Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tuberculosis (TB) is a growing international health concern, since it is the leading infectious cause of death in the world today. Moreover, the resurgence of TB in industrialized countries and the worldwide increase in the prevalence of Mycobacterium avium complex (MAC) infections in immunocompromised hosts have prompted the quest for new antimycobacterial drugs. In particular, the appearance of multidrug-resistant (MDR) strains of M. tuberculosis, which exhibit in vitro resistance to at least two major antituberculous drug (usually INH and RFP) and cause intractable TB, has greatly contributed to the increased incidence of TB. Because of the global health problems of TB, the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new antituberculous drugs without cross-resistance with known antimycobacterial agents is urgently needed. In this article, I reviewed the following areas. First, I briefly reviewed some new findings (mainly reported after 2000) on the pharmacological status of rifamycin derivatives (rifabutin, rifapentine, and rifalazil), fluoroquinolones (ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin, gatifloxacin, sitafloxacin, moxifloxacin, and others), and new macrolides (clarithromycin, azithromycin, and roxithromycin). Second, I described other types of agents which are being developed as antimycobacterial drugs. Some of the agents discussed are already under preliminary clinical investigation, and others appear to be promising candidates for future development. In this review, the status of the development of new antimycobacterial, especially antituberculous agents including oxazolidinone (PNU-100480), 5'-nitroimidazole (CGI 17341), 2-pyridone (ABT-255), new riminophenazines, nitroimidazopyran (PA-824), new ketolides (ABT-773, telithromycin) and defensins (human neutrophil peptide-I), was examined. Third, the development of new antitubercular drugs was discussed according to the potential pharmacological target. New critical information on the whole genome of M. tuberculosis recently elucidated and increasing knowledge on various mycobacterial virulence genes will promote the progression in the identification of genes that code for new drug targets. Using such findings on mycobacterial genomes, drug development using quantitative structure-activity relationship may be possible in the near future. In this review, I described the screening of drugs that have an inhibitory activity against dTDP-rhamnose synthesis of M. tuberculosis, as a new drug target of the organism. In addition, I discussed the usefulness of antisense oligo DNAs specific to mycobacterial genes encoding certain metabolic enzymes or virulence factors that play roles in the bacterial escape from antimicrobial mechanisms of host macrophages. Fourth, I reviewed the drug vehicles which enable efficacious drug delivery to their target in vivo. The usefulness of poly (DL-lactide-co-glycolide) microsphere technology, which enables the encapsulated drugs to deliver the requested doses of them for prolonged time periods by a single shot without causing any toxicity and, moreover, enables the highly targeted delivery of the drugs to host macrophages, was discussed. Fifth, I described adjunctive immunotherapy for the management of patients with mycobacterial infections by giving certain immunomodulators in combination with antimycobacterial drugs. Adjuvant clinical trials using IL-2 or GM-CSF have been found to be efficacious to some extent in improving patients with tuberculosis or disseminated MAC infections. However, it seems that these immunopotentiating cytokines as well as IFN-gamma and IL-12 are not so promising for the therapeutic agents of mycobacterial infections because of the possible induction of immunosuppressive cytokines during adjuvant therapy and, in some cases, severe side-effect. Thus, the development of new classes of immuno-modulators other than cytokines, particularly those with no severe side-effect, is needed. This review dealt with ATP and its analogues which potentiate macrophage antimycobacterial activity via a purinergic P2X7 receptor. Finally, I described the roles of type II alveolar epithelial cells in the establishment of mycobacterial infections in the host lungs and the profiles of drug susceptibilities of M. tuberculosis and MAC organisms replicating within the type II pneumocytes. These findings are useful to precisely assess or predict the in vivo therapeutic activity of a given antimycobacterial drug from its in vitro activity. In this article, I have thoroughly reviewed the status of the development of new antimycobacterial drugs. There are a number of difficulties in the drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of tuberculosis and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable tuberculosis is rapidly increasing in the latter.
 ...
PMID:[Prospects for development of new antituberculous drugs]. 1223 50

