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

1995 ◽  
Vol 182 (4) ◽  
pp. 1067-1077 ◽  
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.

scholarly journals In Vitro Human Immunodeficiency Virus Eradication by Autologous CD8+ T Cells Expanded with Inactivated-Virus-Pulsed Dendritic Cells

2001 ◽  
Vol 75 (19) ◽  
pp. 8949-8956 ◽  
Author(s):  
Wei Lu ◽  
Jean-Marie Andrieu
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Specific Antigen ◽  
Lymphoid Tissues ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Despite significant immune recovery with potent highly active antiretroviral therapy (HAART), eradication of human immunodeficiency virus (HIV) from the bodies of infected individuals represents a challenge. We hypothesized that an inadequate or inappropriate signal in virus-specific antigen presentation might contribute to the persistent failure to mount efficient anti-HIV immunity in most HIV-infected individuals. Here, we conducted an in vitro study with untreated (n = 10) and HAART-treated (n = 20) HIV type 1 (HIV-1) patients which showed that pulsing of monocyte-derived dendritic cells (DC) with aldrithiol-2-inactivated autologous virus resulted in the expansion of virus-specific CD8+ T cells which were capable of killing HIV-1-infected cells and eradicating the virus from cultured patient peripheral blood mononuclear cells independently of the disease stages and HAART response statuses of the patients. This in vitro anti-HIV effect was further enhanced by the HIV protease inhibitor indinavir (at a nonantiviral concentration), which has been shown previously to be able to up-regulate directly patient T-cell proliferation following immune stimulation. However, following a 2-day treatment with culture supernatant derived from immune-activated T cells (which mimics an in vivo environment of HIV-disseminated and immune-activated lymphoid tissues), DC lost their capacity to present de novo inactivated-virus-derived antigens. These findings provide important information for understanding the establishment of chronic HIV infection and indicate a perspective for clinical use of DC-based therapeutic vaccines against HIV.

scholarly journals Changes in cytokine secretion patterns of CD4+ T-cell clones in human immunodeficiency virus infection

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4262-4268 ◽  
Author(s):  
L Meyaard ◽  
SA Otto ◽  
IP Keet ◽  
RA van Lier ◽  
F Miedema
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Cytokine Secretion ◽  
Ifn Gamma ◽  
T Cell Clones ◽  
Cell Clones ◽  
Immunodeficiency Virus

In addition to the loss of CD4+ T cells in later stages of human immunodeficiency virus (HIV) infection, functional defects of Th cells can already be observed in early infection. Decreased interleukin (IL)- 2 and interferon (IFN)-gamma production by CD4+ T cells and diminished delayed type hypersensitivity reactions are indicative for impaired Th1 responses. We studied the cytokine secretion patterns of T-cell clones (TCC) generated by mitogenic stimulation of CD4+ memory T cells. Compared with TCC from HIV-negative controls, TCC isolated from HIV- infected individuals consistently showed increased IL-4 production, often paralleled by increased IL-5 and decreased IFN-gamma production. This resulted in a decreased percentage of Th1 clones with an increase in Th0 clones. To rule out the influence of interindividual differences, we studied two individuals from whom cells were available before and after infection with HIV. Indeed, an increase in Th2 cytokine secretion was observed after HIV-infection. Loss of Th1 and enhanced Th2 responses might further curtail cellular responses resulting in deficiency of cellular immunity in HIV infection.

scholarly journals Selection following isolation of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and herpesvirus saimiri-transformed T cells is comparable

2002 ◽  
Vol 83 (6) ◽  
pp. 1343-1352 ◽  
Author(s):  
Natalie N. Zheng ◽  
Cherelyn Vella ◽  
Philippa J. Easterbrook ◽  
Rod S. Daniels
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Herpesvirus Saimiri ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
Hiv 1

In attempts to improve isolation rates and virus yields for human immunodeficiency virus (HIV), the use of herpesvirus saimiri-immortalized T cells (HVS T cells) has been investigated as an alternative to/improvement over peripheral blood mononuclear cells (PBMCs). Here we characterize isolates rescued, in the two cell types, from two asymptomatic, long-term non-progressing HIV-1-infected individuals. All rescued viruses replicated in PBMCs and HVS T cells only, displaying a non-syncytium inducing (NSI) phenotype, and using CCR5 as co-receptor. Furthemore, PBMC/HVS T cell virus pairs displayed similar neutralization profiles. Full-length, expression-competent env genes were rescued from all virus isolates and directly from the patient samples using proviral DNA and viral RNA as templates. Compared with the sequences retrieved directly from the patient samples, both cell types showed similar selection characteristics. Whilst the selections were distinct for individual patient samples, they shared a common characteristic in selecting for viruses with increased negative charge across the V2 domain of the viral glycoproteins. The latter was observed at the env gene sequencing level for three other patients whose HIV strains were isolated in PBMCs only. This further supports a common selection for viral sequences that display a macrophage-tropic/NSI phenotype and shows that HVS T cells are a viable alternative to PBMCs for HIV-1 isolation.

