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

Listeria monocytogenes is a facultative intracellular pathogen which, following uptake by macrophages, escapes from the phagosome and replicates in the cytoplasm. This property has been exploited using recombinant L. monocytogenes as a carrier for the intracytoplasmic expression of antigens when MHC class I-restricted cytotoxic T lymphocyte responses are required. Much less is known of the ability of these bacteria to trigger MHC class II-restricted responses. Here, we demonstrate that after ingestion of L. monocytogenes expressing a T helper epitope from the gp120 envelope glycoprotein of HIV, human adherent macrophages and dendritic cells can process and present the epitope to a specific CD4+ T cell line in the context of MHC class II molecules. No significant differences were observed when the attenuated strains were trapped in the phagolysosome or impaired in the capacity to spread intracellularly or from cell to cell. Similar results were obtained using carrier proteins that were either secreted, associated with the bacterial surface, or restricted to the bacterial cytoplasm. A dominant expression of the TCR Vbeta 22 gene subfamily was observed in specific T cell lines generated after stimulation with the recombinant strains or with soluble gp120. Our data show that in this in vitro system L. monocytogenes can efficiently deliver antigens to the MHC class II pathway, in addition to the well-established MHC class I pathway. The eukaryotic cell compartment in which the antigen is synthesized, and the mode of display seem to play a minor role in the overall efficiency of epitope processing and presentation.
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PMID:Attenuated Listeria monocytogenes carrier strains can deliver an HIV-1 gp120 T helper epitope to MHC class II-restricted human CD4+ T cells. 964 61

Peptide vaccines against HIV-1 were prepared according to the cassette theory that we had proposed previously. An amino acid sequence of B subtype consensus of the HIV-1 V3 region was introduced into the MHC binding component with a supermotif for various MHC class II. The peptide vaccines induced T-cell responses in the DQ6 mice in which only DQ6 molecules were expressed as MHC class II. By contrast, an original V3 peptide including the consensus sequence was non-immunogenic in the DQ6 mice. Antibodies obtained from the DQ6 mice immunized with the peptide vaccines neutralized laboratory B subtype strains of HIV-1 in vitro. It may be anticipated that these peptide vaccines protect infection of HIV-1 in DQ6 positive individuals.
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PMID:Development of peptide vaccines inducing production of neutralizing antibodies against HIV-1 viruses in HLA-DQ6 mice. 971 1

SCID-hu mouse models are of interest in the pathologic investigation of HIV infection, but obtaining a T cell response in SCID-hu-PBL mice is still controversial. We have developed a SCID model by engrafting human skin and autologous PBLs from HIV-seronegative individuals. The study describes the ability of this human-mouse chimera to generate in vivo a primary T lymphocyte response against HIV Ag. The injection of human autologous PBLs was performed 4 to 5 wk after the skin engraftment. Two weeks after injection of PBLs, chimeric mice were immunized with recombinant canary pox virus expressing HIV-1 LAIgp160 (vCP-LAIgp160) and supplemented or not with rIL-2. Intradermal vCP-LAIgp160 injection induced an intradermal perivascular human lymphocytic infiltrate and an epidermic network of CD1a+, CD80+, and CD86+ cells. We derived CD4+ T cell lines (STLs) from the human skin graft of immunized mice, showing that STLs mediated an MHC class II-restricted cytolytic activity directed against HIV-LAIgp160 Ags. Cytokine gene expression in both human skin cells and in STLs showed a predominance of IL-2, IFN-gamma, and IL-12 transcripts. Finally, the T cell repertoire analysis using the immunoscope technique showed a very limited CDR3 length polymorphism in the skin infiltrating lymphocytes suggesting an Ag-specific repertoire. The ability to induce a primary Th1 cell response in vivo affords a useful preclinical model for testing vaccine strategies.
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PMID:Primary Th1 cell immunization against HIVgp160 in SCID-hu mice coengrafted with peripheral blood lymphocytes and skin. 971 80

Whole inactivated viral particles have been successfully used as vaccines for some viruses, but procedures historically used for inactivation can denature virion proteins. Results have been inconsistent, with enhancement of disease rather than protection seen in some notable instances following vaccination. We used the compound 2,2'-dithiodipyridine (aldrithiol-2; AT-2) to covalently modify the essential zinc fingers in the nucleocapsid (NC) protein of human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) virions, thereby inactivating infectivity. The inactivated virus was not detectably infectious in vitro (up to 5 log units of inactivation). However, in contrast to virions inactivated by conventional methods such as heat or formalin treatment, viral and host cell-derived proteins on virion surfaces retained conformational and functional integrity. Thus, immunoprecipitation of AT-2-treated virions was comparable to precipitation of matched untreated virus, even when using antibodies to conformational determinants on gp120. AT-2 inactivated virions bound to CD4(+) target cells and mediated virus-induced, CD4-dependent "fusion from without" comparably to native virions. However, viral entry assays demonstrated that the viral life cycle of AT-2-treated virions was arrested before initiation of reverse transcription. The major histocompatibility complex (MHC) class II molecules on the surface of AT-2-treated virions produced from MHC class II-expressing cells retained the ability to support class II-dependent, superantigen-triggered proliferative responses by resting T lymphocytes. These findings indicate that inactivation via this method results in elimination of infectivity with preservation of conformational and functional integrity of virion surface proteins, including both virally encoded determinants and proteins derived from the host cells in which the virus was produced. Such inactivated virions should provide a promising candidate vaccine antigen and a useful reagent for experimentally probing the postulated involvement of virion surface proteins in indirect mechanisms of HIV-1 pathogenesis.
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PMID:Inactivation of human immunodeficiency virus type 1 infectivity with preservation of conformational and functional integrity of virion surface proteins. 973 38

