UMLS:C0019693 - FACTA Search

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

Because of their relative resistance to viral cytopathic effects, APC can provide an alternative reservoir for latently integrated HIV. We used an HIV-transgenic mouse model in which APC serve as the major source of inducible HIV expression to study mechanisms by which integrated virus can be activated in these cells. When admixed with transgenic APC, activated T lymphocytes provided a major contact-dependent stimulus for viral protein expression in vitro. Using blocking anti-CD154 mAb as well as CD154-deficient T cells, the HIV response induced by activated T lymphocytes was demonstrated to require CD40-CD154 interaction. The role of this pathway in the induction of HIV expression from APC in vivo was further studied in an experimental model involving infection of the HIV-transgenic mice with PLASMODIUM: chabaudi parasites. Enhanced viral production by dendritic cells and macrophages in infected mice was associated with up-regulated CD40 expression. More importantly, in vivo treatment with blocking anti-CD154 mAb markedly reduced viral expression in P. chabaudi-infected animals. Together, these findings indicate that immune activation of integrated HIV can be driven by the costimulatory interaction of activated T cells with APC. Because chronic T cell activation driven by coinfections as well as HIV-1 itself is a characteristic of HIV disease, this pathway may be important in sustaining viral expression from APC reservoirs.
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PMID:In vivo CD40-CD154 (CD40 ligand) interaction induces integrated HIV expression by APC in an HIV-1-transgenic mouse model. 1120 74

HSV establish a lifelong persistent infection in their host even among immunocompetent persons. The viruses use a variety of immune evasion strategies, presumably to assist persistent replication in the human host. We have observed that infection of human B lymphoblastoid cells (B-LCL) by HSV resulted in a strong inhibition of their ability to induce CD4(+) T cell clone proliferation and cytokine secretion. This inhibitory effect occurs in a variety of both HSV- and HIV-specific clones from three different patients. The inhibition is observed when the Ag is provided either as a soluble protein or as a synthetic peptide and is not associated with detectable down-modulation of the MHC class II molecules or costimulatory molecules. Expression of the HSV-1 unique sequence 1 gene (US1) is necessary and sufficient to induce this inhibition of APC function. US1 gene expression also made B-LCL less susceptible to CD4(+) T cell-mediated lysis. These data indicate a novel immune evasion strategy by HSV-1 in which Ag-processing cells that become infected by HSV-1 are inhibited in their ability to induce subsequent CD4(+) T cell activation.
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PMID:Herpes simplex inhibits the capacity of lymphoblastoid B cell lines to stimulate CD4+ T cells. 1134 47

Blood dendritic cells (DC) efficiently carry HIV-1 and transmit infection to CD4+ T cells in the absence of productive infection of the APC. Fluorescent latex beads were used to define the endocytic pathways that may contribute to this non-infectious pathway of virus carriage. Beads between 14 nm and 2300 nm in diameter were taken up by uncultured blood DC, but uptake of beads larger than 280 nm was much reduced in the DC compared to monocytes. After culture, there was a reduction in bead carriage in DC compared to monocytes. In the DC, beads were found as small aggregates in class II containing compartments or as single beads just below the cell surface. Beads accumulated in monocytes as aggregates in class II negative compartments. Bead recycling occurred in DC, but not in the fresh or cultured monocytes. Electron microscopy of HIV-1-pulsed DC cultured with CD4+ T cells showed accumulation of apoptotic debris and virions within endosomes in the DC. The peripheral location and recycling of endocytosed material in DC provides a pathway for virion transfer from DC to T cells that does not occur in monocytes.
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PMID:Uptake of HIV and latex particles by fresh and cultured dendritic cells and monocytes. 1138 Jun 79

