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

Studies in both monkeys and humans have suggested that transient infection with HIV-1 can occur without provoking a measurable humoral immune response. The objective of this study was to look for genetic and immunologic correlates of transient HIV-1 infection in antibody-negative men from whom HIV-1 had been isolated. The distributions of MHC class I, class II, and TAP (transporter protein associated with antigen processing) region genes were compared between 23 persistently seronegative men from whom HIV-1 was isolated at least once (isol+/Ab-) and 137 men who seroconverted. A subset of 13 of the 23 isol+/Ab- men were compared to 27 seronegative men for distribution of CD25+CD4+ and CD25+CD8+ cells in the absence of exogenous immunologic stimulation. The prevalences of the TAP1.4, and a combination of TAP1.4, and TAP2.3 variants were significantly higher in the isol+/Ab- men. The proportion of CD8+ cells that expressed CD25+ antigen was also significantly higher in the isol+/Ab- men than in the seronegative men. We conclude that isol+/Ab- men may be genetically and immunologically distinct from HIV-1 susceptible men. We hypothesize that activated CD8+ cells may have cleared HIV-1 infection in these men through genetically mediated influences of the TAP genes on the presentation of peptides by HLA class I molecules.
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PMID:Persistently seronegative men from whom HIV-1 has been isolated are genetically and immunologically distinct. 881 41

Neutralization of HIV-1 in vitro by anti-HLA class I antibodies suggests that class I molecules are involved in HIV-1 infection. HIV-infected cells can fuse with uninfected cells in a process that leads to the formation of multinucleated syncytia, involving an interaction between host and viral antigens expressed at the cell surfaces. We used a syncytium assay between the 8E5 cell line chronically infected with a pol-defective variant of LAV IIIb, and the CD4-positive cell line MOLT3, to study the role of HLA class I in HIV-1-induced cell fusion. By probing cells with a panel of anti-HLA monoclonal antibodies (MABs) we demonstrated that the fusion process is modulated specifically by C alleles of HLA class I expressed on uninfected cells but not by that on already infected cells. Addition of beta 2-microglobulin to the cocultures resulted in a dose-dependent enhancement in both the number and size of syncytia, whereas exogenous HLA-C-restricted peptides inhibited syncytium formation, implying that only certain conformational states of HLA class I are permissive for syncytium formation. Treatment of cocultures with HLA-Cw4-restricted peptides containing amino acid substitutions in the anchor residues showed that syncytium inhibition was dependent on conventional binding of the peptide inside the groove. The data indicate that HLA class I, in a conformation free of peptide but associated with beta 2-microglobulin, can directly influence virus-induced cell fusion.
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PMID:Role of HLA class I in HIV type 1-induced syncytium formation. 882 19

Novel Strategy to identify CTL epitopes called "reverse immunogenetics" was introduced. CTL epitopes were identified as follows; (i) Identification of the motif of HLA class I binding peptides (ii) Selection of sequences matched to the motif of HLA class I binding peptides from HIV proteins and synthesis of peptides (iii) Identification of HLA class I binding peptides by the peptide binding assay (iv) Induction of CTL from PBL of HIV 1 infected individuals by HLA class I binding peptides. Multiple HIV-I epitopes presented by HLA-B35 were identified using this strategy.
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PMID:[Identification of T cell epitopes by reverse immunogenetics]. 897 24

In the cellular immune response, recognition by CTL-TCRs of viral antigens presented as peptides by HLA class I molecules, triggers destruction of the virally infected cell (Townsend, A.R.M., J. Rothbard, F.M. Gotch, G. Bahadur, D. Wraith, and A.J. McMichael. 1986. Cell. 44:959-968). Altered peptide ligands (APLs) which antagonise CTL recognition of infected cells have been reported (Jameson, S.C., F.R. Carbone, and M.J. Bevan. 1993. J. Exp. Med. 177:1541-1550). In one example, lysis of antigen presenting cells by CTLs in response to recognition of an HLA B8-restricted HIV-1 P17 (aa 24-31) epitope can be inhibited by naturally occurring variants of this peptide, which act as TCR antagonists (Klenerman, P., S. Rowland Jones, S. McAdam, J. Edwards, S. Daenke, D. Lalloo, B. Koppe, W. Rosenberg, D. Boyd, A. Edwards, P. Giangrande, R.E. Phillips, and A. McMichael. 1994. Nature (Lond.). 369:403-407). We have characterised two CTL clones and a CTL line whose interactions with these variants of P17 (aa 24-31) exhibit a variety of responses. We have examined the high resolution crystal structures of four of these APLs in complex with HLA B8 to determine alterations in the shape, chemistry, and local flexibility of the TCR binding surface. The variant peptides cause changes in the recognition surface by three mechanisms: changes contributed directly by the peptide, effects transmitted to the exposed peptide surface, and induced effects on the exposed framework of the peptide binding groove. While the first two mechanisms frequently lead to antagonism, the third has more profound effects on TCR recognition.
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PMID:Antagonist HIV-1 Gag peptides induce structural changes in HLA B8. 897 83