Binding of the HIV envelope glycoprotein gp120 to CD4 inhibits T cell activation. We have used a murine T cell clone transfected with either wild-type human CD4 or mutated forms of CD4 to characterize the pathways involved in this inhibitory effect of gp120. Ag-induced proliferation of T cell clones transfected with human CD4 was completely inhibited in the presence of gp120, even though stimulation of this clone is independent of a CD4/MHC class II interaction. In addition, our results demonstrate that the inhibition by gp120 is not due to the sequestration of lck from TCR and does not require activation of lck by gp120. This suggests that CD4 can regulate the initiation of T cell activation independently of its interaction with lck. Moreover, we demonstrate that the nonresponsiveness induced by gp120 can be reversed by soluble CD4 when added early after onset of stimulation and that gp120 exerts its inhibitory effect when cells are in the G0 > or = 1 phase of the cell cycle.
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PMID:lck-independent inhibition of T cell antigen response by the HIV gp120. 975 76

Enhancement of immunity in the setting of HIV infection is difficult owing to loss of functional CD4+ T cells. The MHC class II-deficient mouse (II-/-) environment simulates that of the immunocompromised HIV-infected individual, since these mice have low CD4+ T cell numbers, defective CD4-dependent responses, and are susceptible to opportunistic infection. This strain was used to test whether heat-killed Brucella abortus (BA), covalently conjugated to the V3 peptide of HIV-1 (MN), could elicit anti-HIV responses. V3-BA, but not the T-dependent antigen V3-KLH, induced high levels of IL-12, IFN-gamma, and IL-10 mRNA in both wild-type (WT) and II-/- mice within 24 hr of injection. V3-BA-treated, but not V3-KLH-treated, II-/- mice developed serum IgG and IgA anti-V3 antibodies, with IgG2b and IgG3 as the predominant isotype. Viral neutralization studies, using a syncytium inhibition assay, demonstrated that the antibodies generated by V3-BA in II-/- mice were capable of neutralizing HIV. These experiments demonstrate that a heat-inactivated bacterium such as BA, when used as a carrier, can generate a cytokine environment that results in the production of neutralizing antiviral antibodies in an immunodeficient host. Such strategies could be important in the development of immunotherapies and vaccines for HIV-1 patients.
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PMID:HIV peptide conjugated to heat-killed bacteria promotes antiviral responses in immunodeficient mice. 976 10

We have analyzed the ability of three molecular clones of feline immunodeficiency virus (FIV) and an ex vivo variant to infect nine distinct specific-pathogen-free feline cell lines in tissue culture. The purpose of these studies was to elucidate mechanisms by which host cells regulate the level of virus infection and expression and to assess host cell cytokine responses to virus infection. Cells used for the analyzes included four IL-2-dependent continuous T-cell lines (104-C1, 104-C7, MCH5-4 and DB FeTs) which arose from long-term passage, followed by limiting dilution cloning of peripheral blood mononuclear cells (PBMCs); two IL-2-independent T-cell lines (104-C1DL and MCH5-4DL) which originated from two of the IL-2-dependent lines, 104-C1 and MCH5-4; respectively; Crandell feline kidney cells (CrFK); G355-5 brain-derived glial cells; and the T-cell lymphoma line, 3201. Cells were infected with FIV-PPR, FIV-34TF10, FIV 34TF10orf2rep, and a variant arising from FIV-PPR during ex vivo passage on 104-C1DL cells, termed FIV-PPRglial. Infection of the IL-2-dependent T-cell line, 104-C1, by FIV-PPR resulted in the specific and distinct upregulation of cytokine expression. In particular, these cells doubled their expression of the pleiotropic cytokines, interleukin-4 and interleukin-12 after FIV infection. Interferon-gamma production also increased after infection with FIV whereas, TNFalpha expression remained constant. Also, a marked upregulation of MHC class II expression was noted post infection of MCH5-4 and 104-C1 cells with FIV-PPR. Similar results were obtained after infection with FIV-34TF10orf2rep, indicating that the upregulation of cytokine expression is not an isolate-specific phenomenon. Changes in cytokine and class II expression are similar to various reports for the in vivo cytokine alterations in FIV, SIV and HIV infections. The ex vivo infection of these cell lines offers amanipulable system to examine the mechanism(s) by which lentiviruses alter cytokine expression.
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PMID:FIV infection of IL-2-dependent and -independent feline lymphocyte lines: host cells range distinctions and specific cytokine upregulation. 983 80