The B-cell tumor-derived Ig receptor may be considered a model tumor antigen for cancer vaccine development. However, as a non-immunogenic, self-antigen, it also must be first rendered immunogenic by chemical or genetic fusion to carriers which enable the induction of protective antitumor immunity in experimental tumor models. Our group has demonstrated that active immunization of human patients with idiotypic protein vaccines containing soluble GM-CSF elicited antigen specific CD8+ T cell responses and antitumor effects. An alternative strategy to develop vaccines is the genetic fusion of tumor idiotype-derived single chain antigen with a chemokine moiety. Administration of these vaccines as fusion proteins or naked DNA vaccines may allow more efficient targeting of antigen presenting cells in vivo. Potent antitumor immunity was elicited in mice which was dependent on the generation of specific antibodies and both CD4+ and CD8+ effector T-cells. We propose that chemokine fusion may represent a novel, general strategy for formulating existing or newly identified tumor and HIV antigens into vaccines for cancer and AIDS, respectively, which elicit potent CD8+ T-cell immunity.
 ...
PMID:Translational development of active immunotherapy for hematologic malignancies. 1243 Aug 73

Monocytes, macrophages and dendritic cells play an important role in the initial infection and contribute to its pathogenesis throughout the course of infection. Myeloid cells express CD4 and chemokine receptors known for HIV-1 fusion and entry. The beta-chemokine receptor, CCR5, is the major co-receptor in conjunction with CD4 for macrophage (M)-tropic or (R5) isolates of HIV-1, whereas the alpha-chemokine receptor, CXCR4, facilitates entry of T-tropic or (X4) HIV-1 strains. Cells of myeloid lineage may be infected predominantly with R5- strains, although infection with dual-tropic isolates of HIV-1 (exhibiting the capacity to use CCR-5 and/or CXCR-4 for entry) or some strains of X4- isolates has also been reported. The expression of chemokine receptors, HIV-1 infection and replication is under continuous regulation by a complex cytokine network produced by a variety of cells. The effects of cytokines/chemokines on HIV-1 replication in cells of myeloid lineage can be inhibitory (IFN-alpha, IFN-beta, IFN-gamma, GM-CSF, IL-10, IL-13 and IL-16 and beta-chemokines), stimulatory (M-CSF, TNF-alpha, TNF-beta, IL-1, IL-6) or bifunction al, that is both inhibitory and stimulatory (IL-4). This review focuses on the overall expression of chemokine receptors on cells of myeloid lineage and considers the mechanisms of entry of R5-, X4- and dual-tropic strains of HIV-1 into these cells. The effects of cytokines/chemokines on viral entry and productive HIV-1 infection are also reviewed.
 ...
PMID:The influence of cytokines, chemokines and their receptors on HIV-1 replication in monocytes and macrophages. 1251 61

Immunization with peptide mimetics of carbohydrate antigens can induce functional carbohydrate-reactive antibodies. Here, we examine the immune characteristics of alternative approaches in prime and boost strategies using glycosylated HIV-1 envelope protein and model tumor associated carbohydrate antigens. Our results indicate that peptide mimotopes either in a DNA or carrier-conjugated format can induce comparable levels of IgM and IgG. Carbohydrate boosting of peptide-primed animals does not affect end-point titer, however, boosting mediates a stable long lasting carbohydrate reactive IgM response, not achievable by carbohydrate immunization alone. Boosting with carbohydrate in animals primed with DNA- or peptide-conjugate, facilitates the induction of detectable IgG with a dominant IgG2a isotype. Immunization with HIV-1 envelope glycoprotein of peptide-primed animals induces different IgG isotype profiles with a dominant IgG1 antibody. We observed that HIV-1 envelope glycoprotein immunization of peptide primed mice induces a cross-reactive cellular response, as detected by cytokine secretion, which lends to IFN-gamma production upon splenocyte stimulation and CTL activity against recombinant vaccinia virus infected cells after in vitro stimulation. DNA immunization with mimotope, inclusion of a T-cell epitope from the HIV-1 envelope protein in the expression cassette and co-administration with IL-12 or GM-CSF encoding plasmids activate a cellular response to the HIV-1 envelope protein.
 ...
PMID:Priming characteristics of peptide mimotopes of carbohydrate antigens. 1253 55