Using the polymerase chain reaction (PCR), we designed a study concept to evaluate the safety of plasma derivatives in previously treated patients who are non-infected by the specific viruses studied. Several product lots can be studied in a single patient, with a study period for each lot of 3 months. In the present study 19 patients were included for treatment with Baxter Hyland Immuno's PCR-screened factor VIII concentrate Immunate (n=7), factor IX concentrate Immunine (n=10), the by-passing agent FEIBA plus Immunine (n=1), and the protein C concentrate Ceprotin (n=1). PCR testing for hepatitis B, C or HIV genomic material in patient samples was done as well as serological testing. All patients remained negative for the tested markers. All seven Immunate patients completed three treatment periods with three different lots of the study drug. The median study period was 282 days and the median dose 115 000 units, with a median of 115 exposure days. Five of the 10 Immunine patients completed three treatment periods and four patients, two treatment periods. One Immunine patient was discontinued from the study for reasons unrelated to the study drug administration. The median study period was 305 days and the median total dose 82 200 units, with a median of 88 exposure days. Our study presents a new design to approach the evaluation of viral safety of new plasma derivatives in previously treated, non-infected patients (NIPs) and offers several advantages over the currently recommended studies using testing for serological markers of infection in previously untreated patients (PUPs).
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PMID:An approach to study the viral safety of plasma-derived products in previously treated, non-infected patients. 1144 39

Since the rhesus is often used as a "gatekeeper" model for the evaluation of malaria and simian immunodeficiency virus (SIV)/HIV vaccines, the identification of strategies to enhance the activation of rhesus T cells would potentially aid in the generation of more potent vaccines directed against these infectious agents. Several molecules normally found on the surface of professional human APCs are capable of providing the second signals critical for T cell activation: B7-1 (CD80), ICAM-1 (CD54), and LFA-3 (CD58). With the exception of B7, T cell costimulatory molecules in the rhesus have not been identified. We have recently designed and characterized both recombinant vaccinia and recombinant avipox vectors containing the transgenes for a triad of human T cell costimulatory molecules (B7-1, ICAM-1, LFA-3; designated TRICOM). Here, we demonstrate the enhanced activation of rhesus T cells stimulated with rhesus APCs infected with TRICOM vectors in the presence of signal 1. Infection with TRICOM vectors led to significant improvement of APC capabilities in terms of reduction of the amount of signal 1 needed to activate naive T cells, and reduction in the amount of APCs required to activate T cells using a constant amount of signal 1. Antibody blocking studies demonstrated that each of the three costimulatory molecule transgenes contributed to the enhanced proliferation of T cells. TRICOM-enhanced T cell activation was shown to correspond to increases in type 1 cytokines and a reduced level of apoptosis. TRICOM-infected autologous B cells from rhesus immunized with either an SIV vaccine or a malaria vaccine stimulated significantly greater levels of IFN-gamma in response to specific peptide than stimulation with uninfected autologous B cells or B cells infected with wild-type vector. The ability to augment immune responses using poxvirus-based vaccines containing multiple costimulatory molecule transgenes can now be addressed in the rhesus macaque model.
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PMID:Enhanced activation of rhesus T cells by vectors encoding a triad of costimulatory molecules (B7-1, ICAM-1, LFA-3). 1173 38

Vaccination of cynomolgus monkeys with the biologically active HIV-1 Tat protein induces specific Th1 responses, including CTLs. Similar responses are also induced by vaccination with tat DNA, but not by vaccination with inactivated Tat or Tat peptides. This suggested that the native Tat protein may act differently on APC as compared with inactivated Tat or peptide Ag. In this study, we show that biologically active Tat is very efficiently taken up by monocyte-derived dendritic cells (MDDC) in a time (within minutes)- and dose-dependent (starting from 0.1 ng/ml) fashion, whereas uptake is very poor or absent with other APC, including T cell blasts and B lymphoblastoid cell lines. Although maturation of MDDC reduces their pino/phagocytic activity, mature MDDC take up Tat much more efficiently than immature cells. In addition, Tat uptake is abolished or greatly hampered by oxidation/inactivation of the protein or by performing the experiments at 4 degrees C, suggesting that MDDC take up native Tat by a receptor-mediated endocytosis. After uptake, active Tat protein induces up-regulation of MHC and costimulatory molecules and production of IL-12, TNF-alpha, and beta chemokines, which drive Th1-type immune response. In contrast, these effects are lost by oxidation and inactivation of the protein. Finally, native Tat enhances Ag presentation by MDDC, increasing Ag-specific T cell responses. These data indicate that native Tat selectively targets MDDC, is taken up by these cells via specialized pathways, and promotes their maturation and Ag-presenting functions, driving Th1-type immune responses. Thus, Tat can act as both Ag and adjuvant, capable of driving T cell-mediated immune responses.
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PMID:Native HIV-1 Tat protein targets monocyte-derived dendritic cells and enhances their maturation, function, and antigen-specific T cell responses. 1175 63

