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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Measurements of antigen-specific T cell responses in chronic diseases are limited by low frequencies of antigen-specific cells in the peripheral blood. Therefore, attempts have been made to add costimulatory molecules such as anti-CD28 or IL-7/IL-15 to ELISPOT assays to increase sensitivity. While this approach has been successful under certain circumstances, results are often inconsistent. To date, there are no comprehensive studies directly comparing the in vitro effects of multiple costimulatory molecules in different disease settings. Therefore, in the present study we tested the effects of IL-7/IL-15, IFN-alpha, anti-ICOS, and anti-CD28 on antigen-specific T cell responses in patients infected with HCV or HIV versus healthy individuals. Our data show that none of the aforementioned molecules could significantly increase ELISPOT sensitivity, neither in HCV nor in HIV. Moreover, all of them caused false-positive responses to HCV and HIV antigens in healthy individuals. Our results question the broad use of in vitro costimulation.
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PMID:Lack of disease specificity limits the usefulness of in vitro costimulation in HIV- and HCV-infected patients. 1867 Jun 52

A novel intrinsic HIV-1 antisense gene was previously described with RNA initiating from the region of an HIV-1 antisense initiator promoter element (HIVaINR). The antisense RNA is exactly complementary to HIV-1 sense RNA and capable of forming approximately 400 base-pair (bp) duplex RNA in the region of the long terminal repeat (LTR) spanning the beginning portion of TAR in the repeat (R) region and extending through the U3 region. Duplex or double-stranded RNA of several hundred nucleotides in length is a key initiating element of RNA interference (RNAi) in several species. This HIVaINR antisense RNA is also capable of forming multiple stem-loop or hairpin-like secondary structures by M-fold analysis, with at least one that perfectly fits the criteria for a microRNA (miRNA) precursor. MicroRNAs (miRNAs) interact in a sequence-specific manner with target messenger RNAs (mRNAs) to induce either cleavage of the message or impede translation. Human mRNA targets of the predicted HIVaINR antisense RNA (HAA) microRNAs include mRNA for the human interleukin-2 receptor gamma chain (IL-2RG), also called the common gamma (gammac) receptor chain, because it is an integral part of 6 receptors mediating interleukin signalling (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R and IL-21R). Other potential human mRNA targets include interleukin-15 (IL-15) mRNA, the fragile x mental retardation protein (FMRP) mRNA, and the IL-1 receptor-associated kinase 1 (IRAK1) mRNA, amongst others. Thus the proposed intrinsic HIVaINR antisense RNA microRNAs (HAAmiRNAs) of the human immunodeficiency virus form complementary targets with mRNAs of a key human gene in adaptive immunity, the IL-2Rgammac, in which genetic defects are known to cause an X-linked severe combined immunodeficiency syndrome (X-SCID), as well as mRNAs of genes important in innate immunity. A new model of intrinsic RNA silencing induced by the HIVaINR antisense RNA in the absence of Tat is proposed, with elements suggestive of both small interfering RNA (siRNA) and miRNA.
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PMID:RNA silencing and HIV: a hypothesis for the etiology of the severe combined immunodeficiency induced by the virus. 1878 56

The programmed death (PD)-1 molecule and its ligands (PD-L1 and PD-L2), negative regulatory members of the B7 family, play an important role in peripheral tolerance. Previous studies have demonstrated that PD-1 is up-regulated on T cells following TCR-mediated activation; however, little is known regarding PD-1 and Ag-independent, cytokine-induced T cell activation. The common gamma-chain (gamma c) cytokines IL-2, IL-7, IL-15, and IL-21, which play an important role in peripheral T cell expansion and survival, were found to up-regulate PD-1 and, with the exception of IL-21, PD-L1 on purified T cells in vitro. This effect was most prominent on memory T cells. Furthermore, these cytokines induced, indirectly, the expression of PD-L1 and PD-L2 on monocytes/macrophages in PBMC. The in vivo correlate of these observations was confirmed on PBMC isolated from HIV-infected individuals receiving IL-2 immunotherapy. Exposure of gamma c cytokine pretreated T cells to PD-1 ligand-IgG had no effect on STAT5 activation, T cell proliferation, or survival driven by gamma c cytokines. However, PD-1 ligand-IgG dramatically inhibited anti-CD3/CD28-driven proliferation and Lck activation. Furthermore, following restimulation with anti-CD3/CD28, cytokine secretion by both gamma c cytokine and anti-CD3/CD28 pretreated T cells was suppressed. These data suggest that gamma c cytokine-induced PD-1 does not interfere with cytokine-driven peripheral T cell expansion/survival, but may act to suppress certain effector functions of cytokine-stimulated cells upon TCR engagement, thereby minimizing immune-mediated damage to the host.
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PMID:The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. 1898 Oct 91

