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

The novel allogeneic presentation of an immunodominant determinant within the HIV-1 gp160 V3 loop by three different class I MHC molecules to the same CD8+ CTL is used to study the influence of the MHC molecule on the fine specificity of CTL recognition. We previously reported that four distinct class I molecules of H-2d,u,p,q presented the V3 decapeptide P18-I10 (RGPGRAFVTI) to CTL. Surprisingly, we found that H-2d,u,p cells mutually cross-present the P18-I10 peptide to allogeneic CTL clones of each of the other haplotypes, whereas none of these cross-presents to H-2q CTL, nor do H-2q targets present to CTL of the other haplotypes. Here, we explore the critical amino acid residues for the cross-presentation using 10 variant peptides with single amino acid substitutions. The fine specificity examined using these mutant peptides presented by the same MHC class I molecule showed striking similarity among the CTL of each haplotype, expressing either V beta 8.1 or V beta 14. In contrast, the fine specificity is different between the distinct MHC class I molecules even for the lysis by the same CTL, as shown by reciprocal effects of the same substitutions. Thus, peptide fine specificity of a single TCR is influenced by changes in the class I MHC molecules presenting the Ag.
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PMID:Degenerate MHC restriction reveals the contribution of class I MHC molecules in determining the fine specificity of CTL recognition of an immunodominant determinant of HIV-1 gp160 V3 loop. 912 Feb 72

When HIV-infected leukocytes are activated by the CD28 costimulatory receptor, HIV-1 is rapidly cleared from cultures, suggesting that costimulation can render T cells resistant to HIV-1 infection. In this study we tested the hypothesis that enhanced secretion of cytokines or chemokines could account for CD28-induced antiviral effects. In an acute infection system, resistance to infection with macrophage-tropic strains of HIV-1 was shown to be comprised of both soluble and cell-associated components. Induction of HIV-1 resistance was specific for CD28 costimulation, in that a variety of other accessory receptors, such as CD2, CD4, CD5, and MHC class I, failed to confer the antiviral resistance. The soluble component was secreted by both CD4 and CD8 T cells, was not unique to CD28 costimulation, and could be neutralized by removal of C-C chemokines (RANTES (regulated upon activation, normal T cell expressed and secreted) and macrophage inflammatory protein-1alpha and -1beta) from the culture supernatants of costimulated CD4 T cells. In contrast, CD28 stimulation of CD4 cells resulted in the specific induction of a pronounced intrinsic resistance to HIV-1 infection by macrophage tropic isolates of HIV-1.
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PMID:Intrinsic resistance to T cell infection with HIV type 1 induced by CD28 costimulation. 916 79

The variable domain V3 in the outer glycoprotein gp120 of HIV-1 is a highly important region with respect to immune response during the course of viral infection. Neutralizing antibodies are produced against this domain: in addition, it has been shown to be a functionally active epitope for T helper and cytotoxic T cells. The high degree of amino acid variability in individual HIV-isolates, however, limits the use of the V3-domain in approaches to vaccine development. In order to characterize the residues important for antibody interaction and binding to MHC class I proteins, we constructed a consensus sequence of the V3-domain with broad reactivity [1] and used synthetic peptides derived from this consensus sequence with individual residues altered to alanine. These peptides were used as antigens in ELISA tests to define the amino acids which are important for binding to human and rabbit/anti-peptide immunoglobulins. In addition, we used these alanine-derived peptides in interaction studies with human HLA-A2.1 and mouse H-2Dd by testing their capacity to stabilize the respective MHC class I protein complexes on the surface of mutant cell lines T2 and RMA-S transfected with Dd gene. The experimental tests allowed us to define individual residues involved in antibody and MHC-protein interaction, respectively. In a further approach, we used those results to design interaction models with HLA-A2.1 and H-2Dd. Therefore, a structural model for H-2Dd was built that exhibits an overall similar conformation to the parental crystal structure of HLA-A2.1. The resulting interaction models show V3-peptide bound in an extended beta-conformation with a bulge in its centre for both H-2Dd and HLA-A2.1 complexes. The N- and C-termini of V3 peptide reside in conserved pockets within both MHC-proteins. Anchoring residues could be determined that are crucial for the binding of the respective MHC class I haplotype. The cross-reactivity of V3-peptide in enhancing the expression of two different MHC class I molecules (H-2Dd and HLA-A2.1) is shown to be based on similar peptide binding that induces an almost identical peptide conformation.
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PMID:Structural and immunological reactivity of the principal neutralizing determinant V3 of glycoprotein gp120 of HIV-1. 922 88