Most studies of human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocytes (CTL) have been confined to the evaluation of these effector cells in the peripheral blood. What has not been clear is the extent to which CTL activity in the blood actually reflects this effector cell function in the lymph nodes, the major sites of HIV-1 replication. To determine the concordance between CTL activity in lymph nodes and peripheral blood lymphocytes (PBL), CTL specific for simian immunodeficiency virus of macaques (SIVmac) have been characterized in lymph nodes of infected, genetically selected rhesus monkeys by using both Gag peptide-specific functional CTL assays and tetrameric peptide-major histocompatibility complex (MHC) class I molecule complex staining techniques. In studies of six chronically SIVmac-infected rhesus monkeys, Gag epitope-specific functional lytic activity and specific tetrameric peptide-MHC class I staining were readily demonstrated in lymph node T lymphocytes. Although the numbers of tetramer-binding cells in some animals differed from those documented in their PBL, the numbers of tetramer-binding cells from these two different compartments were not statistically different. Phenotypic characterization of the tetramer-binding CD8(+) lymph node T lymphocytes of the infected monkeys demonstrated a high level of expression of the activation-associated adhesion molecules CD11a and CD49d, the Fas molecule CD95, and MHC class II-DR. These studies documented a low expression of the naive T-cell marker CD45RA and the adhesion molecule CD62L. This phenotypic profile of the tetramer-binding lymph node CD8(+) T cells was similar to that of tetramer-binding CD8(+) T cells from PBL. These observations suggest that characterization of AIDS virus-specific CTL activity by sampling of cells in the peripheral blood should provide a reasonable estimation of CTL in an individual's secondary lymphoid tissue.
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PMID:Comparative analysis of cytotoxic T lymphocytes in lymph nodes and peripheral blood of simian immunodeficiency virus-infected rhesus monkeys. 988 63

Highly polymorphic HLA class I molecules may influence rates of disease progression of HIV-infected individuals. Recent evidence suggests that individuals who mount vigorous CTL responses to multiple HIV-1 epitopes have reduced viral loads, and survive longer than individuals that make a less robust or less diverse CTL response. It has been difficult, however, to define associations between particular HLA class I alleles and rates of disease progression. This may be due, in part, to the uncontrolled variables associated with naturally acquired HIV infections. Studies using MHC-defined, non-human primates infected with well characterized viral stocks should help to clarify this relationship. To explore the possibility that MHC class I polymorphism can influence disease progression, we infected four Mamu-DRB-identical individuals from a family of MHC-defined rhesus macaques intravenously with 40 TCID50SIVmac239. Two of these macaques developed severe wasting and were euthanized within 80 days of infection, while the other two survived for more than 400 days without showing any symptoms of disease. Since all four of these macaques were Mamu-DRB-identical, we were able to exclude the MHC class II DRB loci as determinant of disease progression. Interestingly, both of the slow progressors made CTL responses to the same three SIV CTL epitopes, which were restricted by two molecules (Mamu-B*03 and B*04) encoded by their common maternal haplotype. The two rapid progressors did not share this haplotype with the slow progressors, and we were unable to detect CTL responses in these two siblings. These observations implicate products of the Mamu-B*03 and B*04 alleles in resistance to disease progression in this family of SIV-infected macaques, and provide additional evidence that certain MHC class I-restricted CTL responses may play a significant role in delaying the onset of AIDS.
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PMID:Rapid and slow progressors differ by a single MHC class I haplotype in a family of MHC-defined rhesus macaques infected with SIV. 1020 34

Both HIV-1 primary isolates and laboratory strains incorporate cell-derived molecules into their envelopes depending on the host cell in which they are grown. This incorporation is not random and, specifically, HIV-1 has been shown to select against the incorporation into its surface of CD4, its main receptor. In this study, we have looked at the incorporation of HIV coreceptors CXCR4, CCR5, and CCR3 into the HIV envelope. For this purpose, we grew HIV-1 primary isolate BZ167 in several cell lines and PBMCs, and the envelope profiles of the resulting viruses were determined with a virus-binding ELISA. While the virus particle gained several molecules when passed through the different cell lines (e.g., ICAM-3, LFA-1, ICAM-1, or MHC class II), BZ167 never incorporated significant levels of CXCR4, CCR5, or CCR3 into its envelope even though some or all of the cell lines in which it was grown expressed them. These results show that HIV-1 selects against the incorporation of these chemokine receptors into its envelope molecule, as it does against the incorporation of CD4.
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PMID:Exclusion of HIV coreceptors CXCR4, CCR5, and CCR3 from the HIV envelope. 1040 26


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