A depressed level of natural killer (NK) activity is one of the various immunological abnormalities in HIV infection. Defective NK cell functions can be partially restored in vitro by interleukin (IL)-2 and IL-12. IL-15 shares receptor and several biological properties with IL-2. The effect of IL-15 on NK cells in patients with HIV and tuberculosis coinfection (HIV-TB) is unclear. This study examined the cytotoxic activity and cytokine response of NK cells in HIV-TB after stimulation with IL-15 and IL-12/IL-2. The study includes 16 normal healthy subjects (NHS), 15 patients with pulmonary tuberculosis (TB), 15 HIV-infected subjects (HIV), and 15 HIV-TB patients. The cytotoxic activity of NK cells was assessed by dioctadecyloxacarbocyanine dye-based flow cytometry. Interferon-gamma present in the culture supernatants was measured by enzyme-linked immunosorbent assay. Basal NK cytotoxicity was found to be lower in HIV-TB (p < 0.05) and HIV when compared to NHS or TB. Maximal NK cytotoxicity (p < 0.05) was observed with an IL-15 and IL-12 combination in all the groups. At a 50:1 effector/target ratio, the mean fold increase in NK cytotoxicity upon stimulation was 2.11 for HIV and 1.84 for HIV-TB. Interferon-gamma levels from the stimulated cultures were elevated (p < 0.05) in the HIV and HIV-TB groups. We found no correlation between NK cytotoxicity and CD4 counts in HIV-TB. There is a positive correlation between NK cytotoxicity and interferon-gamma secretion for HIV-TB. The combination of IL-15 and IL-12 may have potential to improve the NK activity of HIV and HIV-TB.
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PMID:Augumentation of natural killer activity with exogenous interleukins in patients with HIV and pulmonary tuberculosis coinfection. 1900 24

Impaired control of chronic pathogen replication may be associated to alterations of NK-cell function. Whether mechanisms underlying this dysfunction involve perturbations of differentiating NK cells is still unknown. We studied an "in vitro" model of differentiation from CD34(+)Lin(-) precursors growing only myelomonocytes and maturing NK cells and where myelomonocytes could be suitably infected with HSV, HIV, or vaccinia. Cultures were evaluated by cytofluorometry and cytotoxicity assays for perturbations in differentiating NK cells. Increased expression of natural cytotoxicity receptors on maturing NK cells with increased cytolytic activity was observed with HSV-1 infection, and with vaccinia while no modulation of NK-cell phenotype nor cytotoxic activity were evident with an ssRNA lentivirus (HIV-1). In the presence of constant IL-12 and IL-15 concentrations, the observed effect did not require cell contact, involved IFN-alpha and was not reproduced by the addition of TLR9 agonist, nor blocked by TLR9 antagonists. Virus replication at sites of NK-cell precursor development may have different outcomes depending on the interaction between invading viruses and maturing NK cells. Thus, NK-cell precursors may be involved in the immune response to dsDNA viruses and possibly contribute to efficient control of virus infection.
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PMID:IFN-alpha-mediated increase in cytolytic activity of maturing NK cell upon exposure to HSV-infected myelomonocytes. 1908 10

While highly active antiretroviral therapy (HAART) regimens have proven to be effective in controlling active HIV replication, complete recovery of CD4+ T cells does not always occur, even among patients with high level virologic control. Recent advances in understanding the biology of T cell production and homeostasis have created the potential to augment anti-viral therapies with immunotherapies designed to facilitate recovery of the HIV-damaged immune system, in particular, the recovery of CD4+ T cell populations. The common gamma-chain cytokines IL-2, IL-7 and IL-15 are primary regulators of T cell homeostasis and thus have been considered prime candidate immunotherapeutics, both for increasing T cell levels/function and for augmenting vaccine-elicited viral-specific T cell responses. Recent studies have established that these cytokines have distinct functional roles in immune homeostasis, which focus on specific T cell populations. The ability of these cytokines to provide immunotherapeutic benefit to HIV+ patients will depend on their ability to stably increase or functionally enhance the desired T cell target population without adverse virologic or clinical consequences.
Curr HIV Res 2009 Jan
PMID:IL-2, IL-7 and IL-15 as immuno-modulators during SIV/HIV vaccination and treatment. 1914 57

Characterization of the immune responses induced in the initial stages of human immunodeficiency virus type 1 (HIV-1) infection is of critical importance for an understanding of early viral pathogenesis and prophylactic vaccine design. Here, we used sequential plasma samples collected during the eclipse and exponential viral expansion phases from subjects acquiring HIV-1 (or, for comparison, hepatitis B virus [HBV]or hepatitis C virus [HCV]) to determine the nature and kinetics of the earliest systemic elevations in cytokine and chemokine levels in each infection. Plasma viremia was quantitated over time, and levels of 30 cytokines and chemokines were measured using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. The increase in plasma viremia in acute HIV-1 infection was found to be associated with elevations in plasma levels of multiple cytokines and chemokines, including rapid and transient elevations in alpha interferon (IFN-alpha) and interleukin-15 (IL-15) levels; a large increase in inducible protein 10 (IP-10) levels; rapid and more-sustained increases in tumor necrosis factor alpha and monocyte chemotactic protein 1 levels; more slowly initiated elevations in levels of additional proinflammatory factors including IL-6, IL-8, IL-18, and IFN-gamma; and a late-peaking increase in levels of the immunoregulatory cytokine IL-10. Notably, there was comparatively little perturbation in plasma cytokine levels during the same phase of HBV infection and a delayed response of more intermediate magnitude in acute HCV infection, indicating that the rapid activation of a striking systemic cytokine cascade is not a prerequisite for viral clearance (which occurs in a majority of HBV-infected individuals). The intense early cytokine storm in acute HIV-1 infection may have immunopathological consequences, promoting immune activation, viral replication, and CD4(+) T-cell loss.
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PMID:Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. 1917 32