A condition of oxidative stress, due to perturbation of oxidant/antioxidant balance, has been suggested to play a role not only in the pathogenesis of human immunodeficiency virus (HIV) infection, but also in the promotion of a thrombophilic condition. Because various hemostatic dysfunctions usually considered as risk factors for thrombotic events were reported in HIV infection, this study was undertaken to investigate whether the oxidative phenomenon could promote a prothrombotic state in such condition. Erythrocyte glutathione peroxidase (GSH-Px), the major free-radical scavenger enzyme, and serum tumor necrosis factor-alpha (TNF-alpha) were evaluated in 33 consecutive HIV-infected out-patients and 35 matched HIV-negative healthy controls at a distance of any acute episode. Thrombin generation was explored by measuring the plasma levels of prothrombin fragment 1 + 2 (F1 + 2), whereas fibrin degradation products (D-dimer) and plasminogen activator inhibitor (PAI-1) activity were evaluated as indices of plasmin activity and fibrinolytic derangement. The anticoagulant pathway was investigated by measuring the plasma levels of antithrombin and protein C. Erythrocyte GSH-Px activity and serum TNF-alpha were significantly higher in HIV-infected patients when compared to controls. F1 + 2, D-dimer, and PAI-1 activity were increased in HIV-infected patients by comparison with controls. Normal antithrombin, but decreased protein C, was instead detected in HIV-infected patients. In the latter patients, serum TNF-alpha negatively correlated with both erythrocyte GSH-Px activity and plasma D-dimer. On the other hand, a positive correlation was shown between F1 + 2 and D-dimer and between D-dimer and GSH-Px activity. Furthermore, a trend toward increasing levels of GSH-Px with increasing PAI-1 activity was reported. These findings suggest a relationship between erythrocyte oxidative stress and the hypercoagulable condition during HIV infection.
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PMID:Increased erythrocyte glutathione peroxidase activity and serum tumor necrosis factor-alpha in HIV-infected patients: relationship to on-going prothrombotic state. 1198 8

Fifteen years after the first, definitive reports of HIV-1-specific, CD8+ T cells [147,148], there is ample evidence for the importance of these cells in control of HIV-1 infection. As much is known of their role in the natural history of HIV-1 infection and their cellular and molecular mechanisms of reactivity than of T-cell responses to any other human virus. Indeed, HIV-1-related research has led the scientific field in revealing many new, fundamental principles of cellular immunity in the last 15 years. From these data, there are multiple, posited mechanisms for loss of CD8+ T-cell control of HIV-1 infection. These include both intrinsic defects in T-cell function and loss of T-cell recognition of HIV-1 because of its extraordinary genetic diversity and disruption of antigen presentation. Efforts have begun on devising approaches to reverse these immune defects in infected individuals and develop vaccines that induce T-cell immunity for protection from infection. Combination antiretroviral drug regimens now provide exceptional, long-lasting control of HIV-1 infection, even though they do not restore anti-HIV-1 T-cell immunity fully in persons with chronic HIV-1 infection. Very encouraging results show that such treatment can maintain normal T-cell reactivity specific for this virus in some persons with early HIV-1 infection. Unfortunately, the antiviral treatment does not cure the host of this persistent, latent virus. This has led to new strategies for immunotherapeutic intervention to enhance the level and breadth of the T-cell repertoire specific for the host's residual virus in persons with chronic HIV-1 infection. Although the principles of immunotherapy stem from early in the last century, modern era approaches are integrating highly sophisticated, molecular and cell biology reagents and methods for control of HIV-1 infection. The most promising immunotherapies are autologous virus activated in vivo by STI or administered in autologous DC that have been engineered ex vivo. There are also compelling rationales supported by animal models and early clinical trials for use of cytokines and chemokines as recombinant proteins or DNA to augment anti-HIV-1 T-cell reactivity and trafficking of T cells and APC to tissue sites of infection. For prevention of HIV-1 infection, the discouragingly poor results of vaccine development in the late 1980s and early 1990s have led to very encouraging, recent studies in monkeys that show partially protective and possibly sterilizing immunity. Finally, clinical trials of new-generation DNA and live vector vaccines already have indications of improved induction of HIV-1-specific T-cell responses. Knowledge of HIV-1-specific T-cell immunity and its role in protection from HIV-1 infection and disease must continue to expand until the goal of complete control of HIV-1 infection is accomplished.
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PMID:CD8+ T-cell immunity to HIV infection. 1224 97