Protection against most intracellular pathogens requires T cells that recognize pathogen-derived peptides in association with MHC class I molecules on the surface of infected cells. However, because exogenous proteins do not ordinarily enter the cytosol and access the MHC class I-processing pathway, protein-based vaccines that induce class I-restricted CTL responses have proved difficult to design. We have addressed this problem by conjugating proteins, such as OVA, to a short cationic peptide derived from HIV-1 tat (residues 49-57). When APC were exposed in vitro to such protein conjugates, they processed and presented the peptides in association with MHC class I molecules and stimulated CD8+ Ag-specific T cells. Moreover, Ag-specific CTLs were generated in vivo by immunizing mice with histocompatible dendritic cells that had been exposed to protein-tat conjugates.
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PMID:Introduction of soluble proteins into the MHC class I pathway by conjugation to an HIV tat peptide. 925 26

Viruses that establish persistent infections in their host, such as herpesviruses, adenoviruses or HIV, express proteins designed to pre-empt or evade recognition and elimination by MHC class I restricted CD8+ T lymphocytes. Notable discoveries during the annual period of review have demonstrated that, in principle, each single step within the MHC class I pathway of antigen processing and presentation is fair game for manipulation by viral functions. The viral factors that are natural inhibitors of this pathway have been instrumental for the elucidation of the distinct molecular mechanisms that are exploited by viruses. The viral stealth strategies that downregulate MHC class I protein surface expression may lead, however, to a higher susceptibility of virus-infected cells to natural killer cell activity. Strikingly, there is evidence that some viruses counteract increased natural killer cell recognition by expressing viral MHC class I homologues that function as surrogate inhibitors of natural killer cell activity.
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PMID:Interference with antigen processing by viruses. 928 82

A challenge for subunit vaccines whose goal is to elicit CD8(+) cytotoxic T lymphocytes (CTLs) is to deliver the antigen to the cytosol of the living cell, where it can be processed for presentation by major histocompatibility complex (MHC) class I molecules. Several bacterial toxins have evolved to efficiently deliver catalytic protein moieties to the cytosol of eukaryotic cells. Anthrax lethal toxin consists of two distinct proteins that combine to form the active toxin. Protective antigen (PA) binds to cells and is instrumental in delivering lethal factor (LF) to the cell cytosol. To test whether the lethal factor protein could be exploited for delivery of exogenous proteins to the MHC class I processing pathway, we constructed a genetic fusion between the amino-terminal 254 aa of LF and the gp120 portion of the HIV-1 envelope protein. Cells treated with this fusion protein (LF254-gp120) in the presence of PA effectively processed gp120 and presented an epitope recognized by HIV-1 gp120 V3-specific CTL. In contrast, when cells were treated with the LF254-gp120 fusion protein and a mutant PA protein defective for translocation, the cells were not able to present the epitope and were not lysed by the specific CTL. The entry into the cytosol and dependence on the classical cytosolic MHC class I pathway were confirmed by showing that antigen presentation by PA + LF254-gp120 was blocked by the proteasome inhibitor lactacystin. These data demonstrate the ability of the LF amino-terminal fragment to deliver antigens to the MHC class I pathway and provide the basis for the development of novel T cell vaccines.
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PMID:Targeting HIV proteins to the major histocompatibility complex class I processing pathway with a novel gp120-anthrax toxin fusion protein. 934 62

Dendritic cells (DC) are potent APC that may be involved in the pathogenesis of HIV-1 infection. We studied the APC function of DC from HIV-1-infected subjects that were derived from monocyte-depleted PBMC by culture in human IL-4 and human granulocyte-macrophage CSF. The cultured cells from the HIV-1-infected subjects had similar morphology and phenotype of mature DC (CD80 = 41 +/- 8%, CD86 = 77 +/- 5%, CD40 = 87 +/- 6%, CD1a = 1 +/- 1%) to DC cultured from seronegative subjects. The yield of these DC was lower than from HIV-1-seronegative subjects (4 +/- 0% vs 11 +/- 2%, p < 0.01), and the lower DC yields correlated with lower numbers of blood CD4+ T cells (r = 0.60, p < 0.01) and higher plasma viral load (r = -0.49, p < 0.01). DC from HIV-1-infected subjects were infected with recombinant vaccinia virus vectors expressing Gag, Pol, and Env and were able to stimulate equal or higher levels of MHC class I-restricted, anti-HIV-1 memory CTL (CTLm) than were similarly treated, autologous B lymphocyte cell lines. DC pulsed with peptides representing HIV-1 CTL epitopes stimulated higher levels of anti-HIV-1 CTLm responses than did DC infected with the vaccinia virus-HIV-1 constructs. Allogeneic, MHC class I-matched DC also stimulated anti-HIV-1 CTLm activity in cells from HIV-1-infected subjects. DC from early and late stages of HIV-1 infection had a similar ability to activate CTLm specific for targets expressing either HIV-1 genes via vaccinia virus vectors or HIV-1 immunodominant synthetic peptides. However, DC from either early or late stages of HIV-1 infection could not overcome the defect in anti-HIV-1 CTLm response in advanced infection.
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PMID:Cultured blood dendritic cells retain HIV-1 antigen-presenting capacity for memory CTL during progressive HIV-1 infection. 936 24