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-Negative Cells Bind Human Immunodeficiency Virus Type 1 and Efficiently Transfer Virus to T Cells

2000 ◽  
Vol 74 (18) ◽  
pp. 8550-8557 ◽  
Author(s):  
Gene G. Olinger ◽  
Mohammed Saifuddin ◽  
Gregory T. Spear
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Virus Binding ◽  
Peripheral Blood Mononuclear ◽  
Human Immunodeficiency Virus Strain ◽  
Immunodeficiency Virus

ABSTRACT The ability of human immunodeficiency virus strain MN (HIVMN), a T-cell line-adapted strain of HIV, and X4 and R5 primary isolates to bind to various cell types was investigated. In general, HIVMN bound to cells at higher levels than did the primary isolates. Virus bound to both CD4-positive (CD4+) and CD4-negative (CD4−) cells, including neutrophils, Raji cells, tonsil mononuclear cells, erythrocytes, platelets, and peripheral blood mononuclear cells (PBMC), although virus bound at significantly higher levels to PBMC. However, there was no difference in the amount of HIV that bound to CD4-enriched or CD4-depleted PBMC. Virus bound to CD4− cells was up to 17 times more infectious for T cells in cocultures than was the same amount of cell-free virus. Virus bound to nucleated cells was significantly more infectious than virus bound to erythrocytes or platelets. The enhanced infection of T cells by virus bound to CD4− cells was not due to stimulatory signals provided by CD4− cells or infection of CD4− cells. However, anti-CD18 antibody substantially reduced the enhanced virus replication in T cells, suggesting that virus that bound to the surface of CD4−cells is efficiently passed to CD4+ T cells during cell-cell adhesion. These studies show that HIV binds at relatively high levels to CD4− cells and, once bound, is highly infectious for T cells. This suggests that virus binding to the surface of CD4− cells is an important route for infection of T cells in vivo.

scholarly journals 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

2007 ◽  
Vol 82 (1) ◽  
pp. 471-486 ◽  
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.

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

2002 ◽  
Vol 185 (3) ◽  
pp. 306-314 ◽  
Author(s):  
Jesús Saavedra‐Lozano ◽  
Cynthia McCoig ◽  
Jinbo Xu ◽  
Yanying Cao ◽  
Philip Keiser ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cd4 T Cells ◽  
Hiv Positive ◽  
Immunodeficiency Virus ◽  
Latently Infected

scholarly journals Response to Superantigen Stimulation in Peripheral Blood Mononuclear Cells from Children Perinatally Infected with Human Immunodeficiency Virus and Receiving Highly Active Antiretroviral Therapy

2004 ◽  
Vol 11 (5) ◽  
pp. 957-962 ◽  
Author(s):  
Thomas W. McCloskey ◽  
Viraga Haridas ◽  
Lucy Pontrelli ◽  
Savita Pahwa
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
Ifn Γ

ABSTRACT Our understanding of the pathogenesis of perinatal human immunodeficiency virus (HIV) infection is still evolving. We sought to characterize the response to the bacterial superantigen Staphylococcus enterotoxin B (SEB) of lymphocytes from HIV-infected children receiving treatment with highly active antiretroviral therapy (HAART). Using the flow cytometric methodology, we quantified apoptosis, proliferation, cytokine production, and activation antigen upregulation in CD4 and CD8 T lymphocytes following in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with SEB. The levels of proliferation, CD4 interleukin-2 (IL-2) production, CD8 gamma interferon (IFN-γ) production, and upregulation of CD69 expression by cells from HIV-infected children were indistinguishable from those by cells from controls. However, stimulation with SEB dramatically decreased the ratio of resting apoptotic cells to cycling apoptotic cells in the controls but not in the patients. In addition, unstimulated spontaneous apoptosis of CD4 T cells remained greater in the patients than in the controls. The percentages of IL-2-positive CD8 T cells and IFN-γ-positive CD4 T cells following SEB stimulation were significantly lower in the patients than in the controls. Our multiparameter approach was able to demonstrate differences in lymphocyte superantigen responsiveness in HIV-infected children receiving HAART in comparison to that in uninfected controls, notably, an apoptotic versus a proliferative response to stimulation.

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