Incorporation of an 11 amino acid region of the HIV TAT protein transduction domain (TAT PTD) into proteins facilitates rapid, efficient entry into cells. We previously showed that rTAT-PTD-OVA-transduced dendritic cells (DC) stimulated antigen (Ag)-specific CTL and Th cells, and vaccinated against OVA-expressing tumors. Here we studied B16 melanoma in C57BL/6 mice, using murine tyrosinase-related protein 2 (Trp2) as a candidate tumor Ag. We produced a 472-amino acid N-terminal fragment of Trp2 protein (rTrp2Delta) with or without PTD. Although PTD-deficient rTrp2Delta was ineffective, mice given rTAT-PTD-Trp2Delta-transduced DC were efficiently primed for Trp2(180-188) peptide-specific and B16-reactive CTL. In 58% of such mice, growth of melanomas was prevented. Trp2(180-188) peptide-pulsed DC protected 35% of recipients, and irradiated GM-CSF-producing B16 cells protected 75%. rTAT-PTD-Trp2Delta-transduced DC induced a more vigorous memory response to B16 rechallenge than the other regimens, and protected 30% of recipients from progressive tumor development in treatment studies. In this setting, Trp2 peptide-treated DC protected 20% and irradiated GM-CSF-producing cells protected 0%. Both tumor prevention and tumor treatment were CD8(+) T cell dependent. Vaccination with rTAT-PTD-Trp2Delta-transduced DC induced a robust CTL response and durable anti-melanoma immunity. This approach should be clinically applicable, and offers theoretical and practical advantages to those that are in current use.
 ...
PMID:Dendritic cells transduced with TAT protein transduction domain-containing tyrosinase-related protein 2 vaccinate against murine melanoma. 1267 50

Human herpesvirus 8 (HHV-8), the etiologic agent of Kaposi's sarcoma (KS), encodes a chemokine receptor homologue, the viral G protein-coupled receptor (vGPCR), that has been implicated in KS pathogenesis. Expression of vGPCR constitutively activates several signaling pathways, including NF-kappa B, and induces the expression of proinflammatory and angiogenic factors, consistent with the inflammatory hyperproliferative nature of KS lesions. Here we show that vGPCR also constitutively activates the nuclear factor of activated T cells (NF-AT), another transcription factor important in regulation of the expression of inflammatory cytokines and related factors. NF-AT activation by vGPCR depended upon signaling through the phosphatidylinositol 3-kinase-Akt-glycogen synthetase kinase 3 (PI3-K/Akt/GSK-3) pathway and resulted in increased expression of NF-AT-dependent cell surface molecules (CD25, CD29, Fas ligand), proinflammatory cytokines (interleukin-2 [IL-2], IL-4), and proangiogenic factors (granulocyte-macrophage colony-stimulating factor GMCSF and TNF alpha). vGPCR expression also increased endothelial cell-T-cell adhesion. Although infection with HHV-8 is necessary to cause KS, coinfection with human immunodeficiency virus type 1 (HIV-1), in the absence of antiretroviral suppressive therapy, increases the risk of KS by many orders of magnitude. NF-AT and NF-kappa B activation by vGPCR was greatly increased by the HIV-1 Tat protein, although Tat alone had little effect on NF-AT. The enhancement of NF-AT by Tat appears to be mediated through collaborative stimulation of the PI3-K/Akt/GSK-3 pathway by vGPCR and Tat. Our data further support the idea that vGPCR contributes to the pathogenesis of KS by a paracrine mechanism and, in addition, provide the first evidence of collaboration between an HIV-1 protein and an HHV-8 protein.
 ...
PMID:Human herpesvirus 8-encoded vGPCR activates nuclear factor of activated T cells and collaborates with human immunodeficiency virus type 1 Tat. 1271 69

We compared the differences in growth inhibition of Mycobacterium bovis by monocytes and neutrophils from human immunodeficiency virus (HIV)-infected persons (n = 12; mean CD4 count = 451/mm(3)) and healthy controls (n = 6). Phagocytes from all HIV-infected patients were incubated with or without exogenous granulocyte-macrophate colony-stimulating factor (GMCSF; 500-1000 U/mL). In two of the HIV-infected patients, phagocytes were incubated with or without interleukin (IL)-2 or IL-8 (500-1000 U/mL). Compared with that in HIV-infected patients, the reduction of M. bovis growth at 24 hours was 81% greater among monocytes and 69% greater among neutrophils from healthy controls (P =.03 and.04, respectively). Among HIV-infected patients, we noted greater mycobacterial reduction in monocytes (49%, P =.04) and neutrophils (42%, P =.05) from the early-stage patients (mean CD4 count = 760/mm(3)) compared with that in late-stage patients (mean CD4 count = 172/ mm(3)). Incubation with GM-CSF, IL-2, or IL-8 did not augment mycobactericidal activity. These findings suggest that the capacity of neutrophils and monocytes from HIV-infected patients to inhibit the growth of M. bovis is impaired, and this impairment is more pronounced in later stages of HIV infection.
 ...
PMID:Capacity of neutrophils and monocytes from human immunodeficiency virus-infected patients and healthy controls to inhibit growth of Mycobacterium bovis. 1276 2