Plasmid-encoded DNA vaccines appear to be a safe and effective method for delivering antigen; however, the immunogenicity of such vaccines is often suboptimal. Cytokine adjuvants including interleukin (IL)-12, RANTES, granulocyte-macrophage colony-stimulating factor, IL-15, and others have been used to augment the immune response against DNA vaccines. In particular, IL-15 binds to a unique high-affinity receptor, IL-15R alpha; is trans-presented to CD8(+) T cells expressing the common betagamma chain; and has been shown to play a role in the generation, maintenance, and proliferation of antigen-specific CD8(+) T cells. In this study, we took the unique approach of using both a cytokine and its receptor as an adjuvant in an HIV-1 vaccine strategy. To study IL-15R alpha expression, a unique monoclonal antibody (KK1.23) was generated to confirm receptor expression in vitro. Coimmunization of IL-15 and IL-15R alpha plasmids with HIV-1 antigenic plasmids in mice enhanced the antigen-specific immune response 2-fold over IL-15 immunoadjuvant alone. Furthermore, plasmid-encoded IL-15R alpha augments immune responses in the absence of IL-15, suggesting its role as a novel adjuvant. Moreover, pIL-15R alpha enhanced the cellular, but not the humoral, immune response as measured by antigen-specific IgG antibody. This is the first report describing that IL-15R alpha itself can act as an adjuvant by enhancing an antigen-specific T cell response. Uniquely, pIL-15 and pIL-15R alpha adjuvants combined, but not the receptor alpha chain alone, may be useful as a strategy for generating and maintaining memory CD8(+) T cells in a DNA vaccine.
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PMID:Plasmid-encoded interleukin-15 receptor alpha enhances specific immune responses induced by a DNA vaccine in vivo. 1984 97

Heterologous adenovirus-based vectors hold promise as preventative HIV vaccines but their capacity to induce effective T-cell immunity in established infection has not been explored. We vaccinated rhesus macaques chronically infected with SIVmac251 and undergoing antiretroviral therapy (ART) with human adenovirus serotype 5-based vectors expressing SIV Gag, Env, and Nef with and without IL-15 and evaluated vaccine immunogenicity. Vaccination increased Ag-specific T cells 20-fold but did not expand the breadth of epitopes recognized or the quality of response, as the majority of CD8(+) and CD4(+) T cells produced only one cytokine irrespective of vaccination. Immunization transiently restored blood CD4(+) central memory T cells (Tcm) and boosted CD4(+) and CD8(+) Tcm and effector cell responses but did not prevent virus rebound upon cessation of ART. Boosting with human adenovirus serotype 35-based vectors during a second ART cycle increased Ag-specific T cells to 50-fold above pre-vaccination levels and boosted CD4(+) Tcm numbers but did not expand the breadth or quality of immunity or control virus levels following drug discontinuation. The number of blood CD4(+) Tcm correlated positively with complexity of T-cell responses and negatively with virus load, suggesting that more complete restoration of this subset through vaccination would be beneficial.
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PMID:Adenovirus 5- and 35-based immunotherapy enhances the strength but not breadth or quality of immunity during chronic SIV infection. 1967 Mar 80

Immunosuppression following infection with HIV-1 predisposes patients to a myriad of opportunistic pathogens, one of the most important of which is Mtb. Granulysin, expressed by NK cells and CTL, exhibits potent antimicrobial activity against Mtb and several other opportunistic pathogens associated with HIV-1 infection. The immune signals that promote granulysin expression in human CTL are not fully understood. Using primary human CD8+ T cells, in this study, we identify IL-21 as a strong inducer of granulysin, demonstrate that IL-21 and IL-15 activate granulysin expression within CD8+ CD45RO+ T cells, and establish a role for Jak/STAT signaling in the regulation of granulysin within CD8+ T cells. We show that infection of PBMC from healthy donors in vitro with HIV-1 suppresses granulysin expression by CD8+ T cells, concomitant with reduced p-STAT3 and p-STAT5, following activation with IL-15 and IL-21. Of note, simultaneous signaling through IL-15 and IL-21 could partially overcome the immunosuppressive effects of HIV-1 on granulysin expression by CD8+ T cells. These results suggest that HIV-1 infection of PBMC may reduce the antimicrobial profile of activated CD8+ T cells by disrupting signaling events that are critical for the induction of granulysin. Understanding the effects of HIV-1 on CD8+ T cell activation is essential to understanding the physiological basis for inadequate cytotoxic lymphocyte activity in HIV+ patients and for informed guidance of cytokine-based therapy to restore T cell function.
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PMID:Induction of granulysin in CD8+ T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1. 1968 90


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