Based on our findings that the immunosuppressive peptide (ISP, amino acids (aa) 583-599) of human immunodeficiency virus type 1 (HIV-1) gp41 shows sequence-similarity with human type I interferons (IFN-alpha and IFN-beta) and HIV-1 soluble gp41 (sgp41, aa 539-684) enhanced cell surface expression of major histocompatibility complex (MHC) class I molecule on human H9 (T cells), Raji (B cells) and U937 (monocytic cells) cells, we examined the effect of HIV-1 immunosuppressive peptide on the surface expression of MHC class I molecules on H9 and U937 cells. Flow cytometry analysis demonstrated that ISP-BSA (conjugate) could enhance MHC class I expression by about 40% on H9 cells and by about 45% on U937 cells, while monomer ISP (not conjugated) and EDCI-treated carrier protein (BSA-EDCI) did not increase the expression. By comparison, human type I interferons, IFN-alpha and IFN-beta, showed similar effects (enhanced the expression by about 40-60%) to ISP-BSA on the MHC class I expression on H9 and U937 cells. The results suggest that HIV-1 gp41 in a polymerized form by its immunosuppressive domain upregulates human MHC class I expression. The basis for this similar effect of HIV-1 gp41 and IFN-alpha and -beta, i.e. upregulation of MHC class I molecule expression, may be based on the sequence-similarity between these otherwise different molecules.
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PMID:The immunosuppressive peptide of HIV-1 gp41 like human type I interferons up-regulates MHC class I expression on H9 and U937 cells. 937 17

The clinical outcomes of both hepatitis B and C virus infection are immensely variable, ranging from subclinical, self-limiting infection to end-stage liver disease with hepatocellular carcinoma. Knowledge of the host factors that determine these outcomes is important for the understanding and management of these diseases and may in the future guide rational drug development. Epidemiologic studies have elucidated the role of age (at the time of infection) and sex on disease outcome and the complex role of HIV coinfection has become clearer with time. More recently, investigation of genetic susceptibility to the most adverse outcomes of infection has identified the importance of polymorphisms in the MHC class I and II loci, mannose-binding protein, and the TNF alpha promoter. However, relative to malaria, the study of genetic susceptibility in viral hepatitis is still in its infancy.
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PMID:Host factors in chronic viral hepatitis. 940 70

To evaluate an antigen delivery system in which exogenous antigen can target the major histocompatibility complex (MHC) class I pathway, a single human papillomavirus (HPV) 16 E7 cytotoxic T lymphocyte (CTL) epitope and a single HIV gp160 CTL epitope were separately fused to the C-terminus of bovine papillomavirus 1 (BPV1) L1 sequence to form hybrid BPV1L1 VLPs. Mice immunized with these hybrid VLPs mounted strong CTL responses against the relevant target cells in the absence of any adjuvants. In addition, the CTL responses induced by immunization with BPV1L1/HPV16E7CTL VLPs protected mice against challenge with E7-transformed tumor cells. Furthermore, a high titer-specific antibody response against BPV1L1 VLPs was also induced, and this antiserum could inhibit papillomavirus-induced agglutination of mouse erythrocytes, suggesting that the antibody may recognize conformational determinates relevant to virus neutralization. These data demonstrate that hybrid BPV1L1 VLPs can be used as carriers to target antigenic epitopes to both the MHC class I and class II pathways, providing a promising strategy for the design of vaccines to prevent virus infection, with the potential to elicit therapeutic virus-specific CTL responses.
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PMID:Papillomavirus virus-like particles can deliver defined CTL epitopes to the MHC class I pathway. 944 99


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