The major histocompatibility complex (MHC) contains at least a hundred genes over 4 megabases of DNA. Within the MHC there are several new multigene families which have been recently described. PERB11 is a multigene family which occurs over the class I and central region of the MHC. Two members of the family have been shown to be functional and share domains with members of the supergene family including HLA class I, FcRn, and Zn-alpha2-glycoprotein molecules. The two functional members are contained within an area of the MHC which has been associated with increased susceptibility to autoimmune diseases such as insulin-dependent diabetes mellitus and also rapid progression to AIDS following HIV-1 infection. Intralocus and interlocus differences between PERB11.1 and PERB11.2 include: (1) several nucleotide substitutions leading to amino acid changes; (2) presence and absence of potential glycosylation sites; (3) insertions and deletions leading to a frame shift resulting in diversity at the amino acid level and an early termination signal. There are ten different alleles of PERB11.1 including one allele which contains a frame shift in the transmembrane region causing a putative truncated molecule lacking the cytoplasmic tail. The significance of this polymorphism in disease associations is under investigation. The most divergent domain is the transmembrane region when PERB11.1 and PERB11.2 are compared. The results suggest that these two molecules may have different functions.
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PMID:Allelic and interlocus comparison of the PERB11 multigene family in the MHC. 899 88

Characterization of the cytotoxic T lymphocyte (CTL) response against HIV-1 has been limited by the use of target cells expressing viral proteins from laboratory isolates of HIV-1. This approach has favored identification of group-specific CTL responses and precluded assessment of the extent of type-specific CTL responses directed against HIV-1. Using cells expressing viral proteins from the HIV-1 IIIB strain, we performed a detailed characterization of HIV-1-specific CTL response in three laboratory workers accidentally infected with HIV-1 IIIB. Eight of the epitopes identified were group specific, lying in relatively conserved regions of Gag, reverse transcriptase, and envelope. Three type-specific epitopes were identified, two of them in highly variable regions of envelope. In longitudinal studies in one subject, seven different epitopes and five different restricting HLA class I alleles were identified, with a progressive increase in the number of CTL epitopes recognized by this subject over time. Our data demonstrate that type-specific CTL responses make up a significant proportion of the host cellular immune response against HIV-1 and that a broadening of epitope specificity may occur.
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PMID:Identification of type-specific cytotoxic T lymphocyte responses to homologous viral proteins in laboratory workers accidentally infected with HIV-1. 904 80

Although CD8+ lymphocytes in human immunodeficiency virus type 1 (HIV-1)-infected individuals have been demonstrated to suppress viral replication, the mechanisms of inhibition have not been defined precisely. A large body of evidence indicates that these cells act via soluble inhibitory factors, but the potential role of HLA class I-restricted cytolysis has remained controversial. Here we demonstrate that HIV-1-specific cytotoxic T lymphocytes (CTL) mediate antiviral suppression by both cytolytic and noncytolytic mechanisms. The predominant mechanism requires direct contact of CTL with the infected cells, is HLA class I restricted, and can achieve complete elimination of detectable virus in infected cell cultures. Inhibition occurs even at high multiplicities of infection or at ratios of CTL to CD4 cells as low as 1:1,000. The other mechanism is mediated by soluble inhibitory factors which are triggered in an antigen-specific and HLA-restricted fashion but then act without HLA restriction. These include MIP-1alpha, MIP-1beta, and RANTES, as well as a distinct factor(s) capable of inhibiting HIV-1 strains insensitive to these chemokines. These data indicate that HIV-1-specific CTL are potent mediators of HIV-1 suppression at cell ratios existing in vivo and demonstrate an antigen-specific trigger for CD8+ cell-derived soluble inhibitory factors. These results suggest that CTL play an important role in the observed antiviral activity of CD8+ cells from infected individuals.
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PMID:Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. 906 Jun 75