A major challenge of AIDS research is the development of therapeutic vaccine strategies capable of inducing the humoral and cellular arms of the immune responses against HIV-1. In this work, we evaluated the capability of DCs pulsed with aldrithiol-2-inactivated HIV-1 in inducing a protective antiviral human immune response in SCID mice reconstituted with human PBL (hu-PBL-SCID mice). Immunization of hu-PBL-SCID mice with DCs generated after exposure of monocytes to GM-CSF/IFN-alpha (IFN-DCs) and pulsed with inactivated HIV-1 resulted in a marked induction of human anti-HIV-1 antibodies, which was associated with the detection of anti-HIV neutralizing activity in the serum. This vaccination schedule also promoted the generation of a human CD8+ T cell response against HIV-1, as measured by IFN-gamma Elispot analysis. Notably, when the hu-PBL-SCID mice immunized with antigen-pulsed IFN-DCs were infected with HIV-1, inhibition of virus infection was observed as compared with control animals. These results suggest that IFN-DCs pulsed with inactivated HIV-1 can represent a valuable approach of immune intervention in HIV-1-infected patients.
 ...
PMID:Potent immune response against HIV-1 and protection from virus challenge in hu-PBL-SCID mice immunized with inactivated virus-pulsed dendritic cells generated in the presence of IFN-alpha. 1287 66

The immunogenicity of plasmid DNA vaccines may be limited by the availability of professional antigen-presenting cells (APC) at the site of inoculation. Here we demonstrate that the types of APC recruited to the injection site can selectively modulate CD4(+) or CD8(+) T lymphocyte responses elicited by an HIV-1 Env DNA vaccine in mice. Coadministration of plasmid GM-CSF with the DNA vaccine resulted in the recruitment of macrophages to the site of inoculation and specifically augmented vaccine-elicited CD4(+) T lymphocyte responses. In contrast, coadministration of plasmid MIP-1 alpha with the DNA vaccine resulted in the recruitment of dendritic cells to the injection site and enhanced vaccine-elicited CD8(+) T lymphocyte responses. Interestingly, coadministration of both plasmid GM-CSF and plasmid MIP-1 alpha with the DNA vaccine recruited both macrophages and dendritic cells and led to a synergistic and sustained augmentation of CD4(+)and CD8(+) T lymphocyte responses. These data demonstrate the critical importance of locally recruited professional APC in determining the magnitude and nature of immune responses elicited by plasmid DNA vaccines. Moreover, these studies show that different subsets of professional APC can selectively modulate DNA vaccine-elicited T lymphocyte responses.
 ...
PMID:Recruitment of different subsets of antigen-presenting cells selectively modulates DNA vaccine-elicited CD4+ and CD8+ T lymphocyte responses. 1504 11

We determined if the genetic adjuvants, granulocyte-macrophage colony stimulating factor (GM-CSF) and B7-2, could improve the immunogenicity and efficacy of an HIV-2 DNA vaccine. The vaccine consisted of the HIV-2 tat, nef, gag, and env genes synthesized using optimized codons and formulated with cationic liposomes. Baboons (Papio cynocephalus hamadryas) were immunized by the intramuscular, intradermal, and intranasal routes with these expression constructs and challenged with HIV-2(UC2) by the intravaginal route. In the first month after HIV-2 vaginal challenge, the baboons receiving the HIV-2 DNA vaccine with or without the genetic adjuvants had significant reductions in the viral loads in the peripheral blood mononuclear cells (PBMC) (P = 0.028) while the reductions in their plasma viremia were suggestive of a protective effect (P = 0.1). These data demonstrate that partial protection against HIV-2 vaginal challenge, as measured by reduced viral load, can be achieved using only a DNA vaccine formulation.
 ...
PMID:Human immunodeficiency virus type 2 DNA vaccine provides partial protection from acute baboon infection. 1514 85


<< Previous 1 2 3 4 5 6 7 8 9 10