Despite the advances in supportive care and the availability of potent antimicrobial agents, mortality from sepsis, a leading cause of death in intensive care units, has not improved. Over the last decade, clinical trials with numerous adjunctive therapies, including antiendotoxin antibodies and inhibitors of the inflammatory response, have yielded disappointing results. Recently, treatment with recombinant human activated protein C reduced mortality 6% compared with controls. Given the likelihood that many processes in the complex pathophysiology of sepsis are simultaneously activated, it is unlikely that therapy directed at any one of them, as has been done in the past, will dramatically improve survival. Rather, a combination of therapies directed at many arms of the septic process, much like the strategy used for cancer and HIV infection, is required. Given the likelihood that sepsis represents an excessive innate immune response to microbial products, vigorous attempts must be made to develop rapid assays that reflect the level of innate immune activation. Such assays could be used to identify patients who would benefit from therapy and to monitor their response so that overtreatment does not completely abrogate host defense mechanisms and render these patients susceptible to fatal infection. It is now time to test a new therapeutic paradigm based on an improved understanding of the pathophysiology of the septic process and the recognition that we may have reached the limits of adjunctive monotherapy.
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PMID:A new paradigm for the treatment of sepsis: is it time to consider combination therapy? 1263 85

APC infection and dysfunction may contribute to the immunopathogenesis of HIV disease. In this study, we examined immunologic function of highly enriched populations of HIV-infected monocyte-derived dendritic cells (DC). Compared with uninfected DC, HIV-infected DC markedly down-regulated surface expression of CD4. HIV p24(+) DC were then enriched by negative selection of CD4(+)HIV p24(-) DC and assessed for cytokine secretion and immunologic function. Although enriched populations of HIV-infected DC secreted increased IL-12p70 and decreased IL-10, these cells were poor stimulators of allogeneic CD4(+) T cell proliferation and IL-2 production. Interestingly, HIV-infected DC secreted HIV gp120 and the addition of soluble (s) CD4 (a known ligand for HIV gp120) to DC-CD4(+) T cell cocultures restored T cell proliferation in a dose-dependent manner. By contrast, addition of antiretroviral drugs did not affect CD4(+) T cell proliferation. Furthermore, recombinant HIV gp120 inhibited proliferation in uninfected cocultures of allogeneic DC and CD4(+) T cells, an effect that was also reversed by addition of sCD4. In summary, we show that HIV gp120 produced by DC infected by HIV in vitro impairs normal CD4(+) T cell function and that sCD4 completely reverses HIV gp120-mediated immunosuppression. We hypothesize that HIV-infected DC may contribute to impaired CD4(+) T cell-mediated immune responses in vivo and that agents that block this particular immunosuppression may be potential immune adjuvants in HIV-infected individuals.
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PMID:Decreased stimulation of CD4+ T cell proliferation and IL-2 production by highly enriched populations of HIV-infected dendritic cells. 1268 60

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