiency virus-infected individuals: roles of interleukin (IL)-2, IL-12, and IL-15.

Journal of Experimental Medicine ◽

10.1084/jem.182.4.1067 ◽

1995 ◽

Vol 182 (4) ◽

pp. 1067-1077 ◽

Cited By ~ 73

Author(s):

R A Seder ◽

K H Grabstein ◽

J A Berzofsky ◽

J F McDyer

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Tetanus Toxoid ◽

Cd4 T Cells ◽

Mononuclear Cells ◽

Specific Antigen ◽

Neutralizing Antibody ◽

Dependent Manner ◽

Ifn Gamma ◽

Immunodeficiency Virus

Cytokines have been shown to be powerful regulators of the immune response. In this study, we analyze the effect that the newly recognized cytokine interleukin (IL)-15 has on proliferation and cytokine induction using peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells from patients infected with human immunodeficiency virus (HIV) who are at various stages in their disease. We observed that IL-15 enhances the proliferative response in a dose-dependent manner from PBMCs of HIV-infected individuals when stimulated by polyclonal mitogen, tetanus toxoid, or HIV-specific antigen. The effects of exogenous IL-15 are substantially diminished by adding a neutralizing antibody to the beta chain of the IL-2 receptor. Moreover, the ability of IL-15 to increase proliferation is enhanced by the presence of endogenous IL-2 produced in the cultures. The effect that exogenous IL-15 had on IL-2, IL-4, and interferon (IFN)-gamma induction from PBMC's or CD4+ T cells in response to mitogen or tetanus toxoid was also examined. This was compared to the effect that exogenous IL-2 and IL-12 had under the same conditions. Addition of IL-2 or IL-15 to short-term in vitro cultures of either PBMCs or CD4+ T cells had little effect on IL-2, IL-4, or IFN-gamma production. By contrast, IL-12 caused substantial enhancement of both IL-2 and IFN-gamma production from these cultures. The role that endogenous cytokines have on IFN-gamma induction was also studied. Addition of a neutralizing antibody to the alpha chain of the IL-2 receptor or IL-12 to antigen stimulated cultures caused a striking decrease in IFN-gamma production. Neutralization of endogenous IL-15 also resulted in diminished IFN-gamma production from cultures stimulated with mitogen. IL-4 and IFN-gamma protein production by PBMCs and CD4+ T cells stimulated with mitogen was assessed to see if we could detect a specific bias of cytokine production. Small amounts of IL-4 were detected from CD4+ T cells but not PBMCs from most individuals tested. IFN-gamma and IL-2, however, were also produced from these same cultures. These results further elucidate the mechanism of cytokine regulation in HIV-infected individuals, and they provide evidence that IL-15 may be a useful immune modulator.

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Priming of CD4+ T cells specific for conserved regions of human immunodeficiency virus glycoprotein gp120 in humans immunized with a recombinant envelope protein.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.87.16.6136 ◽

1990 ◽

Vol 87 (16) ◽

pp. 6136-6140 ◽

Cited By ~ 16

Author(s):

S. Abrignani ◽

D. Montagna ◽

M. Jeannet ◽

J. Wintsch ◽

N. L. Haigwood ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Envelope Protein ◽

Cd4 T Cells ◽

Virus Glycoprotein ◽

Conserved Regions ◽

Immunodeficiency Virus ◽

Glycoprotein Gp120 ◽

Recombinant Envelope Protein

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Diminished frequency of hepatitis C virus specific interferon secreting CD4+ T cells in human immunodeficiency virus/hepatitis C virus coinfected patients

Gut ◽

10.1136/gut.2005.083758 ◽

2006 ◽

Vol 55 (10) ◽

pp. 1484-1487 ◽

Cited By ~ 42

Author(s):

G Harcourt

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Cd4 T Cells ◽

Virus Hepatitis ◽

Immunodeficiency Virus

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Viral-Specific Cytotoxic T Lymphocytes Lyse Human Immunodeficiency Virus–Infected Primary T Lymphocytes by the Granule Exocytosis Pathway

Blood ◽

10.1182/blood.v94.9.3084.421k02_3084_3093 ◽

1999 ◽

Vol 94 (9) ◽

pp. 3084-3093 ◽

Cited By ~ 2

Author(s):

Premlata Shankar ◽

Zhan Xu ◽

Judy Lieberman

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

T Lymphocytes ◽

Cell Lines ◽

Cytotoxic T Lymphocytes ◽

Cd4 T Cells ◽

Target Cells ◽

Granule Exocytosis ◽

Immunodeficiency Virus ◽

Bystander Cells

Cytotoxic T lymphocytes (CTL) lyse antigen-bearing target cells by two distinct pathways. Whereas granule exocytosis targets any antigen-bearing cell, fas-mediated cytotoxicity kills only fas-expressing cells and does not require antigen expression. Fas pathway activation can potentially lead to lysis of uninfected bystander cells. We examined the relative usage of the two pathways by CTL clones and cell lines directed against four different human immunodeficiency virus (HIV) proteins in lysing primary HIV-infected targets. Although fas was expressed on HIV-infected primary CD4+ T cells, their lysis by antigen-specific CD8+ CTL was only by the granule pathway. Fas ligand (fasL) was not detectable on antigen-specific CD8 clones, T-cell lines, or circulating HIV-specific CD8 T cells from HIV-infected donors, stained with a tetrameric HLA-A2-HIV-peptide complex. FasL expression by HIV-specific CTL clones was not activated by exposure to HIV-presenting cells, but was after unphysiological stimulation with phorbol myristate acetate (PMA). CTL clones did not lyse bystander Jurkat cells, but HIV-infected primary CD4+ T cells lysed uninfected bystander cells by the fas-mediated pathway. These results suggest that HIV-specific CD8+ CTL do not cause HIV immunopathology by lysing bystander cells. On the contrary, fas-mediated lysis of uninfected cells by HIV-infected cells may contribute to CD4 decline.

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