Recent data demonstrate that HLA class I alleles can be grouped into superfamilies based on similarities of their peptide-binding motifs. In this study, we have tested the immunogenicity and antigenicity of peptides capable of degenerate binding to multiple HLA class I molecules of the A3-like superfamily. The assay systems utilized included both primary in vitro cultures of lymphocytes from healthy donors, as well as in vitro restimulation of lymphocytes from HIV-infected individuals. Several of the peptides capable of binding more than one HLA A3-like class I molecule were also found to be immunogenic in the context of this same group of A3-like molecules (degenerate CTL recognition). Furthermore, some of the CTL lines thus generated demonstrated promiscuous recognition of the cognate epitope in the context of MHC molecules from more than one member of the superfamily. The fine Ag specificity of this phenomenon was further analyzed using two promiscuous CTL clones derived from A3 and A11 individuals, respectively, and specific for an epitope in the HIV-1 reverse transcriptase. By the use of single-amino acid-substitution analogues, it was demonstrated that the fine specificity of the TCR is largely maintained between MHC-matched and MHC-mismatched presentation of peptide within the A3-like superfamily. These results indicate that the similar peptide-binding specificities among different members of the A3-like superfamily can be reflected in a remarkable similarity in the peptide-MHC complex structures engaged by the TCR and responsible for T cell activation.
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PMID:Degenerate and promiscuous recognition by CTL of peptides presented by the MHC class I A3-like superfamily: implications for vaccine development. 925 24

An HLA allele-specific cytotoxic T lymphocyte response is thought to influence the rate of disease progression in HIV-1-infected individuals. In a prior study of 139 HIV-1-infected homosexual men, we identified HLA class I alleles and observed an association of specific alleles with different relative hazards for progression to AIDS. Seeking an explanation for this association, we searched HIV-1 protein sequences to determine the number of peptides matching motifs defined by combinations of specific amino acids reported to bind 16 class I alleles. Analyzing complete sequences of 12 clade B HIV isolates, we determined the number of allele motifs that were conserved (occurring in all 12 isolates) and nonconserved (occurring in only one isolate), as well as the average number of allele motifs per isolate. We found significant correlations with an allele's association with disease progression for counts of conserved motifs in gag (R = 0.73; P = 0.002), pol (R = 0.58, P = 0.024), gp120 (R = 0.78, P = 0.00056), and total viral protein sequences (R = 0.67, P = 0.0058) and also for counts of nonconserved motifs in gag (R = 0.62, P = 0.013), pol (R = 0.74, P = 0.0017), gp41 (R = 0.52, P = 0.046), and total viral protein (R = 0.71, P = 0.0033). We also found significant correlations for the average number of motifs per isolate for gag, pol, gp120, and total viral protein. This study provides a plausible functional explanation for the observed association of different HLA alleles with variable rates of disease progression.
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PMID:Frequency of HLA allele-specific peptide motifs in HIV-1 proteins correlates with the allele's association with relative rates of disease progression after HIV-1 infection. 927 6

Vgamma9Vdelta2-encoded T cell receptors (TCR) expressed by most human peripheral blood gammadelta T cells mediate the recognition of nonpeptidic phosphoantigens from various pathogens without any known requirement for HLA molecules. Functionally mature Vgamma9Vdelta2 T cells display a potent natural killer (NK)-like cytotoxic activity, share with NK cells the expression of inhibitory receptors for HLA class I molecules, and release a plethora of cytokines, most notably interferon-gamma and tumor necrosis factor alpha. Hence, through local activation, the early recruitment and stimulation of Vgamma9Vdelta2 T cells may promote efficient anti-infectious immunity. However, a chronic overactivation of this T cell subset may result in immunopathology. The meeting held in St. Vincent, Val d'Aosta, Italy (symposium on gammadelta T cells in natural immunity to infections: a rationale for vaccine development organized by the World Foundation for AIDS Research and Prevention, the UNESCO, and the Italian National Research Council, December 2-4, 1996) focused on the importance of gammadelta T cell activation and anergy for the pathogenesis of tuberculosis, malaria, and HIV infections.
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PMID:Gammadelta T cell activation or anergy during infections: the role of nonpeptidic TCR ligands and HLA class I molecules. 930 66


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